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The Dopamine Hypothesis of Schizophrenia – Advances in Neurobiology and Clinical Application

The dopamine hypothesis stems from early research carried out in the 1960’s and 1970’s when studies involved the use of amphetamine (increases dopamine levels) which increased psychotic symptoms while reserpine which depletes dopamine levels reduced psychotic symptoms.

The original dopamine hypothesis was put forward by Van Rossum in 1967 that stated that there was hyperactivity of dopamine transmission, which resulted in symptoms of schizophrenia and drugs that blocked dopamine reduced psychotic symptoms. [1]

DOPAMINE PRODUCTION AND METABOLISM

Dopamine is synthesised from the amino acid tyrosine. Tyrosine is converted into DOPA by the enzyme tyrosine hydroxylase.

DOPA is converted into dopamine (DA) by the enzyme DOPA decarboxylase (DOPADC).

This dopamine is packed and stored into synaptic vesicles via the vesicular monoamine transporter (VMAT2) and stored until its release into the synapse.

Dopamine Receptors:

When dopamine is released during neurotransmission, it acts on 5 types of postsynaptic receptors (D1-D5).

A negative feedback mechanism exists through the presynaptic D2 receptor which regulates the release of dopamine from the presynaptic neuron.

Dopamine Breakdown

Any excess dopamine is also ‘mopped up’ from the synapse by Dopamine transporter (DAT) and stored in the vesicles via VMAT2.

Dopamine is broken down by monoamine oxidase A (MAO-A), MAO-B and catechol-o-methyltransferase (COMT).

Learning points:

• Tyrosine hydroxylase is the rate-limiting step in the production of dopamine. Its expression is significantly increased in the substantia nigra of schizophrenia patients when compared to normal healthy subjects. [2]
• Carbidopa is a peripheral DOPA-decarboxylase inhibitor co-administered with levodopa. Carbidopa prevents the conversion of levodopa to dopamine in the periphery, thus allowing more levodopa to pass the blood-brain barrier to be converted into dopamine for its therapeutic effect.
• Methamphetamine increases extracellular dopamine by interacting at vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine uptake and promote dopamine release from synaptic vesicles, increasing cytosolic dopamine available for reverse transport by the dopamine transporter (DAT).
• Valbenazine a highly selective VMAT2 inhibitor has been approved by the FDA for the treatment of tardive dyskinesia.
• There is compelling evidence that presynaptic dopamine dysfunction results in increased availability and release of dopamine and this has been shown to be associated with prodromal symptoms of schizophrenia. Furthermore, dopamine synthesis capacity has also been shown to steadily increase with the onset of severe psychotic symptoms. [3] , [Howes & Shatalina, 2022]

• Dopaminergic transmission in the prefrontal cortex is mainly mediated by D1 receptors , and D1 dysfunction has been linked to cognitive impairment and negative symptoms of schizophrenia . [4]

THE 4 DOPAMINE PATHWAYS IN THE BRAIN

1.The Mesolimbic Pathway

• The pathway projects from the ventral tegmental area (VTA) to the nucleus accumbens in the limbic system.
• Hyperactivity of dopamine in the mesolimbic pathway mediates positive psychotic symptoms. The pathway may also mediate aggression.
• The mesolimbic pathway is also the site of the rewards pathway and mediates pleasure and reward. Antipsychotics can block D2 receptors in this pathway reducing pleasure effects. This may be one explanation as to why individuals with schizophrenia have a higher incidence of smoking as nicotine enhances dopamine in the reward pathway (self-medication hypothesis)
• Antagonism of D2 receptors in the mesolimbic pathway treats positive psychotic symptoms.
• There is an occupancy requirement with the minimum threshold at 65% occupancy for treatment to be effective. Observations support this relationship between D2-receptor occupancy and clinical response that 80% of responders have D2-receptor occupancy above this threshold after treatment. [5]

2.The Mesocortical Pathway

• Projects from the VTA to the prefrontal cortex.
• Projections to the dorsolateral prefrontal cortex regulate cognition and executive functioning.
• Projections into the ventromedial prefrontal cortex regulate emotions and affect.
• Decreased dopamine in the mesocortical projection to the dorsolateral prefrontal cortex is postulated to be responsible for negative and depressive symptoms of schizophrenia.
• Nicotine releases dopamine in the mesocortical pathways alleviating negative symptoms (self-medication hypothesis).

3.The Nigrostriatal Pathway

• Projects from the dopaminergic neurons in the substantia nigra to the basal ganglia or striatum.
• The nigrostriatal pathway mediates motor movements.
• Blockade of dopamine D2 receptors in this pathway can lead to dystonia, parkinsonian symptoms and akathisia.
• Hyperactivity of dopamine in the nigrostriatal pathway is the postulated mechanism in hyperkinetic movement disorders such as chorea, tics and dyskinesias.
• Long-standing D2 blockade in the nigrostriatal pathway can lead to tardive dyskinesia. 

4.The Tuberoinfundibular (TI) Pathway

• Projects from the hypothalamus to the anterior pituitary.
• The TI pathway inhibits prolactin release.
• Blockade of D2 receptors in this pathway can lead to hyperprolactinemia which clinically manifests as amenorrhoea, galactorrhoea and sexual dysfunction.
• Long-term hyperprolactinemia can be associated with osteoporosis.

Conceptualisation of Schizophrenia

Based on the above understanding, schizophrenia is best conceptualised as a complex entity which involves multiple pathways.

In clinical practice, there can be a disproportionate focus on positive psychotic symptoms.

It is however, important to recognise that affective (e.g depressive), negative and cognitive symptoms are a core part of schizophrenia and should be taken into account in treatment.

The aim of treatment, thus, is to modulate treatment creating a balance between effectiveness and reduction of side effects.

The balance is achieved by optimal dopamine blockade in the mesolimbic pathway while preserving (or enhancing) dopamine transmission in the other pathways.

DOPAMINE AND SCHIZOPHRENIA

The dopamine hypothesis of schizophrenia has moved from the dopamine receptor hypothesis (increased dopamine transmission at the postsynaptic receptors) to a focus on presynaptic striatal hyperdopaminergia.

According to Howes and Kapur-

This hypothesis accounts for the multiple environmental and genetic risk factors for schizophrenia and proposes that these interact to funnel through one final common pathway of presynaptic striatal hyperdopaminergia. In addition to funneling through dopamine dysregulation, the multiple environmental and genetic risk factors influence diagnosis by affecting other aspects of brain function that underlie negative and cognitive symptoms. Schizophrenia is thus dopamine dysregulation in the context of a compromised brain. [6]

Read more on the molecular imaging of dopamine abnormalities in schizophrenia. 

Clinical Implications

The hypothesis that the final common pathway is presynaptic dopamine dysregulation has some important clinical implications. Firstly, it implies that current antipsychotic drugs are not treating the primary abnormality and are acting downstream. While antipsychotic drugs block the effect of inappropriate dopamine release, they may paradoxically worsen the primary abnormality by blocking presynaptic D2 autoreceptors, resulting in a compensatory increase in dopamine synthesis. This may explain why patients relapse rapidly on stopping their medication, and if the drugs may even worsen the primary abnormality, it also accounts for more severe relapse after discontinuing treatment. This suggests that drug development needs to focus on modulating presynaptic striatal dopamine function, either directly or through upstream effects. [6]

Concept of Salience

Usually, dopamine’s role is to mediate motivational salience and thereby gives a person the ability to determine what stimulus grabs their attention and drives the subsequent behaviour.

The salience network consists of the Anterior Cingulate Cortex (ACC), insula and the amygdala.

Schizophrenia is associated with an aberrant attribution of salience due to dysregulated striatal dopamine transmission.

Dysregulation of the dopamine system ultimately leads to irrelevant stimuli becoming more prominent which provides a basis for psychotic phenomena such as ideas of reference, where everyday occurrences may be layered with a with a heightened sense of bizarre significance.  Furthermore, this misattribution of salience can lead to paranoid behaviour and persecutory delusions. [7]

A stimulus, even if initially lacking inherent salience, once paired with dopaminergic activity, maintains the ability to evoke dopaminergic activity over time. This suggests that in psychosis, once an environmental stimulus has been highlighted by aberrant dopamine signalling, it may maintain its ability to trigger dopaminergic activity, potentially cementing its position in a delusional framework, even if the system subsequently returns to normal function. [McCutcheon, et al, 2019]

LIMITATIONS OF THE DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA

Current research shows that one-third of individuals with schizophrenia do not respond to non-clozapine antipsychotics despite high levels of D2-receptor occupancy.

Furthermore, a study using tetrabenazine (used as augmentation) which depletes presynaptic dopamine was not found to be effective in augmenting a clinical response in schizophrenia. [8]

Therefore, for a significant number of patients with schizophrenia, the basis of their symptoms is either unrelated to dopaminergic dysfunction or is associated with something more than just dopamine excess.

Alternatively, this could also mean that for some patients with schizophrenia there might be a non-dopaminergic sub-type of schizophrenia.

The current dopamine hypothesis of schizophrenia does not adequately explain the cognitive and negative symptoms. Current treatments which modulate dopamine transmission have only modest effects in improving these symptoms.

It has taken two decades for the dopamine hypothesis to evolve and reach its current state. More recent evidence shows another neurotransmitter, glutamate playing an essential role in schizophrenia.

The future likely holds a lot more secrets about schizophrenia which should unravel with the advances in understanding the brain.

Learn more:

Simplified Guide to Mechanisms of Action of Oral Antipsychotics

RECOMMENDED BOOKS

Howes O, et al . Midbrain dopamine function in schizophrenia and depression: a post-mortem and positron emission tomographic imaging study. Brain . 2013

Howes OD, Shatalina E. Integrating the Neurodevelopmental and Dopamine Hypotheses of Schizophrenia and the Role of Cortical Excitation-Inhibition Balance. Biol Psychiatry. 2022 Sep 15;92(6):501-513.

Howes, O., McCutcheon, R., & Stone, J. (2015). Glutamate and dopamine in schizophrenia: an update for the 21st century. Journal of psychopharmacology , 29 (2), 97-115.

Kapur S, et al . Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. American Journal of Psychiatry . 2000

Howes O, Murray R. Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet . 2014

McCutcheon, R. A., Abi-Dargham, A., & Howes, O. D. (2019). Schizophrenia, dopamine and the striatum: from biology to symptoms.  Trends in neurosciences ,  42 (3), 205-220

Schizophrenia A-level Revisions Notes

Bruce Johnson

A-level Psychology Teacher

B.A., Educational Psychology, University of Exeter

Bruce Johnson is an A-level psychology teacher, and head of the sixth form at Caterham High School.

Learn about our Editorial Process

Saul Mcleod, PhD

Editor-in-Chief for Simply Psychology

BSc (Hons) Psychology, MRes, PhD, University of Manchester

Saul Mcleod, PhD., is a qualified psychology teacher with over 18 years of experience in further and higher education. He has been published in peer-reviewed journals, including the Journal of Clinical Psychology.

On This Page:

What do the examiners look for?

• Accurate and detailed knowledge
• Clear, coherent, and focused answers
• Effective use of terminology (use the “technical terms”)

In application questions, examiners look for “effective application to the scenario” which means that you need to describe the theory and explain the scenario using the theory making the links between the two very clear. If there is more than one individual in the scenario you must mention all of the characters to get to the top band.

Difference between AS and A level answers

The descriptions follow the same criteria; however you have to use the issues and debates effectively in your answers. “Effectively” means that it needs to be clearly linked and explained in the context of the answer.

Read the model answers to get a clearer idea of what is needed.

Exam Advice

You MUST revise everything – because the exam board could choose any question, however, it does make sense to spend more time on those topics which have not appeared for a while.

With these particular questions there is a sizeable risk that people don’t understand the difference between the questions, and then write about the wrong thing.

Make sure you know which is which, for example do you understand the difference between “genetic explanation” and “neural correlates explanation”, and do you have a model essay for each?

Schizophrenia is a severe mental illness where contact with reality and insight are impaired, an example of psychosis.

Section 1: Diagnosis and Classification of Schizophrenia

Classification is the process of organising symptoms into categories based on which symptoms cluster together in sufferers. Psychologists use the DSM and ICD to diagnose a patient with schizophrenia.

Diagnosis refers to the assigning of a label of a disorder to a patient. The ICD-10 (only negative symptoms need to be present) is used worldwide and the DSM-5 (only positive symptoms need to be present) is used in America.

In order to diagnose Schizophrenia the Mental Health Profession developed the DSM (Diagnostic and Statistical Manual) still used today as a method of classifying mental disorders (particularly in the USA).

It is also used as a basis for the ICD (International Classification of Diseases) used by the World Health Organisation in classifying all disorders (mental and physical).

Note: you may come across the terms DSM-IV and ICD-10. These refer to the latest editions of the two classification systems.

Positive Symptoms

an excess or distortion of normal functions: including hallucinations and delusions.

Positive symptoms are an excess or distortion of normal functions, for example hallucinations, delusions and thought disturbances such as thought insertion.

• Hallucinations are usually auditory or visual perceptions of things that are not present. Imagined stimuli could involve any of the senses. Voices are usually heard coming from outside the person’s head giving instructions on how to behave. • Delusions are false beliefs. Usually the person has convinced him/herself that he/she is someone powerful or important, such as Jesus Christ, the Queen (e.g. Delusions of Grandeur). There are also delusions of being paranoid, worrying that people are out to get them. • Psychomotor Disturbances: Stereotypyical – Rocking backwards and forwards, twitches, & repetitive behaviors. Catatonia- staying in position for hours/days on end, cut off from the world.

Negative Symptoms

where normal functions are limited: including speech poverty and avolition.

Negative symptoms are a diminution or loss of normal functions such as psychomotor disturbances, avolition (the reduction of goal-directed behavior), disturbances of mood and thought disorders.

• Thought disorder in which there are breaks in the train of thought and the person appears to make illogical jumps from one topic to another (loose association). Words may become confused and sentences incoherent (so called ‘word salad). Broadcasting is a thought disorder whereby a person believes their thoughts are being broadcast to others, for example over the radio or through TV. Alogia – aka speech poverty – is a thought disorder were correct words are used but with little meaning. • Avolition: Lack of volition (i.e. desire): in which a person becomes totally apathetic and sits around waiting for things to happen. They engage in no self motivated behavior. Their get up and go has got up and gone!

Classification

Slater & Roth (1969) say that hallucinations are the least important of all the symptoms, as they are not exclusive to schizophrenic people.

Classification and diagnosis does have advantages as it allows doctors to communicate more effectively about a patient and use similar terminology when discussing them. In addition, they can then predict the outcome of the disorder and suggest related treatment to help the patient.

Scheff (1966) points out that diagnosis classification labels the individual, and this can have many adverse effects, such as a self-fulfilling prophecy (patients may begin to act how they are expected to act), and lower self-esteem.

Ethics – do the benefits of classification (care, treatment, safety) outweigh the costs (possible misdiagnosis, mistreatment, loss of rights and responsibility, prejudice due to labelling).

Reliability and Validity in Diagnosis and Classification of Schizophrenia

with reference to co-morbidity, culture and gender bias and symptom overlap.

Reliability

For the classification system to be reliable, differfent clinicians using the same system (e.g. DSM) should arrive at the same diagnosis for the same individual.

Reliability is the level of agreement on the diagnosis by different psychiatrists across time and cultures; stability of diagnosis over time given no change in symptoms.

Diagnosis of schizophrenia is difficult as the practitioner has no physical signs but only symptoms (what the patient reports) to make a decision on.

Jakobsen et al. (2005) tested the reliability of the ICD-10 classification system in diagnosing schizophrenia. A hundred Danish patients with a history of psychosis were assessed using operational criteria, and a concordance rate of 98% was obtained. This demonstrates the high reliability of the clinical diagnosis of schizophrenia using up-to-date classification.

Comorbidity describes people who suffer from two or more mental disorders. For example, schizophrenia and depression are often found together. This makes it more difficult to confidently diagnose schizophrenia. Comorbidity occurs because the symptoms of different disorders overlap. For example, major depression and schizophrenia both involve very low levels of motivation. This creates problems of reliability. Does the low motivation reflect depression or schizophrenia, or both?

Gender bias: Loring and Powell (1988) found that some behavior which was regarded as psychotic in males was not regarded as psychotic in females.

Validity – the extent to which schizophrenia is a unique syndrome with characteristics, signs and symptoms.

For the classification system to be valid it should be meaningful and classify a real pattern of symptoms, which result from a real underlying cause.

The validity of schizophrenia as a single disorder is questioned by many. This is a useful point to emphasise in any essay on the disorder. There is no such thing as a ‘normal’ schizophrenic exhibiting the usual symptoms.

Since their are problems with the validity of diagnois classification, unsuitable treatment may be administered, sometimes on an involuntary basis. This raises practical and ethical issues when selecting different types of tretment.

Problems of validity: Are we really testing what we think we are testing? In the USA only 20% of psychiatric patients were classed as having schizophrenia in the 1930s but this rose to 80% in the 1950s . In London the rate remained at 20%, suggesting neither group had a valid definition of schizophrenia.

Neuropsychologist Michael Foster Green suggests that neurocognitive deficits in basic functions such as memory, attention, central executive and problem solving skills may combine to have an outcome which we are labelling “Schizophrenia” as if it was the cause when in fact it is simply an umbrella term for a set of effects.

Predictive validity. If diagnosis leads to successful treatment, the diagnosis can be seen as valid. But in fact some Schizophrenics are successfully treated whereas others are not. Heather (1976) there is only a 50% chance of predicting what treatment a patient will receive based on diagnosis, suggesting that diagnosis is not valid.

Aetiological validity – for a diagnosis to be valid, all patients diagnosed as schizophrenic should have the same cause for their disorder. This is not the case with schizophrenia: The causes may be one of biological or psychological or both.

David Rosenhan (1973) famous experiment involving Pseudopatients led to 8 normal people being kept in hospital despite behaving normally. This suggests the doctors had no valid method for detecting schizophrenia. They assumed the bogus patients were schizophrenic with no real evidence. In a follow up study they rejected genuine patients whom they assumed were part of the deception.

Culture – One of the biggest controversies in relation to classification and diagnosis is to do with cultural relativism and variations in diagnosis. For example in some Asian countries people are not expected to show emotional expression, whereas in certain Arabic cultures public emotion is encouraged and understood. Without this knowledge a person displaying overt emotional behavior in a Western culture might be regarded as abnormal. Cochrane (1977) reported that the incidence of schizophrenia in the West Indies and the UK is 1 %, but that people of Afro-Caribbean origin are seven times more likely to be diagnosed as schizophrenic when living in the UK.

Cultural bias – African Americans and those of Afro-carribean descent are more likely to be diagnosed than their white counterparts but diagnostic rates in Africa and the West Indies is low – Western over diagnosis is a result of cultural norms and the diagnosis lacks validity.

Section 2: Biological Explanations for Schizophrenia

Family studies find individuals who have schizophrenia and determine whether their biological relatives are similarly affected more often than non-biological relatives.

There are two types of twins – identical (monozygotic) and fraternal (dizygotic). To form identical twins, one fertilised egg (ovum) splits and develops two babies with exactly the same genetic information.

• Gottesman (1991) found that MZ twins have a 48% risk of getting schizophrenia whereas DZ twins have a 17% risk rate. This is evidence that the higher the degree of genetic relativeness, the higher the risk of getting schizophrenia. • Benzel et al. (2007) three genes: COMT, DRD4, AKT1 – have all been associated with excess dopamine in specific D2 receptors, leading to acute episodes, positive symptoms which include delusions, hallucinations, strange attitudes. • Research by Miyakawa et al. (2003) studied DNA from human families affected by schizophrenia and found that those with the disease were more likely to have a defective version of a gene, called PPP3CC which is associated with the production of calcineurin which regulates the immune system. Also, research by Sherrington et al. (1988) has found a gene located on chromosome 5 which has been linked in a small number of extended families where they have the disorder. • Evidence suggests that the closer the biological relationship, the greater the risk of developing schizophrenia. Kendler (1985) has shown that first-degree relatives of those with schizophrenia are 18 times more at risk than the general population. Gottesman (1991) has found that schizophrenia is more common in the biological relatives of a schizophrenic, and that the closer the degree of genetic relatedness, the greater the risk.

Very important to note genetics are only partly responsible, otherwise identical twins would have 100% concordance rates.

One weakness of the genetic explanation of schizophrenia is that there are methodological problems. Family, twin and adoption studies must be considered cautiously because they are retrospective, and diagnosis may be biased by knowledge that other family members who may have been diagnosed. This suggests that there may be problems of demand characteristics.

A second weakness is the problem of nature-v-Nurture. It is very difficult to separate out the influence of nature-v-nurture. The fact that the concordance rates are not 100% means that schizophrenia cannot wholly be explained by genes and it could be that the individual has a pre-disposition to schizophrenia and simply makes the individual more at risk of developing the disorder. This suggests that the biological account cannot give a full explanation of the disorder.

A final weakness of the genetic explanation of schizophrenia is that it is biologically reductionist. The Genome Project has increased understanding of the complexity of the gene. Given that a much lower number of genes exist than anticipated, it is now recognised that genes have multiple functions and that many genes behavior.

Schizophrenia is a multi-factorial trait as it is the result of multiple genes and environmental factors. This suggests that the research into gene mapping is oversimplistic as schizophrenia is not due to a single gene.

The Dopamine Hypothesis

• Dopamine is a neurotransmitter. It is one of the chemicals in the brain which causes neurons to fire. The original dopamine hypothesis stated that schizophrenia suffered from an excessive amount of dopamine. This causes the neurons that use dopamine to fire too often and transmit too many messages. • High dopamine activity leads to acute episodes, and positive symptoms which include: delusions, hallucinations, confused thinking. • Evidence for this comes from that fact that amphetamines increase the amounts of dopamine . Large doses of amphetamine given to people with no history of psychological disorders produce behavior which is very similar to paranoid schizophrenia. Small doses given to people already suffering from schizophrenia tend to worsen their symptoms. • A second explanation developed, which suggests that it is not excessive dopamine but that fact that there are more dopamine receptors. More receptors lead to more firing and an over production of messages. Autopsies have found that there are generally a large number of dopamine receptors (Owen et al., 1987) and there was an increase in the amount of dopamine in the left amygdale (falkai et al. 1988) and increased dopamine in the caudate nucleus and putamen (Owen et al, 1978).

One criticism of the dopamine hypothesis is there is a problem with the chicken and egg. Is the raised dopamine levels the cause of the schizophrenia, or is it the raised dopamine level the result of schizophrenia?

It is not clear which comes first. This suggests that one needs to be careful when establishing cause and effect relationships in schizophrenic patients.

One of the biggest criticisms of the dopamine hypothesis came when Farde et al found no difference between schizophrenics’ levels of dopamine compared with ‘healthy’ individuals in 1990.

Noll (2009) also argues around one third of patients do not respond to drugs which block dopamine so other neurotransmitters may be involved.

A final weakness of the dopamine hypothesis is that it is biologically deterministic. The reason for this is because if the individual does have excessive amounts of dopamine then does it really mean that thy ey will develop schizophrenia? This suggests that the dopamine hypothesis does not account for freewill.

Neural Correlates

• Neural correlates are patterns of structure or activity in the brain that occur in conjunction with schizophrenia • People with schizophrenia have abnormally large ventricles in the brain . Ventricles are fluid filled cavities (i.e. holes) in the brain that supply nutrients and remove waste. This means that the brains of schizophrenics are lighter than normal. The ventricles of a person with schizophrenia are on average about 15% bigger than normal (Torrey, 2002).

A strength is that the research into enlarged ventricles and neurotransmitter levels have high reliability. The reason for this is because the research is carried out in highly controlled environments, which specialist, high tech equipment such as MRI and PET scans.

These machines take accurate readings of brain regions such as the frontal and pre-frontal cortex, the basil ganglia, the hippocampus and the amygdale. This suggests that if this research was tested and re-tested the same results would be achieved.

Supporting evidence for the brain structure explanation comes from further empirical support from Suddath et al. (1990). He used MRI (magnetic resonance imaging) to obtain pictures of the brain structure of MZ twins in which one twin was schizophrenic.

The schizophrenic twin generally had more enlarged ventricles and a reduced anterior hypothalamus. The differences were so large the schizophrenic twins could be easily identified from the brain images in 12 out of 15 pairs.

This suggests that there is wider academic credibility for enlarged ventricles determining the likelihood of schizophrenia developing.

A second weakness of the neuroanatomical explanations is that it is biologically deterministic. The reason for this is because if the individual does have large ventricles then does it really mean that they will develop schizophrenia? This suggests that the dopamine hypothesis does not account for freewill.

Section 3: Psychological Explanations for Schizophrenia

Family dysfunction.

Family Dysfunction refers to any forms of abnormal processes within a family such as conflict, communication problems, cold parenting, criticism, control and high levels of expressed emotions. These may be risk factors for the development and maintenance of schizophrenia.

• Laing and others rejected the medical / biological explanation of mental disorders. They did not believe that schizophrenia was a disease. They believed that schizophrenia was a result of social pressures from life. Laing believed that schizophrenia was a result of the interactions between people, especially in families. • Bateson et al. (1956) suggested the double bind theory, which suggests that children who frequently receive contradictory messages from their parents are more likely to develop schizophrenia. For example parents who say they care whilst appearing critical or who express love whilst appearing angry. They did not believe that schizophrenia was a disease. They believed that schizophrenia was a result of social pressures from life. • Prolonged exposure to such interactions prevents the development of an internally coherent construction of reality; in the long run, this manifests itself as typically schizophrenic symptoms such as flattening affect, delusions and hallucinations, incoherent thinking and speaking, and in some cases paranoia. • Another family variable associated with schizophrenia is a negative emotional climate, or more generally a high degree of expressed emotion (EE). EE is a family communication style that involves criticism, hostility and emotional over-involvement. The researchers concluded that this is more important in maintaining schizophrenia than in causing it in the first place, (Brown et al 1958). Schizophrenics returning to such a family were more likely to relapse into the disorder than those returning to a family low in EE. The rate of relapse was particularly high if returning to a high EE family was coupled with no medication.

One strength of the double bind explanation comes from further empirical support provided by Berger (1965). They found that schizophrenics reported a higher recall of double bind statements by their mothers than non-schizophrenics.

However, evidence may not be reliable as patient’s recall may be affected by their schizophrenia. This suggests that there is wider academic credibility for the idea of contradictory messages causing schizophrenia.

A second strength of the research into expressed emotion (EE) is that it has practical applications. For example Hogarty (1991) produced a type of therapy session, which reduced social conflicts between parents and their children which reduced EE and thus relapse rates.

This suggests that gaining an insight into family relationships allows psychiatric professionals to help improve the quality of patient’s lives.

Individual differences – EE is associated with relapse but not all patients who live in high EE families relapse and not all patients in low EE families avoid relapse – Family dysfunction is an incomplete explanation for schizophrenia.

A weakness of the family relationsships appraoch is that there is a problem of cause and effect. Mischler & Waxler (1968) found significant differences in the way mothers spoke to their schizophrenic daughters compared to their normal daughters, which suggests that dysfunctional communication may be a result of living with the schizophrenic rather than the cause of the disorder.

This suggests that there is a problem of the chicken and egg scenario in relation to expressed emotion causing schizophrenia.

A second weakness of the double bind theory is that there are ethical issues. There are serious ethical concerns in blaming the family, particularly as there is little evidence upon which to base this.

Gender bias is also an issue as the mother tends to be blamed the most, which means such research is highly socially sensitive. This suggests that the research therefore does not protect individuals from harm.

Cause and effect – It remains unclear whether cognitive factors cause schizophrenia or if schizophrenia causes these cognitions – Family dysfunction may not be a valid explanation for schizophrenia.

Cognitive explanations

including dysfunctional thought processing.

Cognitive approaches examine how people think, how they process information. Researchers have focused on two factors which appear to be related to some of the experiences and behaviors of people diagnosed with schizophrenia.

First, cognitive deficits which are impairments in thought processes such as perception, memory and attention. Second, cognitive biases are present when people notice, pay attention to, or remember certain types of information better than other.

Cognitive Deficits

• There is evidence that people diagnosed as schizophrenic have difficulties in processing various types of information, for example visual and auditory information. Research indicates their attention skills may be deficient – they often appear easily distracted. • A number of researchers have suggested that difficulties in understanding other people’s behavior might explain some of the experiences of those diagnosed as schizophrenic. Social behavior depends, in part, on using other people’s actions as clues for understanding what they might be thinking. Some people who have been diagnosed as schizophrenic appear to have difficulties with this skill. • Cognitive deficits have been suggested as possible explanations for a range of behaviors associated with schizophrenia. These include reduced levels of emotional expression, disorganised speech and delusions.

Cognitive Biases

• Cognitive biases refer to selective attention. The idea of cognitive biases has been used to explain some of the behaviors which have been traditionally regarded as ‘symptoms’ of ‘schizophrenia’. • Delusions: The most common delusion that people diagnosed with schizophrenia report is that others are trying to harm or kill them – delusions of persecution. Research suggests that these delusions are associated with specific biases in reasoning about and explaining social situations. Many people who experience feelings of persecution have a general tendency to assume that other people cause the things that go wrong with their lives.

A strength of the cognitive explanation is that it has practical applications. Yellowless et al. (2002) developed a machine that produced virtual hallucinations, such as hearing the television telling you to kill yourself or one person’s face morphing into another’s.

The intention is to show schizophrenics that their hallucinations are not real. This suggests that understanding the effects of cognitive deficits allows psychologists to create new initiatives for schizophrenics and improve the quality of their lives.

A final strength is that it takes on board the nurture approach to the development of schizophrenia. For example, it suggests that schizophrenic behavior is the cause of environmental factors such as cognitive factors.

One weakness of the cognitive explanation is that there are problems with cause and effect. Cognitive approaches do not explain the causes of cognitive deficits – where they come from in the first place.

Is it the cognitive deficits which causes the schizophrenic behavior or is the schizophrenia that causes the cognitive deficits? This suggests that there are problems with the chicken and egg problem.

A second weakness of the cognitive model is that it is reductionist. The reason for this is because the approach does not consider other factors such as genes.

It could be that the problems caused by low neurotransmitters creates the cognitive deficits. This suggests that the cognitive approach is oversimplistic when consider the explanation of schizophrenia.

Section 4: Drug Therapy: typical and atypical antipsychotics

Drug therapy is a biological treatment for schizophrenia. Antipsychotic drugs are used to reduce the intensity of symptoms (particularly positive symptoms).

Typical Antipsychotics

• First generation Antipsychotics are called “Typical Antipsychotics” Eg. Chlorpromazine and Haloperidol. • Typical antipsychotic drugs are used to reduce the intensity of positive symptoms, blocking dopamine receptors in the synapses of the brain and thus reducing the action of dopamine. • They arrest dopamine production by blocking the D2 receptors in synapses that absorb dopamine, in the mesolimbic pathway thus reducing positive symptoms, such as auditory hallucinations. • But they tended to block ALL types of dopamine activity, (in other parts of the brain as well) and this caused side effects and may have been harmful.

Atypical Antipsychotics

• Newer drugs, called “atypical antipsychotics” attempt to target D2 dopamine activity in the limbic system but not D3 receptors in other parts of the brain. • Atypical antipsychotics such as Clozapine bind to dopamine, serotonin and glutamate receptors. • Atypical antipsychotic drugs work on negative symptoms, improving mood, cognitive functions and reducing depression and anxiety. • They also have some effect on other neurotransmitters such as serotonin . They generally have fewer side effects eg. less effect on movement Eg. Clozapine, Olazapine and Risperidone.

Since the mid-1950s antipsychotic medications have greatly improved treatment. Medications reduce positive symptoms particularly hallucinations and delusions; and usually allow the patient to function more effectively and appropriately.

Antipsychotic drugs are highly effective as they are relatively cheap to produce, easy to administer and have a positive effect on many sufferers. However they do not “cure” schizophrenia, rather they dampen symptoms down so that patients can live fairly normal lives in the community.

Kahn et al. (2008) found that antipsychotics are generally effective for at least one year, but second- generation drugs were no more effective than first-generation ones.

Some sufferers only take a course of antipsychotics once, while others have to take a regular dose in order to prevent symptoms from reappearing.

There is a sizeable minority who do not respond to drug treatment. Pills are not as helpful with other symptoms, especially emotional problems.

Older antipsychotics like haloperidol or chlorpromazine may produce side effects Sometimes when people with schizophrenia become depressed, so it is common to prescribe anti-depressants at the same time as the anti-psychotics.

All patients are in danger of relapsing but without medication the relapses are more common and more severe which suggests the drugs are effective.

Clozapine targets multiple neurotransmitters, not just dopamine, and has been shown to be more effective than other antipsychotics, although the possibility of severe side effects – in particular, loss of the white blood cells that fight infection.

Even newer antipsychotic drugs, such as risperidone and olanzapine are safer, and they also may be better tolerated. They may or may not treat the illness as well as clozapine, however.

Meta–analysis by Crossley Et Al (2010) suggested that Atypical antipsychotics are no more effective, but do have less side effects.

Recovery may be due to psychological factors – The placebo effect is when patients’ symptoms are reduced because they believe that it should.

However, Thornley et al carried out a meta-analysis comparing the effects of Chlorpromazine to placebo conditions and found Chlorpromazine to be associated with better overall functioning – Drug therapy is an effective treatment for SZ.

RWA – Offering drugs can lead to an enhanced quality of life as patients are given independence – Positive impact on the economy as patients can return to work and no longer need to be provided with institutional care.

Ethical issues – Antipsychotics have been used in hospitals to calm patients and make them easier for staff to work with rather than for the patients’ benefit – Can lead to the abuse of the Human Rights Act (no one should be subject to degrading treatment).

Severe side effects – Long term use can result in tardive dyskinesia which manifests as involuntary facial movements such as blinking and lip smacking – While they may be effective, the severity of the side effects mean the costs outweigh the benefits therefore they are not an appropriate treatment.

In most cases the original “typical antipsychotics” have more side effects, so if the exam paper asks for two biological therapies you can write about typical anti-psychotics and emphasise the side effects, then you can write about the atypical antipsychotics and give them credit for having less side effects.

Section 5: Psychological Therapies for Schizophrenia

Family therapy.

Family therapy is a form of therapy carried out with members of the family with the aim of improving their communication and reducing the stress of living as a family.

Family Therapy aims to reduce levels of expressed emotion, and reduced the likelihood of relapse.

Aims of Family Therapy

• To educate relatives about schizophrenia. • To stabilize the social authority of the doctor and the family. • To improve how the family communicated and handled the situation. • To teach patients and carers more effective stress management techniques.

Methods used in Family Therapy

• Pharoah identified examples of how family therapy works: It helps family members achieve a balance between caring for the individual and maintaining their own lives, it reduces anger and guilt, it improves their ability to anticipate and solve problems and forms a therapeutic alliance. • Families taught to have weekly family meetings solving problems on family and individual goals, resolve conflict between members, and pinpoint stressors. • Preliminary analysis: Through interviews and observation the therapist identifies strengths and weaknesses of family members and identifies problem behaviors. • Information transfer – teaching the patient and the family the actual facts about the illness, it’s causes, the influence of drug abuse, and the effect of stress and guilt. • Communication skills training – teach family to listen, to express emotions and to discuss things. Additional communication skills are taught, such as “compromise and negotiation,” and “requesting a time out” . This is mainly aimed at lowering expressed emotion.

A study by Anderson et al. (1991) found a relapse rate of almost 40% when patients had drugs only, compared to only 20 % when Family Therapy or Social Skills training were used and the relapse rate was less than 5% when both were used together with the medication.

Pharaoh et al. (2003) meta – analysis found family interventions help the patient to understand their illness and to live with it, developing emotional strength and coping skills, thus reducing rates of relapse.

Pharoah identified examples of how family therapy works: It helps family members achieve a balance between caring for the individual and maintaining their own lives, it reduces anger and guilt, it improves their ability to anticipate and solve problems and forms a therapeutic alliance.

Economic Benefits: Family therapy is highly cost effective because it reduces relapse rates, so the patients are less likely to take up hospital beds and resources. The NICE review of family therapy studies demonstrated that it was associated with significant cost savings when offered to patients alongside the standard care – Relapse rates are also lower which suggests the savings could be even higher.

Lobban (2013) reports that other family members felt they were able to cope better thanks to family therapy. In more extreme cases the patient might be unable to cope with the pressures of having to discuss their ideas and feelings and could become stressed by the therapy, or over-fixated with the details of their illness.

Token Economy

• Token economies aim to manage schizophrenia rather than treat it. • They are a form of behavioral therapy where desirable behaviors are encouraged by the use of selective reinforcement and is based on operant conditioning. • When desired behavior is displayed eg. Getting dressed, tokens (in the form of coloured discs) are given immediately as secondary reinforcers which can be exchanged for rewards eg. Sweets and cigarettes. • This manages schizophrenia because it maintains desirable behavior and no longer reinforces undesirable behavior. • The focus of a token economy is on shaping and positively reinforcing desired behaviors and NOT on punishing undesirable behaviors. The technique alleviates negative symptoms such as poor motivation, and nurses subsequently view patients more positively, which raises staff morale and has beneficial outcomes for patients. • It can also reduce positive symptoms by not rewarding them, but rewarding desirable behavior instead. Desirable behavior includes self-care, taking medication, work skills, and treatment participation.

Paul and Lentz (1977) Token economy led to better overall patient functioning and less behavioral disturbance, More cost-effective (lower hospital costs)

Upper and Newton (1971) found that the weight gain associated with taking antipsychotics was addressed with token economy regimes. Chronic schizophrenics achieved 3lbs of weight loss a week.

McMonagle and Sultana (2000) reviewed token economy regimes over a 15-year period, finding that they did reduce negative symptoms, though it was unclear if behavioral changes were maintained beyond the treatment programme.

It is difficult to keep this treatment going once the patients are back at home in the community. Kazdin et al. Found that changes in behavior achieved through token economies do not remain when tokens are with¬drawn, suggesting that such treatments address effects of schizophrenia rather than causes. It is not a cure.

There have also been ethical concerns as such a process is seen to be dehumanising, subjecting the patient to a regime which takes away their right to make choices.

In the 1950s and 60s nurses often “rewarded” patients with cigarettes. Due to the pivotal role of dopamine in schizophrenia this led to a culture of heavy smoking an nicotine addiction in psychiatric hospitals of the era.

Ethical issues – Severely ill patients can’t get privileges because they are less able to comply with desirable behaviors than moderately ill patients – They may suffer from discrimination

Cognitive Behavioral Therapy

In CBT, patients may be taught to recognise examples of dysfunctional or delusional thinking, then may receive help on how to avoid acting on these thoughts. This will not get rid of the symptoms of schizophrenia but it can make patients better able to cope with them.

Central idea: Patients problems are based on incorrect beliefs and expectations. CBT aims to identify and alter irrational thinking including regarding:

• General beliefs.
• Self image.
• Beliefs about what others think.
• Expectations of how others will act.
• Methods of coping with problems.

In theory, when the misunderstandings have been swept away, emotional attitudes will also improve.

Assessment : The therapist encourages the patient to explain their concerns.

• describing delusions • reflecting on relationships • laying out what they hope to achieve through the therapy.

Engagement :

The therapist wins the trust of the patient, so they can work together. This requires honesty, patience and unconditional acceptance. The therapist needs to accept that the illusions may seem real to the patient at the time and should be dealt with accordingly.

ABC : Get the patients to understand what is really happening in their life:

A: Antecedent – what is triggering your problem ? B: behavior – how do you react in these situations ? C: Consequences – what impact does that have on your relationships with others?

Normalisation :

Help the patient realise it is normal to have negative thoughts in certain situations. Therefore there is no need to feel stressed or ashamed about them.

Critical Collaborative Analysis :

Carrying on a logical discussion till the patient begins to see where their ideas are going wrong and why they developed. Work out ways to recognise negative thoughts and test faulty beliefs when they arise, and then challenge and re-think them.

Developing Alternative Explanations :

Helping the patient to find logical reasons for the things which trouble them Let the patient develop their own alternatives to their previous maladaptive behavior by looking at coping strategies and alternative explanations.

Another form of CBT: Coping Strategy Enhancement (CSE)

• Tarrier (1987) used detailed interview techniques, and found that people with schizophrenia can often identify triggers to the onset of their psychotic symptoms, and then develop their own methods of coping with the distress caused. These might include things as simple as turning up the TV to drown out the voices they were hearing! • At least 73% of his sample reported that these strategies were successful in managing their symptoms. • CSE aims to teach individuals to develop and apply effective coping strategies which will reduce the frequency, intensity and duration of psychotic symptoms and alleviate the accompanying distress. There are two components: 1. Education and rapport training: therapist and client work together to improve the effectiveness of the client’s own coping strategies and develop new ones. 2. Symptom targeting: a specific symptom is selected for which a particular coping strategy can be devised Strategies are practised within a session and the client is helped through any problems in applying it. They are then given homework tasks to practice, and keep a record of how it worked.

CBT does seem to reduce relapses and readmissions to hospital (NICE 2014). However, the fact that these people were on medication and having regular meetings with doctors would be expected to have that effect anyway.

Turkington et al. (2006) CBT is highly effective and should be used as a mainstream treatment for schizophrenia wherever possible.

Tarrier (2005) reviewed trials of CBT, finding evidence of reduced symptoms, especially positive ones, and lower relapse rates.

Requires self-awareness and willingness to engage – Held back by the symptoms schizophrenics encounter – It is an ineffective treatment likely to lead to disengagement.

Lengthy – It takes months compared to drug therapy that takes weeks which leads to disengaged treatment as they don’t see immediate effects – A patient who is very distressed and perhaps suicidal may benefit better in the short term from antipsychotics.

Addington and Addington (2005) claim that CBT is of little use in the early stages of an acute schizophrenic episode, but perhaps more useful when the patient is more calm and beginning to worry about how life will be after they recover. In other words, it doesn’t cure schizophrenia, it just helps people get over it.

Research in Hampshire, by Kingdon and Kirschen (2006) found that CBT is not suitable for all patients, especially those who are too thought disorientated or agitated, who refuse medication, or who are too paranoid to form trusting alliances with practitioners.

As there is strong evidence that relapse is related to stress and expressed emotion within the family, it seems likely that CBT should be employed alongside family therapy in order to reduce the pressures on the individual patient.

Section 6: Interactionist Approach

The Interactionist approach acknowledges that there are a range of factors (including biological and psychological) which are involved in the development of schizophrenia.

The Diathesis-stress Model

• The diathesis-stress model states that both a vulnerability to SZ and a stress trigger are necessary to develop the condition. • Zubin and Spring suggest that a person may be born with a predisposition towards schizophrenia which is then triggered by stress in everyday life. But if they have a supportive environment and/or good coping skills the illness may not develop. • Concordance rates are never 100% which suggests that environmental factors must also play a role in the development of SZ. MZ twins may have the same genetic vulnerability but can be triggered by different stressors. • Tienari Et. A. (2004): Adopted children from families with schizophrenia had more chance of developing the illness than children from normal families. This supports a genetic link. However, those children from families schizophrenia were less likely to develop the illness if placed in a “good” family with kind relationships, empathy, security, etc. So environment does play a part in triggering the illness.

Holistic – Identifies that patients have different triggers, genes etc. – Patients can receive different treatments for their SZ which will be more effective.

Falloon et al (1996) stress – such as divorce or bereavement, causes the brain to be flooded with neurotransmitters which brings on the acute episode.

Brown and Birley (1968) 50% people who had an acute schizophrenic episode had experienced a major life event in 3 weeks prior.

Substance abuse: Amphetamine and Cannabis and other drugs have also been identified as triggers as they affect serotonin and glutamate levels.

Vasos (2012) Found the risk of schizophrenia was 2.37 times greater in cities than it was in the countryside, probably due to stress levels. Hickling (1999) the stress of urban living made African-Carribean immigrants in Britain 8 to 10 times more likely to experience schizophrenia.

Faris and Dunham (1939) found clear pattern of correlation between inner city environments and levels of psychosis. Pederson and Mortensen (Denmark 2001) found Scandanavian villages have very LOW levels of psychosis, but 15 years of living in a city increased risk.

Fox (1990): It is more likely that factors associated with living in poorer conditions (e.g. stress) may trigger the onset of schizophrenia, rather than individuals with schizophrenia moving down in social status.

Bentall’s meta-analysis (2012) shows that stress arising from abuse in childhood increases the risk of developing schizophrenia.

Toyokawa, Et. Al (2011) suggest many aspects of urban living – ranging from life stressors to the use of drugs, can have an effect on human epigenetics. So the stressors of modern living could cause increased schizophrenia in future generations.

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REVIEW article

The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue.

A commentary has been posted on this article:

Corrigendum: The Role of Dopamine in Schizophrenia from a Neurobiological and Evolutionary Perspective: Old Fashioned, but Still in Vogue

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• 1 Department of Forensic Medicine, Medical University of Gdańsk, Gdańsk, Poland
• 2 School of Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
• 3 Centre for Evolutionary Medicine, University of Zurich, Zurich, Switzerland
• 4 Department of Psychiatry and Psychotherapy, Ruhr University Bochum, Bochum, Germany
• 5 Department of Psychiatry, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany
• 6 Department of Zoology, Institute of Biology, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany
• 7 Biological Anthropology and Comparative Anatomy Research Unit, School of Biomedical Sciences, The University of Adelaide, Adelaide, SA, Australia

Dopamine is an inhibitory neurotransmitter involved in the pathology of schizophrenia. The revised dopamine hypothesis states that dopamine abnormalities in the mesolimbic and prefrontal brain regions exist in schizophrenia. However, recent research has indicated that glutamate, GABA, acetylcholine, and serotonin alterations are also involved in the pathology of schizophrenia. This review provides an in-depth analysis of dopamine in animal models of schizophrenia and also focuses on dopamine and cognition. Furthermore, this review provides not only an overview of dopamine receptors and the antipsychotic effects of treatments targeting them but also an outline of dopamine and its interaction with other neurochemical models of schizophrenia. The roles of dopamine in the evolution of the human brain and human mental abilities, which are affected in schizophrenia patients, are also discussed.

Brief History of Dopamine Hypothesis in Schizophrenia

Dopamine, adrenaline, and noradrenaline are neurotransmitters that belong to the catecholamine family. Dopamine is produced in the substantia nigra and ventral tegmental regions of the brain, and dopamine alterations are related to schizophrenia ( 1 , 2 ). Dopaminergic projections are divided into the nigrostriatal, mesolimbic, and mesocortical systems. Impairments in the dopamine system result from dopamine dysfunctions in the substantia nigra, ventral tegmental region, striatum, prefrontal cortex, and hippocampus ( 3 – 5 ). The “original dopamine hypothesis” states that hyperactive dopamine transmission results in schizophrenic symptoms. This hypothesis was formed upon the discovery of dopamine as a neurotransmitter in the brain by Arvid Carlsson ( 6 – 12 ). Dopamine receptor blockade by chlorpromazine and haloperidol, proposed in 1963 by Arvid Carlsson and Margit Lindqvist, was a cornerstone in psychiatry ( 13 ). However, the association between schizophrenic symptoms and dopamine over-activity has already been questioned ( 14 ). The positive symptoms of schizophrenia include hallucinations and delusions as a result of increased subcortical release of dopamine, which augments D 2 receptor activation ( 15 ), and are thought to be due to a disturbed cortical pathway through the nucleus accumbens ( 16 ). The negative symptoms of schizophrenia include anhedonia, lack of motivation, and poverty of speech, which result from reduced D 1 receptor activation ( 15 ) in the prefrontal cortex and decreased activity of the nucleus caudatus ( 16 ). Alterations in D (3)-receptors might also be involved in the negative symptoms of schizophrenia ( 17 ). Furthermore, dopaminergic and serotonergic deviations are known to contribute significantly to both the positive and negative symptoms of schizophrenia [review by Davis et al. ( 18 ); Castner and Goldman-Rakic ( 19 ); Carlsson et al. ( 20 )].

The “revised dopamine hypothesis” proposes hyperactive dopamine transmission in the mesolimbic areas and hypoactive dopamine transmission in the prefrontal cortex in schizophrenia patients ( 21 – 23 ). In addition to the mesolimbic brain areas, dopamine dysregulation is also observed in brain regions including the amygdala and prefrontal cortex, which are important for emotional processing ( 24 ). PET-studies (positron emission tomography) have identified differences in dopamine contents in the prefrontal cortex, cingulate cortex, and hippocampus between schizophrenia patients and neuropsychiatric healthy control subjects ( 25 ). In particular, the dopamine system in the hippocampus is overactive in schizophrenia patients [review by Grace ( 26 )].

Recent Animal Models Implicating Dopamine in Schizophrenia

The prepulse inhibition (PPI) of the acoustic SR (ASR) is a neurophysiologic measurement of sensorimotor gating and a marker for information-processing deficits in neuropsychiatric disorders such as schizophrenia ( 27 – 30 ). PPI refers to a reduced startle response to a strong sensory stimulus when the stimulus is preceded by a barely detectable stimulus (i.e., the prepulse). PPI is similar in human and experimental animal models. Deficits in PPI can be produced in rodents by administering psychotomimetics such as dopaminergic and serotonergic agonists and glutamatergic antagonists ( 31 – 34 ). Furthermore, dopaminergic stabilizers have been shown to restore social behavior in a rat model of schizophrenia ( 35 ), and regulatory feedback loops exist among serotonergic, GABAergic, and dopaminergic neurotransmitters ( 36 ). For example, interactions between accumbal dopamine and various non-dopamine receptors, such as N -methyl- d -aspartate (NMDA)-, AMPA-, GABA (A)-, and nicotinic-receptors were reported in a rodent model of schizophrenia ( 37 ). NMDA- and D (1)-receptors in the nucleus accumbens interact with other, and this interaction is controlled by PPI ( 38 ). GABA is also involved in the pathophysiology of PPI. Pregnenolone, a neurosteroid in the central nervous system (CNS), works by improving cognitive deficits through GABA, and pregnenolone improves PPI deficits in dopamine transporter knockout mice ( 39 ). Activation of GABA-receptors in the rat brain results in various receptor interactions with glutamate ( 40 , 41 ), and modulation of GABA (A) a5 receptors improves cognitive deficits in rats ( 42 ). In a rat model of schizophrenia, the increase in dopamine is caused by hyperactivity of the ventral hippocampus ( 43 ). Changes in dopamine receptors (D-2) caused by antipsychotic drugs, such as quinpirole, have been demonstrated in a validated rodent model of schizophrenia ( 44 , 45 ). However, recent work by Bay-Richter et al. ( 46 ) indicates that antipsychotic drugs, such as AMP, clozapine, and haloperidol, cause behavioral changes independent of D (2)-receptors in a mouse model. An up-regulation of D2-high receptors is a consistent feature in animal models of schizophrenia ( 47 ). However, alterations in D (3) dopamine receptors caused by novel antipsychotic drugs, such as cariprazine, decrease cognitive deficits in knockout mice ( 48 ). Therefore, D (3)-receptor antagonists are recommended as a new pharmacological strategy to improve cognitive function in schizophrenia [review by Nakajima et al. ( 49 )]. Social isolation rearing in rats, which is a valid neurodevelopmental model of schizophrenia, reduces dopamine levels in the frontal cortex ( 50 ).

Cognition in Schizophrenia

Cognitive deficits in schizophrenia affect working memory, language and executive function, episodic memory, processing speed, attention inhibition, and sensory processing ( 51 ). The prefrontal region is affected in cognitive discrepancies connected with working memory [see the systematic review by Smieskova et al. ( 52 )], which consists of visual, verbal, central executive, episodic components, and working memory disturbances in schizophrenia are primarily due to altered dorsolateral prefrontal cortex (DLPFC) function ( 51 ). Episodic memory discrepancies in schizophrenia involve the medial temporal cortex, particularly the hippocampus, and the prefrontal cortex, particularly the ventral and dorsolateral prefrontal regions ( 51 ). Additionally, auditory processing involving memory procedures is impaired in the working memory of schizophrenia patients ( 53 ). Cognitive deficits correlate with a decline in dopamine in the prefrontal cortex, primarily at the level of D (1)-receptors ( 54 – 59 ) but also due an imbalance of D (1) and D (2)-receptors in the prefrontal cortex [review by Durstewitz and Seamans ( 60 ); Takahashi ( 61 )]. Several studies have proposed that an inverted U-shaped relation between working memory and activation of the prefrontal cortex exists in schizophrenia patients ( 62 ). There is ongoing discussion regarding the involvement of D (1)- and D (2)-receptors in cognition in schizophrenia patients ( 63 – 66 ). Cognitive discrepancies and working memory deficits in the prefrontal cortex are associated with an increase in dopamine and D (1)-receptors in the prefrontal cortex in schizophrenia patients ( 67 , 68 ). Atypical antipsychotics such as clozapine block D (2)-receptors in the striatum and 5-HT 1A -receptors in the prefrontal cortex, which results in increased dopamine activity ( 69 , 70 ). By blocking D (2)-receptors through antipsychotics, the apoptotic mechanisms in the brain regions involved in cognition are impaired ( 71 ). The disturbed activity of working memory in the DLPFC in schizophrenia patients is influenced by the release of dopamine in the midbrain in schizophrenia patients, which is regulated by a deficit in glutamatergic projection from the DLPFC to midbrain dopamine neurons ( 72 ). Extrastriatal dopamine transmission is necessary for attention and working memory, and these deficits in the fronto–striato–thalamic pathway are involved in cognition in schizophrenia ( 73 ). Newer antipsychotic drugs such as olanzapine and clozapine, which have a better affinity for dopamine receptors and blocking 5-HT 2A receptors, decrease the hyperactivity of the mesolimbic dopaminergic pathway and improve the activity of D (1)-receptors in the prefrontal cortex ( 74 ). Furthermore, nicotine improves cognition in schizophrenia patients ( 75 ).

The COMT-Val-allele leads to a deficit in cognitive abilities. Interactions between dopaminergic and methylation mechanisms may result in cognitive deficits in schizophrenia patients. The COMT Met-allele results in lower COMT-activity, leading to greater production of dopamine and increased D (1)-receptor activity in the prefrontal cortex and, subsequently, better cognitive abilities in carriers of the Met-allele ( 76 – 82 ). A link between Met-carriers and smoking has been recently reviewed ( 83 ), and an association between COMT and cognitive dysfunction in bipolar disorder has also been discussed ( 84 ). The COMT-alleles are composed of two different alleles that result in varied activity levels: the low-activity COMT-allele (L-COMT) and the high-activity COMT-allele (H-COMT) ( 85 ). The L-COMT allele has the Met-/Met-genotype, and the H-COMT allele has the Val-/Val-genotype ( 86 ). Middle-aged healthy women with H-COMT who carry the Val158 allele show better cognitive abilities, including executive processing and cognitive flexibility, than carriers of the Met allele ( 87 ).

Dopamine Receptors and Antipsychotic Effects in Schizophrenia

Dopamine receptors are G-protein-coupled receptors and can be divided into D (1), D (2), D (3), and D (4)-receptors ( 88 ). D (1) receptors in the prefrontal cortex are decreased in schizophrenia patients and are unaffected by chronic treatment of typical neuroleptics [review by Friedmann et al. ( 89 )]. In contrast, D (1)-receptors are increased in the parieto-temporal cortex in schizophrenia patients ( 90 ). Increased D2 mRNA has been found in the frontal cortex in schizophrenia patients when compared with neuropsychiatric healthy control subjects ( 91 ). Both the classic and -current antipsychotic drugs act primarily by increasing high-affinity D (2)-receptor expression ( 92 – 98 ). Haloperidol has been shown to increase high-affinity D (2)-receptors in dopamine-sensitive rats in an animal of schizophrenia ( 99 ). Dopamine agonists bind to D (2)-high and D (2)-low-receptors ( 93 , 100 ). This D (2) two-state model is still controversial, although discussions tend to doubt its validity, as demonstrated by in vitro binding experiments ( 101 ). The action of dopamine agonists is related to dopamine hyperactivity in psychosis ( 102 ). Dopamine antagonists and, to a lesser extent, dopamine agonists increase the D (2)-high-receptors ( 103 ). This increase in D (2)-high-receptors is a necessary basic requirement for the development of a psychosis that correlates with dopamine supersensitivity ( 104 ). This specific increase in D (2)-receptors and dopamine supersensitivity might result in antipsychotic treatment failure ( 105 , 106 ). Although D (2)-receptor antagonists induce dopamine activity ( 107 ), the mechanisms underlying the action of dopamine D (2)-receptor antagonists are not entirely clear. The low therapeutic advantage of dopamine D (2)-receptor antagonists and their high pharmacological selectivity require future research ( 108 ). Antipsychotic drugs block D (2) receptors and increase the release of glutamate in the striatum ( 109 ), particularly on the right side of the striatum, which is a brain region involved in cognition and reward motivation ( 110 ). Glutamate agonists have an effect on D (2) high-receptors in schizophrenia ( 111 , 112 ). For example, alterations in D (2)-receptor function caused by antipsychotic medication in a rodent model of schizophrenia ( 44 ) or by the application of an amphetamine in schizophrenia patients ( 113 ) have been recently demonstrated. A D (2)-receptor occupancy of 80% is considered essential for the positive effects of antipsychotic medication ( 114 , 115 ), whereas continuous high D (2)-receptor occupancy is not required [review by Kapur and Seeman ( 116 ); Remington and Kapur ( 117 ), systematic review by Uchida et al. ( 118 ); Seeman ( 119 )]. The atypical antipsychotic clozapine results in a lower D (2) receptor occupancy than 80% but still has positive effects [review by Nord and Farde ( 120 )]. Schizophrenia patients with extrapyramidal syndromes (EPSs) show an increased D (2)-receptor occupancy (above 80%) in comparison with schizophrenia patients with a good clinical response and no EPSs (i.e., receptor occupancy of 65–80%) [review by Nord and Farde ( 120 )]. Lower doses of antipsychotics such as risperidone are effective and do not induce EPSs ( 121 , 122 ). This specific D (2)-receptor occupancy in the striatum in schizophrenia patients interacts with the antagonistic effects of 5-HT 2A receptors [review by Pani et al. ( 123 )]. D (1)-receptors and NMDA-receptors cooperate with each other ( 124 ). Furthermore, the intensification of D (2)-receptor antagonists by D (1)-receptor agonists results in better NMDA transmission, exemplified by the action of clozapine as a partial D (1)-receptor agonist ( 109 ). NMDA and D (1) dopamine receptor interaction occurs through signal transduction and phosphorylation and dephosphorylation mechanisms ( 125 ). D (1)-receptors are present in GABAergic interneurons ( 54 ). For example, valproic acid affects GABA and, subsequently, dopamine ( 126 ).

A slightly increased density of D (2)-receptors in basal condition and a significant increase in D (2)-receptors in the striatum of schizophrenia patients has been found ( 127 ). This increase of striatal dopamine D (2)-receptors in schizophrenia has also been demonstrated in neuroimaging and molecular imaging studies ( 128 , 129 ). Specific neurotransmitter pathways such as those of glutamate, GABA, and acetylcholine lead to a high-affinity of the D (2)-receptor ( 130 ). Dopamine receptors such as the D (2)-receptor contain receptor mosaics (i.e., RM; dimeric or high-order receptor oligomers). These D 2 /NMDA receptor mosaics have also been found in the ventral striato-pallidal GABA neurons. Decreased D (2)-receptors in the thalamus and anterior cingulate cortex in schizophrenia might suggest that they are involved in abnormalities in dopamine transmission from the thalamus to the prefrontal cortex ( 131 ).

Low doses of D (2)-receptor antagonists and signaling enhancers of NMDA-receptors are recommended as new treatments in schizophrenia [review by Fuxe et al. ( 132 )]. In the associative striatum, an increased D (2)-receptor availability has been found in schizophrenia patients ( 127 ). Increased dopamine release in the striatum is linked to substance dependence, such as amphetamine dependency, in schizophrenia ( 133 ). For example, stimulation of NMDA/AMPA and kainate receptors by direct application of glutamate or glutamate agonists increases the dopaminergic cell-firing rate ( 133 ). However, the role of dopamine in the dysfunction of the striatum in schizophrenia patients requires future research ( 134 ).

It can be summarized that, to date, the mechanism of every effective antipsychotic medication in schizophrenia involves dopamine and its interaction with other neurochemical pathways such as those of glutamate, GABA, serotonin, and acetylcholine.

Alternate Neurochemical Models in Schizophrenia and Their Interactions with Dopamine

Deviations in dopamine and glutamate have been reported in the prefrontal cortex of schizophrenia patients ( 135 ). NMDA-receptors are involved in releasing dopamine into the striatum and frontal cortex in schizophrenia patients [Ref. ( 136 , 137 ), review by Castner and Williams ( 138 ); Javitt ( 139 ); Balla et al. ( 140 ); Laruelle ( 141 )] and in rats in an animal model of schizophrenia ( 142 ). These interactions are accompanied by calcium-dependent changes ( 143 ) and exchanges between DAT and G72 in various brain regions ( 144 ). In contrast to dopamine receptors, glutamate receptors are found in the subcortical and cortical brain regions ( 145 ). The activity of dopamine is regulated by GABA and glutamate. For example, corticostriatal glutamatergic pathways interact with dopamine terminals ( 146 , 147 ), and specific glutamate receptors in the striatum, such as mGlu2, are sensitive to dopamine ( 112 ). High glutamate levels have been found in the dorsal caudate nucleus of schizophrenia patients ( 148 ). Adenosine interacts with glutamate, NMDA-receptors, and dopamine [review by Burnstock et al. ( 149 )]. It can be summarized that NMDA-receptors and D (1)-receptors in cortical brain areas such as the prefrontal cortex and an excess of D (2)-receptors in subcortical brain areas such as the striatum are interconnected with each other through a positive feedback mechanism ( 150 ). However, through its presynaptic action, dopamine reduces the release of glutamate in the pyramidal neurons of layer V in the prefrontal cortex ( 151 ). Dopamine dysregulation in the basal ganglia of schizophrenia patients is an important intrinsic feature in the pathology of schizophrenia and not a medication side effect [review by Perez-Costas et al. ( 3 )].

The finding by Brisch et al. ( 152 ) that astrocyte density is increased in the frontal cortex in schizophrenia suggests a disturbance in the dopamine–glutamate function. Furthermore, Sokoloff et al. ( 153 ) demonstrated that D (3)-receptors either act directly on NMDA-receptors at glutamate synapses on the terminals of pyramidal cells in the nucleus accumbens or act indirectly through dopamine at the presynaptic junction to regulate pyramidal cells in the prefrontal cortex. Indeed, injection of NMDA-antagonists such as MK801 increases glutamate concentration in the frontal, retrosplenial, and cingulate cortices ( 154 ). Glutamate dysfunction in the prefrontal cortex and hippocampus causes the release of dopamine in the striatum ( 155 ). A new focus on glutamatergic signaling mediated by NMDA and metabotropic receptors may benefit new drug developments [review by Field et al. ( 156 ); Javitt ( 139 ); Matosin and Newell ( 157 ); Moghadam and Krystal ( 158 ); Noetzel et al. ( 159 )]. The review by Bernstein et al. ( 160 ) attributes the disturbed function of astrocytes in schizophrenia to diminished glutamate metabolism. The enzyme glutamine synthetase, which degrades glutamate into glutamine, is located in glial cells and is decreased in schizophrenia patients ( 161 ). Additionally, the glutamate transporter for astrocytes, GLT-1, is increased in schizophrenia patients ( 162 ). Although Arai et al. ( 163 ) reported no association between glutamine synthetase and schizophrenia, the enzyme glutamine synthetase displays gender-specific differences in schizophrenia ( 164 ) and is involved in suicidal behavior ( 165 , 166 ). Moreover, the atypical antipsychotic agent risperidone increases glutamine synthetase levels ( 167 ).

Through NMDA-stimulated GABA-release and GABA B -receptor activity, glycine reduces the release of dopamine by modulating DAT-type transporters in the prefrontal cortex and striatum ( 168 ). The GABA B -receptor inhibits the release of glutamate in the ventral tegmental area ( 169 ). A synergistic interaction of adenosine and glutamate affecting the ventral striato-pallidal GABA pathway has been demonstrated in a rat model ( 170 ). The interactions of pyramidal neurons with dopamine receptors on their dendrites and pyramidal cells with glutamate on their spines, and GABAergic interneurons in the prefrontal cortex in schizophrenia patients might offer new insights into receptor-targeted therapies [Ref. ( 53 ); review by Wassef et al. ( 171 ); Lisman et al. ( 172 )]. An increased number of GABA-cells expressing D (1)-receptors exists in the rat prefrontal cortex ( 173 ). In the nucleus accumbens, neurotensin (NT) inhibits dopamine discharge, which increases glutamate release and activates the ventral striato-pallidal GABA pathway, leading to a subsequent increase in glutamate transport from the mediodorsal thalamus to the prefrontal cortex ( 174 ). Another interaction between dopamine in the prefrontal cortex and glutamate in the mediodorsal thalamus might be responsible for the effects of zotepine, which increases the extracellular levels of noradrenaline, dopamine, glutamate, and GABA ( 175 ). GABA interacts with acetylcholine by constraining its excitatory contribution to cholinergic interneurons, which are decreased in the striatum of schizophrenia patients, resulting in prefrontal deviations in schizophrenia ( 176 ). Dopamine also interacts with acetylcholine, which increases with smoking frequency in schizophrenia patients ( 177 ). Acute nicotine administration might have positive effects on cognition in schizophrenia patients [Ref. ( 178 , 179 ), review by Mackowick et al. ( 180 )].

Dopamine neurons in the midbrain release serotonin, which is important during combined drug treatment with serotonin to prevent the so-called serotonin syndrome, a surplus of serotonin in some brain regions ( 181 ). Atypical antipsychotics involving serotonin receptors include 5-HT 1A receptor agonists or antagonists, 5-HT 2A receptor antagonists, 5-HT 2c receptor inverse or partial agonists or neutral antagonists, 5-HT 6 receptor antagonists, and 5-HT 7 receptor antagonists ( 182 ).

Antipsychotics (such as clozapine and aripiprazole) possessing 5-HT- 1A agonist properties induce hippocampal neurogenesis and increase dopamine in the prefrontal cortex [review by Schreiber and Newman-Tancredi ( 183 )]. It can be summarized that various serotonin–dopamine interactions, which include both direct and indirect feedback mechanisms, contribute to the pathology of schizophrenia [Ref. ( 151 , 184 – 189 ), review by Arranz and de Leon ( 190 ); Alex and Pehek ( 191 ); McCreary et al. ( 192 ); Bhattacharyya et al. ( 193 ); Meltzer et al. ( 194 ); McMahon and Cunningham ( 195 ); Gao et al. ( 196 )].

Novel antipsychotic drugs, such as asenapine, increase dopamine and glutamate levels in various subcortical and cortical areas ( 197 ). New antipsychotic drugs with novel mechanisms induce alterations in both dopamine and glutamate [review by Paz et al. ( 198 ); Seeman et al. ( 99 ); Stone ( 199 ); Leroy et al. ( 200 ); Coyle et al. ( 201 )]. For example, metabotropic glutamate and NMDA-receptors are future targets for new drugs ( 202 , 203 ). A range of dopamine/serotonin, glutamate/serotonin, and acetylcholine/serotonin interactions activate receptors and signaling molecules in response to antipsychotic drugs and have been observed in various brain regions, including the prefrontal cortex and limbic regions, in schizophrenia ( 20 , 98 , 176 , 182 , 194 , 204 – 211 ). Future drug development should target signaling molecules involved in dopamine, glutamate, and serotonin neurotransmission such as Akt and glycogen synthase kinase-3 ( 98 , 212 , 213 ) as well as the control of presynaptic dopamine synthesis and release ( 114 ). Stress in schizophrenia patients causes an increased release of dopamine in the prefrontal cortex, which cannot be counteracted by reduced GABA A receptor complex activity, as well as dendritic spine loss in the prefrontal cortex ( 214 , 215 ). When used in schizophrenic patients, cannabis induces hyperdopaminergic and hypoglutamatergic activities with both positive and negative symptoms ( 216 ). In particular, cannabis increases dopamine transmission in the nucleus accumbens, which might cause or aggravate psychoses ( 217 ). A high-low activity polymorphism in COMT interacts with adolescent cannabis abuse, increasing the risk for schizophrenia ( 218 ). Further, genes such as disrupted-in-schizophrenia-1 (DISC1) play a role in stress pathways and the metabolism of dopamine in schizophrenia [review by Hains and Arnsten ( 219 ); Lipina et al. ( 220 )].

Dopamine and Human Evolution

The role of dopamine in human evolution has hitherto received little theoretical attention. It is still unclear to what extent dopaminergic expansion in hominin evolution was due to genetic adaptations or epigenetic factors. Dopamine has expanded throughout primate and hominin evolution and that dopamine is especially concentrated in the prefrontal cortex, which is involved in higher order functioning. The dopaminergic hypothesis contends that climatic changes occurring in sub-Saharan Africa during the Pliocene and Pleistocene periods, which resulted in increases of the Savannah belt expanded hominin locomotory range. It is also speculated that some human groups ventured to the more habitable African southern coast leading to dietary changes (i.e., increasing amounts of fish/shellfish) that aided dopaminergic expansion ( 221 – 223 ). Dopamine increase may have also been linked with a concomitant elevation in thyroid hormone production. Higher T4 found in Homo may have represented an early endocrinological difference between humans and other primates ( 224 ). In humans, T4 concentration is associated with tyrosine conversion to dopa (a precursor to dopamine); deficiencies of T4 concentrations are linked with various neurological impairments ( 224 ).

Recent research suggests that from Homo erectus onward, humans became persistence hunters, requiring various morphological and thermo-regulatory modifications (i.e., vascular reactivity to temperature, large body surface area, plantar arch), which provides approximately 20% energy return during running, elastic tendons, short toes, more pronounced gluteus maximus muscle, long legs, CNS coordination of metabolic, and cardio-vascular responses to sustained running ( 225 ). From Homo erectus onward there is an evident increase in stride size, which also optimized ergonomic requirements of bipedalism while diminishing energy requirements. Greater mass of slow twitch muscles would have also assisted long distance locomotion. Long distance locomotion in conjunction with greater hunting activities in ancestral hominins incorporated all aspects of the CNS such as retention and memory recall of large geographic areas, which maximized resource acquisition. The locomotion/behavior interplay, which was mediated by nerve cells and the dopaminergic system may have evolutionary expanded cortical regions and neuro-hormonal organization in ancestral hominins ( 225 ).

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Abbreviations

AMPA, (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)-propionic acid; COMT, catechol- O -methyltransferase; CNS, central nervous system; D (1), dopamine D 1 receptor; D (2), dopamine D 2 receptor; D (3), dopamine D 3 receptor; DAT, dopamine transporter; DAOA or G72, d -amino acid oxidase activator; DLPFC, dorsolateral prefrontal cortex; GABA, γ-aminobutyric acid; H-COMT, high-activity catechol- O -methyltransferase; L-COMT, low-activity catechol- O -methyltransferase; Met, methionine; mRNA, messenger ribonucleic acid; NMDA-receptor, N -methyl- d -aspartate receptor; PET, positron emission tomography; PPI, prepulse inhibition; RNA, ribonucleic acid; SR, startle reflex; Val, valine.

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Keywords: dopamine, schizophrenia, cognition, glutamate, dopamine receptors, cannabis, animal models of schizophrenia, evolution of the human brain

Citation: Brisch R, Saniotis A, Wolf R, Bielau H, Bernstein H-G, Steiner J, Bogerts B, Braun K, Jankowski Z, Kumaratilake J, Henneberg M and Gos T (2014) The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. Front. Psychiatry 5 :47. doi: 10.3389/fpsyt.2014.00047

Received: 20 January 2014; Accepted: 23 April 2014; Published online: 19 May 2014.

Reviewed by:

Copyright: © 2014 Brisch, Saniotis, Wolf, Bielau, Bernstein, Steiner, Bogerts, Braun, Jankowski, Kumaratilake, Henneberg and Gos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Ralf Brisch, Department of Forensic Medicine, Medical University of Gdańsk, ul. Debowa 23, Gdańsk PL-80-204, Poland e-mail: ralfbrisch@hotmail.com

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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The Relationship Between Schizophrenia and Dopamine

Arlin Cuncic, MA, is the author of The Anxiety Workbook and founder of the website About Social Anxiety. She has a Master's degree in clinical psychology.

Alla Bielikova / Getty Images

• Dopamine and Schizophrenia Symptoms
• Implications for Treatment

What Does This Mean for Patients?

• Causes of Schizophrenia
• High vs. Low Dopamine
• Implications

Serotonin and Schizophrenia

Experts do not fully understand what causes schizophrenia, but evidence suggests that dopamine abnormalities may play a role. High and low levels of dopamine in certain regions of the brain can also affect different symptoms of schizophrenia.

Schizophrenia is a debilitating mental disorder with a multitude of symptoms. These can range from disorganized speech and behavior to delusions and hallucinations. Some cases are far more disabling than others, but in most cases, people with this disorder require lifelong treatment and care.

Current research suggests that schizophrenia is a neurodevelopmental disorder with an important dopamine component. Four decades of research have focused on the role of dopamine in schizophrenia, and it seems clear that excesses or deficiencies in dopamine can lead to schizophrenic symptoms.

At a Glance

While other factors also play a role in the development of schizophrenia, dopamine imbalances have been identified as a key factor affecting symptoms. Too much dopamine in key areas of the brain results in delusions and hallucinations (positive symptoms) or cognitive deficits and reduced social/emotional activity (negative symptoms). Understanding the factors that contribute to dopamine symptoms can help doctors treat the condition more effectively.

What Is the Dopamine Hypothesis of Schizophrenia?

The dopamine hypothesis of schizophrenia was one of the first neurobiological theories for this disease.

Dopamine Hypothesis

This theory suggests that an imbalance of dopamine is responsible for schizophrenic symptoms. In other words, dopamine plays a role in controlling our sense of reality, and too much or too little can cause delusions and hallucinations.

The evidence for this theory comes from many sources, including post-mortem studies that have imbalances of dopamine as well as its metabolites in schizophrenic patients. In addition, drugs that block the receptors for dopamine can help control schizophrenic symptoms.

How Does Dopamine Cause Schizophrenic Symptoms?

There are two types of schizophrenia symptoms that an excess of dopamine may cause: positive and negative . Positive symptoms include delusions and hallucinations. Negative symptoms include a decrease in social activity, emotional range, and cognitive function.

Positive Symptoms

Positive symptoms are those that appear to come from outside the person. These can include delusions, hallucinations, or thought disorders.

Dopamine contributes to the development of positive symptoms through its effects on subtype-3A dopamine receptors (D3) of cortical neurons. The subtype-3A receptor is found in the prefrontal cortex, which controls planning, thinking, and other cortical areas.

When these receptors are activated by dopamine, they overstimulate neurons. This can lead to all three types of positive symptoms. Evidence for this idea comes from studies that show that patients with schizophrenia have significantly lower levels of the D3 receptor than healthy people.

Negative Symptoms

While positive symptoms appear to come from outside, negative symptoms appear to be internal. These include decreased social activity and emotional range, as well as cognitive deficits like poor problem-solving or memory deficit.

The mechanisms contributing to negative symptoms are linked to dopamine levels in the limbic system . Dopamine excess leads to an increase in the activity of dopamine receptors, creating overstimulation similar to that seen in positive symptoms.

Some researchers suggest that this overactivity decreases neuronal inhibition , leading to decreased social behavior and cognitive deficits.

Treatment Implications of the Dopamine Hypothesis

The dopamine hypothesis has important treatment implications. The vast majority of current antipsychotic medications target dopamine, and this makes sense, given that these drugs were discovered through serendipitous observations of their effect on schizophrenia.

The most important dopamine-affecting medications are the typical antipsychotics, which increase post-synaptic receptor stimulation by blocking dopamine receptors.

Unfortunately, these medications produce a number of debilitating side effects, most notably extrapyramidal symptoms (EPS) like tardive dyskinesia . Newer second-generation antipsychotics have fewer side effects, but none are perfect.

Treatment with dopamine agonists is a third possibility suggested by the dopamine hypothesis. Dopamine agonists stimulate post-synaptic dopamine receptors directly, and as such, they can be used to treat schizophrenia without producing EPS.

Being diagnosed with schizophrenia can be extremely hard on patients and their families. It's important that doctors and researchers continually investigate new treatments that could improve the lives of people living with this disorder.

However, it's also important to remember that schizophrenia is a complex disorder, and there are many ways the disease can manifest. Dopamine hyperactivity may not be the primary cause of schizophrenia in all patients. Furthermore, even if dopamine hyperactivity is the primary cause it still doesn't explain why some patients respond more strongly than others to the same treatment.

The best way for patients and their loved ones to navigate these issues is by staying informed and asking questions about any new or experimental treatments. They should also work with doctors to develop a personalized treatment plan that's appropriate for their own needs.

Does Too Much Dopamine Cause Schizophrenia?

Increased activity of the mesolimbic pathway is related to positive symptoms of schizophrenia (delusions, hallucinations, etc.). This means that increasing the activity of dopamine receptors in this brain system could theoretically reduce delusions and hallucinations.

A closely related idea is that by blocking post-synaptic dopamine receptors, scientists can reduce the psychotic symptoms of schizophrenia.

As mentioned previously, this is what most modern medications do: they block post-synaptic dopamine receptors in order to reduce psychotic symptoms. Unfortunately, when scientists block all available dopamine receptors they also produce a number of debilitating side effects such as extrapyramidal symptoms (EPS) and tardive dyskinesia.

Is Dopamine High or Low in Schizophrenia?

The most common theory about the cause of schizophrenia is that there are too many dopamine receptors in certain parts of the brain, specifically the mesolimbic pathway. This causes an increase in mesolimbic activity which results in delusions, hallucinations, and other psychotic symptoms.

Other research suggests that schizophrenia might be caused by a lack of dopamine activity in other parts of the brain. For example, scientists have discovered that the hippocampus is overactive in schizophrenia.

Schizophrenia might also be characterized by low dopamine in the prefrontal cortex, but again the evidence is inconclusive. Some studies have found that schizophrenics have elevated levels of dopamine in this region, while others suggest that there are too few dopamine receptors.

Implications of the Dopamine Hypothesis

It's important to note that schizophrenia is a complex disorder. Even if dopamine hyperactivity is the primary cause, certain types of schizophrenia might be characterized by increased activity in certain brain areas while others are characterized by reduced activity in certain brain areas.

Furthermore, it's also possible that different patients will respond to treatment differently based on how their disease manifests.

It's important for healthcare providers and researchers to continue investigating how schizophrenia works in the brain. This will help them develop better treatments for this complex disorder.

Research also implicates serotonin as a regulator of dopamine release. Antipsychotic medications, including olanzapine and clozapine , reduce serotonin activity and increase dopamine activity.

For example, olanzapine-induced reductions in serotonin metabolism were associated with significant improvements in negative and positive symptoms, but not cognitive deficits.

Schizophrenia is a severe mental disorder that can be treated. If you or someone you know was recently diagnosed with schizophrenia, you might be wondering what the future holds. Healthcare professionals can help you manage your symptoms and chart a course for the best possible outcome.

Sometimes, there may be periods of remission that allow you to live a productive life even when coping with schizophrenia. As new treatments are continually being developed, we can look forward to better options for people who experience this disorder in the future.

Murray RM, Lappin J, Di Forti M. Schizophrenia: from developmental deviance to dopamine dysregulation .  Eur Neuropsychopharmacol . 2008;18 Suppl 3:S129-S134. doi:10.1016/j.euroneuro.2008.04.002

Brisch R, Saniotis A, Wolf R, et al. The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue [published correction appears in Front Psychiatry. 2014;5:110. Braun, Anna Katharina [corrected to Braun, Katharina]; Kumaritlake, Jaliya [corrected to Kumaratilake, Jaliya]].  Front Psychiatry . 2014;5:47. Published 2014 May 19. doi:10.3389/fpsyt.2014.00047

Purves-Tyson TD, Owens SJ, Rothmond DA, et al. Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain .  Transl Psychiatry . 2017;7(1):e1003. Published 2017 Jan 17. doi:10.1038/tp.2016.257

Ceraso A, Lin JJ, Schneider-Thoma J, et al. Maintenance treatment with antipsychotic drugs for schizophrenia .  Cochrane Database Syst Rev . 2020;8:CD008016. doi:10.1002/14651858.CD008016.pub3

Guma E, Rocchetti J, Devenyi GA, et al. Role of D3 dopamine receptors in modulating neuroanatomical changes in response to antipsychotic administration .  Sci Rep . 2019;9(1):7850. doi:10.1038/s41598-019-43955-4

Maia TV, Frank MJ. An Integrative Perspective on the Role of Dopamine in Schizophrenia .  Biol Psychiatry . 2017;81(1):52-66. doi:10.1016/j.biopsych.2016.05.021

Weiner I. The "two-headed" latent inhibition model of schizophrenia: modeling positive and negative symptoms and their treatment .  Psychopharmacology (Berl) . 2003;169(3-4):257-297. doi:10.1007/s00213-002-1313-x

Stępnicki P, Kondej M, Kaczor AA. Current concepts and treatments of schizophrenia .  Molecules . 2018;23(8):2087. doi:10.3390/molecules23082087

Preda A, Shapiro BB. A safety evaluation of aripiprazole in the treatment of schizophrenia .  Expert Opin Drug Saf . 2020;19(12):1529-1538. doi:10.1080/14740338.2020.1832990

Gomes FV, Zhu X, Grace AA. Stress during critical periods of development and risk for schizophrenia .  Schizophr Res . 2019;213:107-113. doi:10.1016/j.schres.2019.01.030

McCutcheon RA, Krystal JH, Howes OD. Dopamine and glutamate in schizophrenia: biology, symptoms and treatment .  World Psychiatry . 2020;19(1):15-33. doi:10.1002/wps.20693

Correll CU. Current Treatment Options and Emerging Agents for Schizophrenia .  J Clin Psychiatry . 2020;81(3):MS19053BR3C. Published 2020 Apr 14. doi:10.4088/JCP.MS19053BR3C

Bever KA, Perry PJ. Olanzapine: a serotonin-dopamine-receptor antagonist for antipsychotic therapy .  Am J Health Syst Pharm . 1998;55(10):1003-1016. doi:10.1093/ajhp/55.10.1003

By Arlin Cuncic, MA Arlin Cuncic, MA, is the author of The Anxiety Workbook and founder of the website About Social Anxiety. She has a Master's degree in clinical psychology.

Reviewed by Psychology Today Staff

Dopamine is known as the feel-good neurotransmitter—a chemical that ferries information between neurons. The brain releases it when we eat food that we crave or while we have sex , contributing to feelings of pleasure and satisfaction as part of the reward system. This important neurochemical boosts mood, motivation , and attention , and helps regulate movement, learning, and emotional responses.

• Dopamine and Behavior
• Dopamine and the Brain
• How to Increase Dopamine

In lab experiments, dopamine prompts a rat to press a lever for food again and again. This is no different in humans; it’s the reason why we partake in more than one helping of cake. This press-the-lever action applies to addiction as well. People with low levels of dopamine may be more prone to addiction; a person seeking pleasure via drugs or alcohol or food needs higher and higher levels of dopamine.

Dopamine causes you to want, desire, seek out, and search. It increases your general level of arousal and your goal-directed behavior. Dopamine makes you curious about ideas and fuels your search for information. Dopamine creates reward-seeking loops in the sense that people will repeat pleasurable behavior, from checking Instagram to taking drugs.

A person with high levels of dopamine, whether due to temperament or to a transient—perhaps chemically induced state—can be described as a  sensation seeker. The upside of sensation seeking is that people see potential stressors as challenges to be overcome rather than threats that might crush them. This mindset is a buffer against the stress of life. It increases their hardiness and  r esilience in the long term.

The release of dopamine creates a reward circuit in the brain. This circuit registers an intense experience (such as getting high) as "important" and creates lasting memories of it as pleasurable. Dopamine changes the brain on a cellular level, commanding the brain to do it again.

Swedish pharmacologist and neuroscientist Arvid Carlsson won the Nobel prize in 2000 for his research on dopamine, showing its importance in brain function. He helped show that the neurotransmitter is heavily involved in the motor system. When the brain fails to produce enough dopamine, it can result in Parkinson’s disease. The primary treatment for Parkinson’s disease is a drug called L-dopa, which spurs the production of dopamine.

Dopamine has also been implicated in schizophrenia and ADHD ; the brain systems underlying these conditions (as well as substance abuse disorder) are complex. The activity of the dopamine system depends on the state of one’s dopamine receptors, and in people with these conditions, the chemical interacts with other factors in ways that have yet to be explained.

It is no exaggeration to say that dopamine makes us human. Beginning in infant development, dopamine levels are critical, and mental disabilities can arise if dopamine is not present in sufficient quantities. Dopamine is implicated in genetic conditions like congenital hypothyroidism. Dopamine deficiency is also implicated in other conditions such as Alzheimer's, depressive disorders, binge-eating, addiction, and gambling.

Drugs currently used to treat ADHD do indeed increase the effectiveness of dopamine. This helps patients with ADHD focus and pay better attention to one thing at a time. How exactly more dopamine translates into better concentration and focus is not yet understood.

In this neurodegenerative disorder, the decline begins with the dopamine-producing cells in the brain where movement is coordinated. As these cells degrade, motor function is compromised , which includes tremors, rigidity, bradykinesia or slowed movement, as well as changes in speech and gait.

Scientists who study neurological and psychiatric disorders have long been interested in how dopamine works and how relatively high or low levels of dopamine in the brain relate to behavioral challenges and disability.

There are ways to up one's dopamine levels naturally, and basic self-care is the place to start. A night of fitful sleep, for one, can reduce dopamine drastically. Here are some tips to boost levels:

• Eat foods rich in tyrosine including cheese, meats, fish, dairy, soy, seeds, nuts, beans, lentils, among others. While tyrosine supplements are available, consuming foods is preferred.
• Up magnesium intake with foods such as seeds, nuts, soy, beans, whole grains, among others.
• Avoid processed foods, high-fats, sugar, caffeine.
• Proper sleep hygiene is mandatory, as it fuels dopamine production.
• Exercise daily.
• Avoid stress, apply techniques such as meditation , visualization , breathing exercises.
• Consider the use of natural nootropics including L-Tyrosine and L-theanine.

Music-induced pleasure relies on the engagement of both higher-order brain regions as well as some primitive reward-related areas.

Discover how challenges that are not fun in the moment—but rewarding in retrospect—can grow resilience, deepen life satisfaction, and lead to transformative personal growth.

Deciding how we are going to eat is not a matter of free will. Our bodies and brains have their own agenda.

We all have our own personalities, preferences, and quirks, and they should all be reflected in our styles. Finding your style can lead to increased self-esteem and confidence.

More than 21 million Americans—celebrities and "regular" folks among them— have both a substance use disorder and a serious psychiatric problem. What do we know about this issue?

Capitalizing on your motivation or eliminating apathy and inaction means keen awareness of the powerful role of rewards and your unique dopamine production.

Oxytocin fuels maternal instincts, tells us who brings us the most joy, helps us make friends, and is associated with the development of empathy but also hatred and prejudice.

Discover how non-alcoholic beverages might impact alcohol recovery; Could they be the key to controlling cravings, or do they pose unseen risks?

Speedballing, combining fentanyl with cocaine or methamphetamine, is the fourth wave of the opioid crisis in the U.S.

How your brain responds to reward matters more than the power of positive emotion.

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Example Answers for Section C Schizophrenia Topic Paper 3 June 2018 (AQA)

Last updated 13 Aug 2018

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Here are a series of suggested answers for the Schizophrenia topic questions in AQA A Level Psychology Paper 3 (Section B) in June 2018.

Question 22 : (2 marks)

Comorbidity is when the same person has two or more disorders at the same time. For example, about 50% of people with schizophrenia are also diagnosed with depression.

- - - - - - - - -

Question 23 : (2 marks)

System overlap refers to the way that disorders have shared symptoms. For example hallucinations are a symptom of both schizophrenia and bipolar disorder. This can lead to problems with reliability of diagnosis as one doctor might diagnose the person as having schizophrenia while another might diagnose bipolar disorder.

Question 24: (4 marks)

Group A’s scores suggest a normal distributed as the mean, median and mode are all almost the same (22). However, group B’s scores suggest a positively skewed distribution as the mean (26) is higher than both the median (22.5) and the mode (16).

Question 25 : (16 marks)

One biological explanation for schizophrenia is that it is passed on through the genes. Gottesman reports that while the rate of schizophrenia in the general population is 1%, if one parent has schizophrenia there is a 12% likelihood their child will develop it and if both parents have schizophrenia, it increases to 40%. Schizophrenia seems to be polygenic, as a number of genes have been implicated. It also seems to be aetiologically heterogeneous as different studies have identified different candidate genes. For example, Ripke et al. found 108 separate genetic variations were associated with increased risk of schizophrenia.

Evidence to support the genetic explanation comes from Gottesman and Shields, who found a concordance rate of 42% for MZ and 9% for DZ. MZ twins share 100% of their genes, compared to DZ twins who only share 50% of their genes, so this suggests that genes must have some influence on the development of schizophrenia. However, the concordance rate for MZ twins is not 100% which suggests that other factors must also be involved. It is also important to note that two-thirds of people with schizophrenia have no relative with a similar diagnosis and therefore have no one to inherit it from. However, one explanation for this is mutation in parental DNA.

The dopamine hypothesis is another biological explanation for schizophrenia. The original version suggested it was due to high levels or activity of dopamine in the subcortex (hyperdopaminergia). For example, an excess of dopamine receptors in Broca’s area might be responsible for poverty of speech and auditory hallucinations. More recent versions have included hypodopaminergia, where low levels of dopamine in the prefrontal cortex are believed to be responsible for some of the negative symptoms of schizophrenia.

Research evidence from autopsies has shown that schizophrenia sufferers have more dopamine receptors, which may lead to more neural firing and therefore an over production of messages. Further support comes from the fact that dopamine agonists (e.g. amphetamines) can produce-schizophrenia like symptoms in non-sufferers. Conversely, antipsychotic drugs work by binding to dopamine receptors and reduce symptoms. However, the newer antipsychotic drugs affect other neurotransmitters such as serotonin and glutamate as well as dopamine. Therefore it appears that several neurotransmitters may be involved in the development of schizophrenia, meaning the dopamine hypothesis is too simplistic. Biological explanations for schizophrenia can be criticised for being biologically reductionist. By oversimplifying schizophrenia in terms of genes and neurotransmitters, the social context within which it develops has not been considered. In order to explain schizophrenia effectively it would be better to take an interactionist approach, such as the diathesis stress model. This suggests that biological factors predispose someone to schizophrenia, but this has to be ‘triggered’ by some sort of experience or stressor. Evidence to support this view comes from the prospective adoption study by Tienari et al. Although this study showed that children with a biological parent were still at greater risk even if they had been adopted into families with no history of schizophrenia, all reported cases of schizophrenia occurred in families rated as ‘disturbed’. When the families were rated as ‘healthy’, the likelihood of developing schizophrenia for those with a biological mother with schizophrenia fell to below 1%. However, biological factors must have had a role to play as none of the adoptees with no family history of schizophrenia from ‘disturbed’ families developed schizophrenia

• Schizophrenia

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• Published: 19 April 2018

The Relationship Between Dopamine Synthesis Capacity and Release: Implications for Psychosis

• Matthew M Nour   ORCID: orcid.org/0000-0003-0858-6184 1 ,
• Robert McCutcheon 1 &
• Oliver D Howes 1 , 2  

Neuropsychopharmacology volume  43 ,  pages 1195–1196 ( 2018 ) Cite this article

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Berry and colleagues report that presynaptic striatal dopamine synthesis capacity (measured with [ 18 F]FMT PET) is not associated with methylphenidate-induced striatal dopamine release (indexed as a reduction in [ 11 C]raclopride non-displaceable binding-potential) in healthy participants ( Berry et al, 2017 ). The authors should be commended for the quality of this study, in which 40 subjects each received three PET scans within a short time window. The results are pertinent to the interpretation of neuroimaging studies investigating the dopamine hypothesis of schizophrenia.

Multiple lines of evidence indicate that presynaptic striatal dopamine dysfunction is central to the pathoetiology of schizophrenia. Striatal dopamine synthesis capacity (also interpreted as dopamine turnover) is elevated in patients compared with healthy participants ( Howes et al, 2012 ). Moreover, patients show exaggerated striatal dopamine release in response to 0.3 mg/kg intravenous amphetamine (measured with [ 123 I]IBZM]-SPECT)( Abi-Dargham et al, 1998 ). A parsimonious hypothesis is that these findings represent two facets of the same underlying presynaptic dopamine dysfunction in schizophrenia. Thus, the lack of a relationship between dopamine synthesis capacity and methylphenidate-induced dopamine release in healthy participants warrants further consideration.

In contrast to the study of Berry and colleagues, the majority of PET/SPECT studies investigating dopamine synthesis capacity and release in schizophrenia used [ 18 F]DOPA or [ 11 C]DOPA, and amphetamine challenge ( Abi-Dargham et al, 1998 ; Howes et al, 2012 ). As the authors note, FMT and DOPA are sensitive to different aspects of presynaptic dopamine function. Moreover, amphetamine and methylphenidate promote dopamine efflux via divergent mechanisms. Whereas both stimulants block the presynaptic dopamine transporter (DAT), recent studies using fast-scan cyclic voltammetry in freely moving rats suggest that amphetamine (1 mg/kg) causes dopamine release via action potential-dependent mechanisms. These include increased frequency, amplitude and duration of spontaneous dopamine transients, which ride on-top of a more sustained dopamine accumulation ( Covey et al, 2016 ; Daberkow et al, 2013 ). At this dose amphetamine also augments phasic dopamine responses to reward-predicting cues, whilst at higher doses (5 mg/kg) it decouples dopamine burst firing from behaviorally relevant cues, with a corresponding breakdown in goal-directed behavior ( Daberkow et al, 2013 ). At high cytoplasmic concentrations, as can be achieved in brain-slice preparations, amphetamine also causes redistribution of vesicular dopamine and reversal of DAT.

Amphetamine-induced dopamine release in vivo , therefore reflects the sensitivity and capacity of presynaptic dopamine neurons to increase spontaneous transients under task-neutral conditions ( Covey et al, 2016 ; Daberkow et al, 2013 ), in a way that methylphenidate-induced release does not. It has been proposed that this sensitivity under amphetamine may correlate with a more general tendency towards spontaneous dopamine transients in the drug-free state ( Maia and Frank, 2017 ). This would result in increased presynaptic dopamine turnover, and manifest as a positive relationship between PET measures of dopamine synthesis capacity and amphetamine-induced dopamine release, but not methylphenidate-induced release, which may be more dependent on DAT function. Interestingly, one study in advanced Parkinson’s Disease patients reported a positive correlation between putamen [ 18 F]DOPA uptake and methamphetamine-induced dopamine release ( R 2 =0.69–0.74) ( Piccini et al, 2003 ).

Under this hypothesis, the findings of increased dopamine synthesis and amphetamine-induced release capacity in schizophrenia may indeed reflect a single underlying abnormality, namely increased phasic dopaminergic responses to behaviorally-irrelevant cues, as proposed by the aberrant salience hypothesis ( Howes and Nour, 2016 ; Kapur, 2003 ). Future PET studies that measure dopamine synthesis and amphetamine-induced release capacity in patients and healthy controls are necessary to test this hypothesis.

Funding and disclosure

MMN is supported by the National Institute for Health Research, UK. RM is supported by the Wellcome Trust, UK. ODH is supported by the Medical Research Council, UK. The authors have no conflicts of interest in relation to this letter.

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Department of Psychosis Studies, Psychiatric Imaging, Institute of Psychiatry Psychology and Neuroscience, King’s College London, London, UK

Matthew M Nour, Robert McCutcheon & Oliver D Howes

MRC London Institute of Medical Sciences, Hammersmith Hospital Campus, London, UK

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Nour, M., McCutcheon, R. & Howes, O. The Relationship Between Dopamine Synthesis Capacity and Release: Implications for Psychosis. Neuropsychopharmacol. 43 , 1195–1196 (2018). https://doi.org/10.1038/npp.2017.293

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Imaging synaptic dopamine availability in individuals at clinical high-risk for psychosis: a [11c]-(+)-phno pet with methylphenidate challenge study.

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Caffeine affects brain dopamine function in patients with Parkinson's disease

Regular high caffeine consumption affects dopamine function in patients with Parkinson's disease, shows a new international study led by the University of Turku and Turku University Hospital in Finland. Caffeine consumption before undergoing diagnostic brain dopamine imaging may also affect the imaging results.

Previous research has shown that regular caffeine intake is associated with a reduced risk of developing Parkinson's disease. However, there is limited research on the effects of caffeine on disease progression in patients who have already been diagnosed.

A follow-up study led by the University of Turku and Turku University Hospital (Tyks) in Finland examined how caffeine consumption affects brain dopamine function over an extended period in patients diagnosed with Parkinson's disease. The dopamine function of the brain was assessed with single photon emission computed tomography (SPECT) to measure dopamine transporter (DAT) binding.

"The association between high caffeine consumption and a reduced risk for Parkinson's disease has been observed in epidemiological studies. However, our study is the first to focus on the effects of caffeine on disease progression and symptoms in relation to dopamine function in Parkinson's disease," says Valtteri Kaasinen, Professor of Neurology at the University of Turku and principal investigator of the study.

Caffeine consumption had no effect on Parkinson's symptoms

A clinical study compared 163 patients with early-stage Parkinson's disease to 40 healthy controls. The examinations and imaging were conducted on two occasions for a subsample, with an average interval of six years between the first and second imaging session. Changes in brain dopamine transporter binding were compared with patients' caffeine consumption, which was assessed both by a validated questionnaire and by determining concentrations of caffeine and its metabolites in blood samples.

The findings revealed that patients with a high caffeine consumption exhibited a 8.3-15.4% greater decrease in dopamine transporter binding compared to those with a low caffeine consumption. However, the observed decline in dopamine function is unlikely to be due to a greater reduction in dopamine neurons following caffeine consumption. Rather, it is more likely to be a downregulatory compensatory mechanism in the brain that has also been observed in healthy individuals following caffeine and other stimulant use.

"While caffeine may offer certain benefits in reducing risk of Parkinson's disease, our study suggests that high caffeine intake has no benefit on the dopamine systems in already diagnosed patients. A high caffeine intake did not result in reduced symptoms of the disease, such as improved motor function," says Kaasinen.

Another significant finding of the study was the observation that a recent dose of caffeine, for example in the morning of the imaging session, temporarily increases the person's DAT binding values. This could potentially complicate the interpretation of clinically commonly used brain DAT imaging results. The research results suggest that patients should refrain from consuming coffee and caffeine for 24 hours before undergoing diagnostic DAT imaging.

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Materials provided by University of Turku . Note: Content may be edited for style and length.

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• Emmi K Saarinen, Tomi Kuusimäki, Kari Lindholm, Kalle Niemi, Emma A Honkanen, Tommi Noponen, Marko Seppänen, Toni Ihalainen, Kirsi Murtomäki, Tuomas Mertsalmi, Elina Jaakkola, Elina Myller, Mikael Eklund, Simo Nuuttila, Reeta Levo, Kallol Ray Chaudhuri, Angelo Antonini, Tero Vahlberg, Marko Lehtonen, Juho Joutsa, Filip Scheperjans, Valtteri Kaasinen. Dietary Caffeine and Brain Dopaminergic Function in Parkinson Disease . Annals of Neurology , 2024; DOI: 10.1002/ana.26957

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Dopamine overdose hypothesis: Evidence and clinical implications

David e. vaillancourt.

1 Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA

2 Department of Neurology, University of Florida, Gainesville, FL, USA

3 Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA

Daniel Schonfeld

Youngbin kwak.

4 Center for Cognitive Neuroscience, Duke University, Durham, NC, USA

Nicolaas I. Bohnen

5 Neurology Service and GRECC, VA Ann Arbor Healthcare system

6 Department of Neurology, University of Michigan, Ann Arbor, MI, USA

7 Department of Radiology, University of Michigan, Ann Arbor, MI, USA

Rachael Seidler

8 Department of Neuroscience, University of Michigan, Ann Arbor, MI, USA

9 Department of Psychology, University of Michigan, Ann Arbor, MI, USA

10 School of Kinesiology, University of Michigan, Ann Arbor, MI, USA

About a half a century has passed since dopamine was identified as a neurotransmitter, and it has been several decades since it was established that people with Parkinson’s disease receive motor symptom relief from oral levodopa. Despite the evidence that levodopa can reduce motor symptoms, there has been a developing body of literature that dopaminergic therapy can improve cognitive functions in some patients but make them worse in others. Over the past two decades, several laboratories have shown that dopaminergic medications can impair the action of intact neural structures and impair the behaviors associated with these structures. In this review we consider the evidence that has accumulated in the areas of reversal learning, motor sequence learning, and other cognitive tasks. The purported inverted-U shaped relationship between dopamine levels and performance is complex and includes many contributory factors. The regional striatal topography of nigrostriatal denervation is a critical factor as supported by multimodal neuroimaging studies. A patient's individual genotype will determine the relative baseline position on this inverted-U curve. Dopaminergic pharmacotherapy and individual gene polymorphisms can affect the mesolimbic and prefrontal cortical dopaminergic functions in a comparable inverted-U dose-response relationship. Depending on these factors, a patient can respond positively or negatively to levodopa when performing reversal learning and motor sequence learning tasks. These tasks may continue to be relevant as our society moves to increased technological demands of a digital world that requires newly learned motor sequences and adaptive behaviors to manage daily life activities.

Introduction

A little over half a century has passed since dopamine was identified as a neurotransmitter and it was recognized that depleting monoamines in the brain through the administration of reserpine caused hunched immobility in rodents 1 . This finding led to the hypothesis of a dopaminergic depletion disorder as the pathophysiological basis of Parkinson’s disease. Since then, dopamine substitution using levodopa (L-3,4-dihydroxyphenylalanine) has been the most widely used pharmacotherapy for Parkinson’s disease. Despite reducing symptom manifestation, a majority of patients chronically exposed to dopamine therapy will eventually develop motor complications, including response fluctuations and drug-induced dyskinesias (abnormal involuntary movements) such as choreic and dystonic limb or truncal movements 2 . In addition, while restoring cognitive functions associated with dopamine depleted brain regions, dopamine substitution can also impair certain cognitive functions, such as probabilistic reversal learning, motor sequence learning and other cognitive tasks, that are associated with intact dopamine-dependent brain regions 3 – 5 . Dopamine overstimulation has been studied for over a decade since the work of Gotham and colleagues 6 , with papers by Swainson and colleagues 7 and Cools and colleagues 3 initially proposing the dopamine overdose hypothesis.

Fronto-executive cognitive deficits can be observed even in early Parkinson’s disease in the areas including executive function, learning, memory, motor inhibition, impulse control, and visuospatial processing 8 . These cognitive deficits may be related to mesocortical, mesolimbic, and nigrostriatal dopaminergic pathways, as well as other pathways associated with acetylcholine and norepinephrine 8 . Cognitive deterioration following dopaminergic therapy can occur in several tasks. In this review of the dopamine overdose hypothesis, we characterize the specific evidence supporting this hypothesis by reviewing the relevant literature in the areas of reversal learning, motor sequence learning, and other cognitive tasks. Issues related to impulsivity and reward processing are not addressed in this review, since these issues have been addressed previously 9 , 10 . First, we discuss the physiology of the dopamine overdose hypothesis. Next, we discuss evidence for the negative effects of dopaminergic medication on probabilistic reversal learning, followed by the evidence for the negative effects of dopaminergic medication on motor sequence learning. We then discuss the evidence that other cognitive tasks can be negatively affected by levodopa when patients with Parkinson’s disease carry specific genetic polymorphisms. Finally, we discuss the clinical implications of the hypothesis as they apply to treatment and management of Parkinson’s disease patients.

Physiological Basis for the Dopamine Overdose Hypothesis

There are two major subtypes of dopaminergic neurons in the brain: the neurons of the substantia nigra pars compacta [A9 neurons] 11 , which give rise to the nigrostriatal pathway; and the A10 neurons of the ventral tegmental area (VTA), which give rise to the mesolimbic and mesocortical pathways that innervate parts of the limbic system and the neocortex 12 . The regional pattern of degeneration within the substantia nigra in patients with Parkinson’s disease appears to be specific such that a loss of pigmented neurons is greatest in the ventral lateral tier, followed by the dorsal tier, which is different to the patterns identified with healthy aging 13 . In vivo diffusion magnetic resonance imaging has provided evidence in support of this selective pattern of degeneration by showing that measures of structural integrity within the ventral and lateral substantia nigra are most affected in early Parkinson’s disease compared with control subjects 14 , 15 , whereas the dorsal substantia nigra is more affected in older adults compared with young adults 16 .

The ventral lateral tier of the substantia nigra sends dopaminergic projections primarily to the dorsal putamen, whereas the dorsal tier of the substantia nigra sends dopaminergic projections primarily to the ventral striatum. The ventral striatum receives also projections from the VTA 11 . Studies using 18 F-dopa positron emission tomography (PET) have shown that patients with unilateral Parkinson’s disease who are Hoehn and Yahr Stage 1 have reduced dopamine storage primarily within the dorsal putamen contralateral to motor symptoms 17 . In a cross-sectional study, it was shown that in early Parkinson’s disease, 18 F-dopa metabolism was reduced by almost 50% in the dorsal rostral putamen and dorsal caudal putamen, whereas the ventral putamen was unaffected 18 . With the progression of disease symptoms, there is a loss of 18 F-dopa metabolism in the ventral putamen. Longitudinal multi-tracer PET studies show that the posterior-dorsal to anterior-ventral striatal gradient of nigrostriatal denervation is maintained while the asymmetry gradient becomes less prominent with progressive Parkinson's disease 19 . Figure 1A shows the posterior-dorsal to anterior-ventral gradient of nigrostriatal denervation in Parkinson's disease across different stages of severity of disease (from mild to severe, left to right). Early and most severe loss of nerve terminals is in the dorsal and posterior putamen. Anterior and ventral striatal regions are relatively spared, at least in the early stage of disease. This pattern of striatal degeneration from dorsal to ventral segments with the progression of Parkinson’s disease provides a fundamental basis for the dopamine overdose hypothesis. That is, regions that are less affected early in the disease could be over stimulated by exogenous dopamine administration.

A, shows the posterior-dorsal to anterior-ventral gradient of nigrostriatal denervation in Parkinson's disease across different stages of severity of disease (from mild to severe, left to right). Early and most severe loss of nerve terminals is in the dorsal and posterior putamen. Anterior and ventral striatal regions are relatively spared, at least in early stage of disease. Abbreviations: P=putamen, C=Caudate. B, individual patients can experience differing performance effects in response to levodopa administration due to a combination of factors including stage of disease, striatal structure used in the task, and genotype for genetic polymorphisms that play a role in dopaminergic metabolism in striatum and prefrontal cortex (Cools, 2006). These factors collectively determine each patient’s starting location on the inverted-U shaped function describing the association between dopamine and performance, which in turn determines whether performance will worsen, improve, or show no change with dopaminergic medications.

It has been several decades since Cotzias and colleagues 20 demonstrated the striking efficacy of oral levodopa for relieving motor symptoms of Parkinson’s disease. Since that time, levodopa has remained the gold standard for antiparkinsonian therapy. Nonetheless, since the dorsal putamen is mostly affected in early Parkinson’s disease whereas the ventral striatum remains relatively intact 18 , a given dose of levodopa that has beneficial effects for most motor tasks that rely upon dorsal putamen, can also have deleterious effects on specific cognitive and motor tasks that specifically rely upon ventral striatum 5 . The administration of levodopa is thought to decarboxylase in remaining dopaminergic neurons, and thus the lack of specificity of dopamine therapy can lead to a possible over stimulation of ventral striatal areas that remain intact. Figure 1B illustrates the many factors which can modulate the effects of dopaminergic medication on performance, including disease stage, striatal structure engaged by the task, and genotype for genes that regulate endogenous dopamine availability. The dopamine overdose hypothesis proposes that when patients with Parkinson’s disease are off levodopa or other dopaminergic medications, their performance on tasks such as probabilistic reversal learning is optimal, whereas their performance on cognitive tasks such as set-switching is impaired. Since reversal learning and set-switching implicate ventral and dorsal striatum respectively 21 , 22 , these tasks have provided excellent paradigms to investigate dopaminergic effects on different striatal regions. Further, when levodopa or other dopaminergic medications are given to the patient the proposal is that performance on probabilistic reversal learning will worsen, whereas set-switching performance improves. While set-switching requires flexible swapping or switching between tasks, reversal learning requires an adaptation to a previously learned stimulus-reward contingency. The central tenet of the dopamine overdose hypothesis is that tasks that rely on the ventral striatum will be impaired by dopaminergic medications in early Parkinson’s disease because of over stimulation of the structure.

In addition to the effects of dopamine on the ventral and dorsal striatum, there is also evidence that dopamine overdose effects can occur in prefrontal cortex 8 . The mesocortical dopaminergic pathway projects from VTA to frontal cortex, and this pathway regulates numerous cognitive functions including set-shifting, working memory, and planning. As reviewed in subsequent sections, the studies in the literature collectively point to a cortical and subcortical role for dopamine overdose effects. In the next sections, we will review the specific evidence in support of the dopamine overdose hypothesis in several domains of learning and cognitive performance.

Reversal Learning and Dopamine in Parkinson’s Disease

Table 1 shows a summary of the studies in which reversal learning paradigms have been investigated in patients with Parkinson’s disease off and on levodopa. The consistent empirical finding has been that when on levodopa reversal learning performance is impaired compared with the performance off levodopa. Initial evidence in support of this finding was from a study by Swainson and colleagues 7 . The authors studied three groups of patients with Parkinson’s disease, including mild/unmedicated, mild/medicated, and severe/medicated. The reversal learning task required subjects to choose between a red pattern and a green pattern, with one pattern rewarded over the other on a probabilistic schedule. The subjects were asked to learn the task and figure out which pattern was correct, and after a series of trials the correct pattern was reversed. This was not immediately detectable given that rewards were assigned probabilistically (e.g. 80-20 ratio). When the reversal occurred, patients in the mild/medicated and severe/medicated group had difficulty adapting to the new pattern. The patients in the mild/unmedicated group had no difficulty adapting in the reversal learning task. In a subsequent study by the same laboratory 3 , set-switching performance and reversal learning were compared in two groups of subjects with Parkinson’s disease while either off or on dopaminergic therapy. The set-switch task required that subjects identify the correct letter or number in a well-learned sequence and did not require that subjects adapt to a new condition as in the reversal learning task. The authors identified that reaction time during the set-switch task was reduced with dopaminergic medication. During the reversal learning task, subjects with Parkinson’s disease in the off and on medication groups made more errors than control subjects at the reversal learning stage, but the patients with Parkinson’s disease off medication were able to adapt to the reversal. Patients on dopaminergic medication had more difficulty shifting their performance when the reward stimuli reversed. While the between group design utilized in these studies may make interpretations difficult, they did provide a critical advance in identifying which type(s) of task is detrimentally affected by dopaminergic medication in mild to moderate Parkinson’s disease.

Summary of studies in which probabilistic learning and motor sequence learning paradigms have been investigated in patients with Parkinson’s disease off and on levodopa

Subsequent studies by the same laboratory and others have used within-subjects designs to test subjects with Parkinson’s disease off and on levodopa. Fifteen subjects with Parkinson’s were tested off and on levodopa monotherapy using an instrumental learning task with constant stimulus-reward assocations, and a reversal learning task with changing reward contingencies. The study counterbalanced whether patients were tested in the on or off state first. A simple instrumental learning task was used since it has been linked mainly with dorsal striatum and frontal circuits 23 , 24 , whereas the reversal learning task has been linked with ventral striatum and frontal circuits 21 , 25 , 26 . The prediction was that dopaminergic medication would have opposite effects on performance during these two tasks. Figure 2 shows experimental findings from the study during the instrumental learning task and the reversal learning task 27 . During the instrumental learning task ( Figure 2A ), which had constant reward contingencies, subjects on levodopa produced a greater percentage of correct choices compared to when off levodopa. Figure 2B shows the opposite pattern for the reversal learning task. Here, subjects on levodopa produced fewer reversal errors than when the subjects were off medication. These findings controlled for the testing order and tested the same subjects, and provide compelling evidence that reversal learning is impaired when subjects with Parkinson’s disease are on medication.

Figure adapted from Graef and colleagues (2010). A, performance of On-beginner (“On first”) and Off-beginner (“Off first”) subgroups across sessions on the reversal learning task. Covariate-corrected estimated means of the number of reversals achieved are shown in boxes. B, performance of On-beginner (“On first”) and Off-beginner subgroups (“Off first”) across sessions on the instrumental learning task. Covariate-corrected estimated means of percentage of correct choices are shown in boxes.

Another probabilistic learning task, developed by Gluck and colleagues, is the Weather Prediction Task 28 . In this task, four “cards” have independent and probabilistic relationships to two possible outcomes, “sun” and “rain”. Patients with Parkinson’s disease exhibit impaired learning on this task when they are on dopaminergic medication, but learn at a rate similar to that of controls when off medication 29 , 30 . In a similar paradigm, Parkinson’s patients and controls were asked to learn which of two stimuli was associated with a reward 31 . The stimuli varied in shape and color, with only dimension predicting reward. Parkinson’s patients were impaired at learning the initial association when on medications, but not when they were off medications. In the next phase of the study, the relevant dimension of each stimulus was held constant whereas the irrelevant feature changed. Control subjects, Parkinson’s patients on medication, and patients off medication all performed equally well during this transfer phase. Given that the weather prediction task has been shown to rely on the head caudate nucleus 32 , a more anterior striatal structure which exhibits dopaminergic denervation later in Parkinson’s disease than the putamen, these findings provide additional support for the dopamine overdose hypothesis playing a role in the behavior of patients with Parkinson’s disease when on levodopa.

Dopamine stimulates receptors in the basal ganglia and prefrontal cortex, and there is an important distinction for D1 and D2 receptors in these brain regions. The dopamine overdose hypothesis is also supported from studies of dopamine synthesis in animals and pharmacological studies in healthy adults. In animal models, stimulating D1 receptors with dopaminergic medication in the prefrontal cortex has revealed changes in the firing of neurons during the delay period of delayed-response tasks 33 – 35 . Computational models have provided insight into how dopamine enhances D1 receptor stimulation such that dopamine can increase the resistance to distracting stimuli 36 , 37 . D2 receptors are more abundant in the basal ganglia than in the prefrontal cortex, and it has been suggested that the basal ganglia may serve as a gating mechanism for updating the prefrontal cortex 38 . D2 receptor stimulation has been tested in healthy adults using the D2 receptor agonist bromocriptine relative to their baseline dopamine synthesis capacity as determined by 18 F-fluoro-L-meta-tyrosine PET tracer 39 . Subjects performed a reward-based reversal learning task with deterministic stimulus-outcome contingencies that required a button press to predict if the face or scene stimulus would lead to a reward or punishment. The authors found that during the placebo drug, striatal dopamine synthesis was positively related to reversal learning performance. Subjects with low striatal dopamine synthesis performed poorly on the reversal learning task, whereas high striatal dopamine synthesis was associated with high reversal learning performance. Subjects with low striatal dopamine synthesis responded positively to bromocriptine. In contrast, subjects with high baseline striatal dopamine synthesis were over-stimulated by bromocriptine, and exhibited impaired reversal learning performance when on drug.

In a study using event-related functional magnetic resonance imaging (fMRI), it was found that in healthy adults performing a probabilistic reversal learning task the ventral striatum and ventrolateral prefrontal cortex were specifically activated when subjects committed reversal errors 21 . A recent study evaluated the effects of bromocriptine versus sulpiride (a D2 receptor antagonist), and the combination of both drugs on reward and punishment reversal learning 40 . It was found that improved reward relative to punishment reversal learning performance occurred with the administration of sulpiride compared with bromocriptine. These findings provide additional insight into the specificity of the D1 and D2 receptors related to reward and punishment during reversal learning 40 . Next, we discuss the pertinent findings for the dopamine overdose hypothesis for motor sequence learning.

Motor Sequence Learning and Dopamine in Parkinson’s Disease

Both probabilistic reversal learning and category learning rely on more ventral subcortical structures such as the nucleus accumbens and caudate nucleus, which remain relatively intact in mild to moderate Parkinson’s disease. Thus, the dopamine overdose hypothesis provides a plausible framework from which to interpret the finding that patients perform these tasks better when off medication. There is a gradient of dopaminergic denervation within the caudate and putamen as well, with the more ventral and anterior portions of these structures affected later in the disease 41 , 42 . The Seidler laboratory has conducted a series of experiments to investigate interactions between this gradient of denervation and anti-parkinsonian medications, working with a motor sequence learning task 4 , 43 , 44 .

Motor sequence learning refers to the capacity to combine individual elements of action into one smooth, cohesive movement. For example, patients moving into an assisted living facility may need to learn an action sequence to navigate their new surroundings. Sequential behavior is also important for skills such as driving and playing a musical instrument and motor sequence learning plays an important role in many physical rehabilitation protocols. In healthy individuals, the process of motor sequence learning is known to rely on the striatum 45 – 47 . In particular, it has been demonstrated that early in sequence learning, the more ventral and anterior portions of the striatum (i.e. associative striatum) are engaged 47 , whereas once a sequence becomes well learned it is represented in the more dorsal and posterior aspects of the striatum (i.e. sensorimotor striatum). Previous studies investigating the effects of medication on sequence learning in Parkinson’s patients have yielded mixed results. Table 1 shows the study by Carbon et al. 48 which references the data from two prior studies from the same laboratory indicating that motor sequence learning was impaired by levodopa. The initial paper by Feigin and colleagues 49 found that levodopa reduced sequence learning in Parkinson’s patients for a subjective measure of self-reported learning. When comparing objective measures, the investigators reported non-significant differences in sequence learning for patients on versus off levodopa 50 , 51 . Although not significant for objective measures of learning, the direction of change was that levodopa may be impairing sequencing learning for some of the subjects, and that was opposite to the effects of DBS which improved sequencing learning 48 , 49 . This line of work averaged performance across time rather than examining performance changes in the context of learning. Based on the purported inverted-U shaped relationship between dopamine levels and performance and established changes in associative and sensorimotor striatum with learning, it could be that Parkinson’s patients learn new motor sequences faster in the early stages of learning when they were off medication in comparison to on medication. In contrast, once sequences become well learned, patients could be able to perform them better when on medication as opposed to off medication.

In an initial experiment 4 , 14 patients with mild to moderate Parkinson’s disease and 11 healthy controls were evaluated within the same age range for their ability to learn a sequence of finger movements. Patients were tested on two separate occasions, once on their anti-parkinsonian medications, which included varying combinations of medications across the participants of L-dopa and/or dopamine agonists. On the second occasion, patients were tested in the functional off state, 12–18 hours after taking their last dose of dopaminergic medications. Testing occurred in a counterbalanced fashion across medication states. As predicted by the dopamine overdose hypothesis, patients off medication exhibited early learning improvements that were equivalent to those of control subjects for the early phase of learning (see Figure 3A ). As learning progressed, performance of the patients on medication began to catch up to that of their off medication performance.

Panel A (from Kwak et al. 2010) illustrates that patients off their medication learn new sequences of action at the same rate as healthy controls, while patients on medication are impaired. For trials 1 – 16 and 49 – 64 participants pressed buttons in response to randomly cued stimuli; trials 17 – 48 were sequence practice trials. Panel B (from Kwak et al. 2012) illustrates a region in the right ventral putamen that is more active when patients learn a motor sequence off medication than when they are on medication. This differential activation is correlated with off-medication improvements in sequence learning.

In a follow up study 44 , new cohorts of 17 Parkinson’s patients and 21 healthy control subjects were studied in order to evaluate brain networks recruited during sequence learning with fMRI. Again, patients were tested across two different days. For this study a single blind placebo controlled medication design was used, with patients being given either levodopa plus carbidopa or placebo plus carbidopa after arriving to the study in the functional off state. The order of drug versus placebo testing was counterbalanced across testing days. It was found that levodopa was associated with decreased recruitment of the ventral putamen during early phase of sequence learning. Moreover, the difference in activation levels in this structure between on and off medication testing days was correlated with differences in sequence learning performance between on and off days across individual patients. That is, patients that showed the largest decrease in ventral putamen activation when on medication versus off medication exhibited the largest decrease in sequence learning abilities when on medication versus off medication, as illustrated in Figure 3B . A PET investigation by another group reported reduced brain deactivation when Parkinson’s patients were learning a sequence of actions on levodopa versus off 52 . Taken together, these findings suggest that both task-relevant and default network activation can be negatively impacted by administration of levodopa in mild to moderate stage Parkinson’s disease.

Another study measured dopaminergic denervation in 18 Parkinson’s patients using 11 C-dihydrotetrabenazine PET scans 53 . Patients acquired new motor sequences on two testing days in a counterbalanced within subjects design, either on placebo or levodopa plus carbidopa. The ratio of denervation in the anterior putamen versus the posterior dorsal putamen predicted the level of levodopa-associated impairments in motor sequence learning. That is, patients with relatively less denervation in the anterior putamen showed greater on-medication sequence learning decrements. Thus, individual differences in the magnitude of motor sequence learning dopamine overdose effects can be predicted by the spatial pattern of dopaminergic denervation across the striatum.

Genotype and Dopaminergic Medication Interact to Influence Cognitive Function

Another set of studies indicates that dopaminergic medication may lead to deleterious performance on specific cognitive tasks depending on the genotype of the patient ( Figure 1B ). A common polymorphism in the catechol O-methyltransferase (COMT) gene has a strong influence on performance on tests of working memory, attention, and planning 54 – 56 . COMT is an important regulator of dopamine levels, and its activity is thought to primarily influence dopamine levels in the prefrontal cortex 57 , 58 . In healthy individuals 59 , low-activity COMT genotypes are associated with improved performance on the Wisconsin Card Sorting Test, and fMRI studies have confirmed that the prefrontal cortex activity is influenced by the COMT genotype. However in Parkinson’s disease, performance on a Tower of London cognitive test in a large cohort of 288 patients with PD found that low COMT activity was associated with impaired performance, and the effect was more pronounced in those patients taking dopaminergic medications 54 . Using fMRI, it was found that patients with Parkinson’s disease who were homozygous for valine (val/val; high COMT activity) performed better and had greater activity in the frontal-parietal cortex compared with patients with Parkinson’s disease who were homozygous for methionine (met/met; low COMT activity) 56 . The authors did not find clear fMRI differences in the putamen and caudate nucleus.

In a task of attention control 55 , people with Parkinson’s disease who tested for the high COMT genotype (val/val) adopted a more optimal attention shifting strategy compared with the Parkinson’s disease group that had the low COMT genotype (met/met). The low COMT genotype group failed to adopt the attention shifting strategy. The authors also found that the fronto-parietal network typically associated with attention was less active in the low COMT genotype compared with the high COMT genotype. There were no differences observed in the putamen and caudate nucleus.

Another gene that may interact with medication effects in Parkinson’s patients is the DRD2 gene, which codes for dopamine D2 receptors in the striatum. A recent study 43 evaluated whether a particular DRD2 polymorphism (rs 1076560, G > T) is associated with the on versus off medication sequence learning effects that were previously reported in patients with Parkinson’s disease. DRD2 T allele carriers of this polymorphism have reduced D2S expression (short isoform of the D2 receptor); thus in comparison G allele carriers have higher D2 receptor availability. It was predicted that Parkinson’s patients who are minor T allele carriers would exhibit a greater benefit of levodopa on early stage sequence learning. This hypothesis was evaluated in a behavioral study with 45 Parkinson’s patients; 1 patient was TT genotype (grouped together with GT patients), 10 were GT, and 34 were GG. Patients were tested on two days following a single blind placebo controlled design. Levodopa improved early sequence learning over the level of placebo pill for only the TT and GT patients, whereas GG patients did not learn better on levodopa. In contrast, levodopa improved performance on the grooved pegboard test, a simple motor execution test that should rely predominately on the sensorimotor striatum, for all patients regardless of genotype.

These findings suggest that endogenous dopamine modulating factors and exogenous dopamine interact to result in dopamine overdose effects in patients with Parkinson’s disease. That is, disease, genetics, and medication status can all influence an individual’s location on the inverted-U shaped function relating dopamine to performance. Moreover, these studies suggest that the viewpoint for the dopamine overdose hypothesis to occur only because of the ventral and dorsal striatum is too narrow and that other factors including the prefrontal cortex and parietal cortex also play a role. Also, these findings further demonstrate that the genotype of the patient is an important factor to consider when interpreting effects of dopamine on cognitive functions.

Clinical Implications and Conclusions

The clear consensus of a large body of literature is that dopaminergic therapy can improve cognitive functions in some patients but make them worse in others (see 5 for an in-depth review). The dopamine overdose hypothesis provides a conceptual framework to better understand patients' individual cognitive responses to dopaminergic pharmacotherapy in Parkinson's disease. The purported inverted-U shaped relationship between dopamine levels and performance is complex and includes many contributory factors. As discussed in this review, the regional striatal topography of nigrostriatal denervation is a critical factor as supported by fMRI and dopaminergic PET studies. Second, a patient's individual genotype will determine the relative baseline position on this inverted-U curve. Third, dopaminergic pharmacotherapy and individual gene polymorphisms, such as COMT, can also affect the mesolimbic and prefrontal cortical dopaminergic functions in a comparable inverted-U dose-response relationship similar as proposed for the striatum. Therefore, at present a patient's individual cognitive response to dopaminergic pharmacotherapy cannot be predicted by a simple formula. However, a number of clinical implications may be inferred based on the available literature and experience in clinical movement disorders practice.

Striatal dopamine overdose effects have been identified for probabilistic reversal learning and motor sequence learning tasks. Implications for instrumental activities of daily living are clearly apparent. Current technological advances in society will affect persons living with Parkinson's disease. Exposure to new electronic gadgets for daily communication, financial management, bill paying, receiving healthcare, and even medication management are essentially unavoidable and will challenge patients' learning skill abilities. This will include sequential motor behaviors that include fine and precise finger movements when using these new gadgets. Navigation in new environments, whether it is driving a car in new surroundings or moving into a new place to live will be equally challenging.

A key predictor for adverse cognitive learning effects of dopaminergic therapy is the presence of early stage and/or mild severity of disease, where overdose effects of dopaminergic medications are predicted to be most prominent. Practical implications of the dopamine overdose hypothesis in the management of the individual patient with Parkinson's disease will first depend on identification of a dopaminergic dose-related cognitive or behavioral problem. If present, a simple pointer will be to implement a new motor learning challenge, such as using a new device, when in a relative medication 'off' state (assuming preservation of critical motor abilities). Apart from learning new motor behaviors in an 'off' state, a rational pharmacological therapy approach based on the principle of the lowest effective dose may also help to prevent or ameliorate dopaminergic 'on' overdose cognitive adverse effects. Most of all, clinicians need to consider a broader range of symptoms and individual patient priorities in adjusting medication dosages by suggesting medication strategies that strike a better balance between motor and cognitive symptoms 60 . It is also important to consider premorbid personality and psychiatric history when making clinical decisions. Future clinical treatment algorithms may include information about specific gene polymorphisms that affects the dopamine system (so-called 'personalized medicine'). It may also be prudent to consider exercise as an adjunct to dopamine therapy to reduce motor symptoms to also minimize the overdose, as recent studies have shown promise using balance training over six months 61 and progressive resistance exercise over two years 62 .

Cognitive functions, including reward based learning, have been the major focus of research of the dopamine overdose hypothesis 60 . However, much is less is known into the neurobehavioral correlates of these impairments and how it affects instrumental activities of daily living. Dopamine dysregulation syndrome (DDS) is a dysfunction of the reward system in patients with Parkinson's disease who are on dopaminergic drugs, in particular dopamine agonists. Patients with DDS show evidence of impulse control disorders 63 . Further research is needed to determine whether an excess of exogenous dopamine release within the anteroventral striatum and related cortical projections may be a mechanistic factor underlying impulsive and/or risk taking behaviors in susceptible patients.

Acknowledgements

This review was funded in part by NIH grants (R01 NS075012, R01 NS052318, P01 NS015655 and R01 NS070856), Bachman-Strauss Foundation, Tyler’s Hope Foundation, NASA NNX11AR02G, NSBRI, Department of Veterans Affairs, and the Michael J. Fox Foundation.

Dr. Vaillancourt receives grant support from NIH, Bachmann-Straus Foundation, Tyler’s Hope Foundation, and consults for projects at UT Southwestern Medical Center, University of Illinois, and Great Lakes NeuroTechnologies. Dr. Bohnen has research support from the NIH, Department of Veteran Affairs, and the Michael J. Fox Foundation. Dr. Seidler receives grant support from NIH, NASA, NSBRI, and the Michigan Parkinson’s Foundation.

Financial Disclosure Statement: Daniel Schonfeld has no financial disclosures. Dr. Kwak has no financial disclosures.

Author Contributions

Mr. Schonfeld – review design, collecting articles, and writing

Dr. Kwak – review design and writing

Dr. Bohnen - review design, obtaining funding, collecting articles, and writing

Dr. Seidler - review design, obtaining funding, collecting articles, and writing

• Open access
• Published: 30 May 2024

Treating depression in patients with borderline personality disorder: clinical clues on the use of antidepressants

• Carmine Tomasetti 1 ,
• G. Autullo 2 ,
• A. Ballerini 3 ,
• A. de Bartolomeis 4 ,
• B. Dell’Osso 5 ,
• A. Fiorentini 6 ,
• F. Tonioni 7 ,
• V. Villari 2 &
• D. De Berardis 8  

Annals of General Psychiatry volume  23 , Article number:  21 ( 2024 ) Cite this article

Metrics details

Personality disorders (PD) are described as enduring patterns of markedly deviant and pervasive inner experiences and behaviors, with onset in adolescence, which lead to severe distress or impairment. Patients suffering from major depressive disorder (MDD) display higher rates of comorbidity with personality disorders, often complicating the treatment, and worsening the outcomes. Borderline personality disorder (BPD) is the most common of PD and is frequently associated with MDD, with which shares several features. The most part of research agrees on the fact that comorbid BPD in MDD patients quite doubles the poor response to treatments. Moreover, no treatment strategy stands out currently to emerge as more effective in these cases, thus urging the call for the need of new approaches. Herein, we revise the current literature on BPD, its neurobiology and comorbidity with MDD, as well as the more recent treatment strategies used. Then, based on its pharmacology, we propose a possible role of trazodone as a valuable tool to approach comorbid BPD-MDD.

Introduction

Major Depressive Disorder (MDD) is a leading contributor to global burden of disease, being considered as a major cause of disability worldwide, with approximately 3.8% of population affected and over 700.000 people dying of suicide every year [ 1 ]. Despite multiple treatment strategies have been developed, MDD remains a serious challenge for psychiatrists, since approximate 30% of patients do not adequately respond to therapies. The largest MDD trial, the so-called STAR*D (Sequenced Treatment Alternatives to Relieve Depression), demonstrated that, even after 4 consequential steps of treatment, the cumulative remission rate reached 67% after 14 months [ 2 ].

Since MDD is a heterogeneous disorder, multiple reasons have been put forward to support these high rates of treatment resistance: misdiagnosis (e.g., bipolar depression, or mixed states); comorbid substance use; untreated medical conditions (e.g., dysthyroidism); undiagnosed underlying traumata (i.e., post-traumatic stress disorder); cognitive impairment (i.e., neurocognitive disorders) [ 3 ].

In addition to the above-mentioned contributors, a large body of evidence points out the essential role of underpinning and/or understated personality disorders (PD) in the scarce responsivity of MDD to treatments. PDs comorbidity has been recognized in almost half of MDD patients in different meta-analyses [ 4 , 5 ]. Indeed, the pervasive symptoms of PDs, such as low self-esteem, self-criticism, mood instability, feeling of emptiness or hopelessness, suicidal thoughts or behaviors, may all represent substantial contributors to worsen or complicate depression, or even to make depressive symptoms persistent and resistant [ 6 ]. Several studies have examined the relationships amongst personality disorders traits and the quality, the severity, and the outcomes of MDD [ 7 , 8 ]. Personality disorders have been correlated to earlier onset of MDD, to specific subtypes of depression (melancholic vs. non melancholic depression) [ 5 ], as well as to severer symptoms (i.e., suicidal behaviors, self-harming, impaired cognition), and poorer outcomes (e.g., greater resistance to pharmacological and non-pharmacological treatments) [ 9 ]. Thus, the frequent association between PDs and MDD poses the classical question whether came first the chicken or the egg, since from a psychological point of view some predisposing risk factors may be associated to both the conditions [ 10 ]. Moreover, given this entangled relationship, a diagnostic issue should be considered, when assessing a patient with MDD; but, more important, a complete revision of therapeutic approaches to the treatment of depression should be contemplated, based on the possible influence of underlying preponderant personality traits in depressed patients.

In the next sections, we will consider the impact of the most devastating PD, the Borderline Personality Disorder, on MDD, and we will discuss the possible revision of classical antidepressant treatments in the light of an integrated neurobiological-psychological approach to MDD therapy.

The influence of comorbid Borderline Personality Disorder on Major Depressive Disorder

Borderline Personality Disorder (BPD) is described in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, text revision 2022, (DSM-5-TR) [ 11 ] as a “pervasive pattern of instability of interpersonal relationships, self-image, and affects, and marked impulsivity, beginning by early adulthood and present in a variety of contexts”. Sensation of abandonment, unstable relationships, identity disturbances, impulsivity, recurrent suicidal behaviors, affective instability, feelings of emptiness, anger and, occasionally, transient dissociative or psychotic symptoms during periods of distress may be all features of BPD. All these features can be grouped in three main categories (“factors”, according to DSM-5-TR): disturbed relatedness, behavioral dysregulation, and affective dysregulation; all of these being strongly correlated with each others, thus representing a unique construct, although with broad and pleiotropic manifestations [ 12 ]. BPD is the most common PD, with a reported prevalence of 10% in all psychiatric outpatients [ 13 ], and 5.9% in non-clinical population [ 14 ]. Moreover, the most part of BPD patients seem not to access psychiatric care, but they represent a significant part of primary care patients, since BPD has been described as four-times more prevalent amongst general practitioners’ costumers as compared to general population [ 15 ].

Several studies have reported a high frequency of co-occurrence between BPD and MDD, since 83–85% of BPD patients have been described to suffer from MDD episodes, with high recurrences [ 16 , 17 , 18 ]. Moreover, amongst PDs, BPD seems to have the highest correlation with both genetic and environmental risk factors of MDD [ 19 ].

Manifold studies have tried to dig up the intrinsic connections between BPD and MDD, and just as many theories and models have been developed, with the precise aim to improve diagnosis and therapy of these disorders, above all when comorbid. Personality has been characteristically described as a dynamic construct of two main components: temperament, the biologically-based structure of emotion regulation, and character, which instead is modulated by social relations [ 20 ]. According to the Five Factors Model (FFM), personality traits may be taxonomically subdivided in five principal characteristics, the so-called Big Fives: neuroticism, extraversion, conscientiousness, agreeableness, and openness to experience. Given the hierarchical relationships amongst these factors, they may be further grouped in two big clusters: positive emotionality and negative emotionality [ 21 ]. There is increasing evidence that, although personality traits have solid genetical and biological bases, they are not rigid constructs, but may be dynamically modulated by development and life experiences [ 22 ]. Psychologically, MDD is characterized by a substantial deficiency in positive emotionality, with a prevalence of negative emotions, such as sadness, guilt, shame, anhedonia, depressed mood, and numbness (i.e., the inability of feeling feelings) [ 23 ]. However, it is not rare that MDD patients may manifest irritability, anger, hostility, which are all factors often correlated to self-harming or suicide [ 24 , 25 ]. By contrast, the whole symptomatologic cortege of BPD is mainly hinged on impulsivity traits, with emotional dysregulation, anger, dyscontrol, dysphoria, self-harming, and hostility [ 26 ]. Nevertheless, some typical features of BPD may resemble those seen in MDD patients, such as the feeling of emptiness, sadness, loneliness of hopelessness [ 27 ].

Therefore, BPD may add an “impulsivity color” to MDD symptoms framework, when the two disturbs manifest comorbidly. Different studies, indeed, reported that BPD patients experiencing MDD show increased levels of anger, fear, and hostility [ 28 ], as well as they manifest considerably higher impulsivity than MDD-only patients [ 29 ]. Moreover, BPD patients diagnosed with MDD tend to describe their depressive symptoms as more serious as compared to MDD-only patients, even severer than those objectively assessed by physicians [ 30 , 31 ].

Notably, BPD has been demonstrated to show significant comorbidity also with Bipolar Disorder (BD). Indeed, by analyzing data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), McDermid et al. found that the lifetime prevalence of BPD was about 29% in BD type I and 24% in BD type II, and that comorbid BPD-BD had severer presentation as compared to BD alone [ 32 ]. Successive studies confirmed that BPD may represent a risk factor for BD, and remarked the negative impact of BPD in BD, such as the higher prevalence of suicidality and the treatment-resistance [ 33 ]. Moreover, about 40% of MDD-diagnosed patients have been reported to have a history of subthreshold hypomania symptoms, this subgroup showing earlier onset and more episodes of depression, as well as more comorbidities as compared to non-hypomanic patients [ 34 ]. Last, MDD episodes where psychomotor agitation and racing thoughts are found (the so-called “agitated depression”) have been robustly associated to mixed states, unfavorably predicting the emergence of suicidal ideation and contraindicating antidepressant therapy [ 35 ]. This tight intermingling between hypomanic symptoms, MDD, and BPD may challenge the dichotomic vision of unipolar-bipolar depression, suggesting a more comprehensive “mood spectrum” diagnostic approach [ 36 ].

Thus, it is possible that the inherent “bipolarity” of BPD may colorize MDD with unstable emotional traits, lending this disorder an increased resistance to treatments, as compared to MDD alone. The Collaborative Longitudinal Personality Disorders Study (CLPS) analyzed the longitudinal course of BPD patients, as compared to other PDs and MDD-only patients [ 37 ]. Amongst the other interesting results, CLPS reported that 80% of BPD patients assessed had MDD, and that MDD-only patients showed a remission rate dramatically faster (80% by 1 year) as compared to BPD patients (30% by one year), thus indicating how much BPD comorbidity may influence MDD outcome. These results have been confirmed by the National Epidemiological Study of Alcoholism and Related Disorders, which reported that BPD was the major predictor of persistent MDD [ 38 ]. The McLean Study of Adult Development (MSAD) further demonstrated that, when BPD and MDD coexist, the remission of MDD strictly depends upon the remission of BPD symptoms [ 39 ], thus confirming a previous landmark study, in which an improvement in MDD symptoms was found when treating BPD symptoms, but not vice versa [ 40 ]. However, the mainstay treatment for MDD, antidepressant drugs, have been demonstrated to promote only partial responses in MDD-BPD patients [ 39 ]. Thus, there is a peculiar tendence to poly-treat BPD patients, which have been described to averagely take three-to-five medications, an over-prescription that could be only reduced by a BPD-specific psychotherapy regimens [ 41 ]. Also, non-pharmacological treatments, such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) have demonstrated partial efficacy in treating comorbid MDD and BPD [ 42 , 43 ]. Therefore, it appears rather obvious that the treatment of MDD in course of BPD relies on an efficacious BPD treatment. Hence, some specific psychotherapy regimens, such as Dialectical behavioral therapy (DBT) have demonstrated a good efficacy in improve MDD symptoms by improving BPD [ 44 ].

So, is there a biological basis on which the BPD-induced MDD treatment-resistance relies? And, in the light of this possible underlying basis, should it be possible to reconsider a targeted pharmacological approach to help reducing the impact of BPD on MDD?

Digging in the deep: the neurobiological bases of BPD and the underpinnings of comorbid MDD

Although BPD has been classically envisioned as a complex multifactorial disorder, in which environmental risk factors (e.g., traumata, abuses, neglect) seems to be preponderantly responsible for its development [ 45 ], increasing evidence has been pointing out the essential role of the genetic factors underlying the specific personality traits at the basis of the disorder. Indeed, twin studies have demonstrated that BPD has a heritability ranging from 46 to 69% [ 46 , 47 ]. Recently, different genome-wide association studies (GWAS) have been performed, in order to study genetic association of the “Big Five” factors of FFM with PDs in general population. BPD was found closely associated with personality traits of neuroticism and openness [ 48 ], and, more interestingly, it was reported to share positive genetic correlations with MDD, Bipolar Disorder and Schizophrenia [ 49 ]. As above-mentioned, BPD represents a unique construct intermingling specific personality traits, such as disturbed relatedness, behavioral and emotional dysregulation. However, despite the manifold researches stating the large heritability of BPD, only a few genetic studies exist, which tried to correlate these personality traits to specific gene dysfunctions. As previously mentioned, Witt and collaborators found a significant overlap of BPD-associated genes with those associated to MDD, Bipolar Disorder and Schizophrenia [ 49 ]. Two genes reached genome-wide significance: dihydropyrimidine dehydrogenase (DPYD) and Plakophilin-4 (PKP4). DPYD is implicated in pyrimidine metabolism and contains a binding site for the micro-RNA miR-137, which has been found associated to Schizophrenia [ 50 ]. PKP4 is involved in the regulation of cell adhesion and cytoskeletal modifications, which have been substantially implicated in cell junction deficits associated to MDD [ 51 ]. Previously, Lubke et al. have described a specifical association of BPD with the serine incorporator 5 gene (SERINC5), which seems to have a peculiar role in myelination, and has been involved in the development of psychiatric disorders characterized by lack of social interactions [ 52 , 53 ]. Finally, a genome-wide linkage study found a significant association of BPD features with chromosome 9 loci, which have been significantly associated also to Bipolar Disorder and Schizophrenia [ 54 ].

Given the essential role of environment in BPD development, it is not surprising that a large number of studies have reported abnormalities in BPD in epigenetic modifications, which are considered the “portal” through which environment may impact gene expression changes, via DNA methylation, histone deacetylation and non-coding RNA silencing [ 55 ]. Altered methylation of specific genes, such as dopamine D2 receptors, serotonin 3A receptors, glucocorticoid receptors and brain-derived neurotrophic factor (BDNF) receptors have been all associated to BPD [ 56 , 57 , 58 , 59 ]. It is interesting to note that these alterations may be directly correlated to the severity of childhood abuse in BPD patients [ 60 ], as well as to the intensity of depressive symptoms, and may be reinstated by specific psychotherapy regimens [ 61 ].

As already discussed, the core symptoms of BPD rely on a substantial emotional dysregulation. Different studies reported altered emotional interoception in BPD patients, the so-called alexithymia (i.e., “no words for emotions”): while their amygdaloid system highly responds to negative emotions, they have a blunted self-report of the experienced emotions [ 62 ]. This may be due to an altered regulatory control of amygdala-based emotion system: indeed, BPD patients have been described to have altered connections between prefrontal cortex and amygdala, thus probably having an impaired top-down emotional modulation [ 63 ]. Moreover, both substance use, and dissociative episodes have been reported to dampen the hyperactive emotional responses in BPD patients, thereby explaining the frequent comorbidity of BPD with substance use disorder (SUD), as well as the higher frequency of dissociative experiences in BPD patients [ 64 , 65 ]. Interestingly, altered amygdaloid responses and neuroplasticity have been demonstrated in MDD patients [ 66 ]. Moreover, a particular kind of treatment-resistant depression, called “dissociative depression”, has been characterized as frequent in younger patients with childhood traumata, and is defined by the higher frequency in dissociative episodes, as well as by its chronicity, mood instability, and often by comorbid BPD [ 67 ]. Finally, SUD is frequently diagnosed also in MDD patients, and some etiopathogenetic models propose that substances may help depressed patients to cope with their altered affective states [ 68 ].

Besides emotional dysregulation, as previously mentioned, BPD patients experience an essential disrupted relatedness, with interpersonal sensitivity leading to social difficulties.

Several studies have associated BPD social dysfunctionality to altered opioidergic and neuropeptidergic neurotransmission. Primarily, opioidergic neurotransmission is correlated in humans with pain responses. Increasing evidence suggests that µ-opioid receptors may mediate both sensory and affective dimension of pain, in different cerebral regions [ 69 ]; moreover, pain may be literally perceived in social exclusion and rejection by means of µ-opioid mediation in brain [ 70 , 71 ]. BPD patients have been demonstrated to possess a lower sensitivity to acute pain, but a heightened sensitivity to chronic pain [ 72 , 73 ]. This altered sensitivity to pain may be essentially due to an abnormal µ-opioid transmission: indeed, BPD patients have been demonstrated to possess a greater number of cortical µ-opioid receptors, probably due to a scarce baseline opioidergic transmission, with altered and enhanced compensatory opioid responses to acute stimuli [ 74 ]. Besides its primary role in pain responses modulation, µ-opioid neurotransmission has been associated to the right development of attachment behaviors in mammals [ 75 , 76 ]. Interestingly, altered µ-opioid gene expression has been found in adolescents prone to develop MDD reactions to social rejection life events [ 77 ].

Oxytocinergic neurotransmission has been also found abnormal in BPD patients, which were reported to have lower levels of oxytocin as compared to healthy individuals, these levels being correlated with childhood traumata and disrupted attachment [ 78 , 79 ]. Moreover, while in healthy subjects oxytocin administration usually enhances social behaviors, in BPD patients it may provoke counterintuitive aversive behaviors, especially correlated to history of childhood traumata [ 80 ]. Last, genetic alterations in oxytocin receptors have been directly correlated to the development of BPD in abused children [ 81 , 82 ]. The increasing evidence of a substantial role of oxytocin in the etiopathogenesis of MDD, as well as in its possible treatments, represents a further bridge between BPD and MDD [ 83 , 84 ].

Monoaminergic neurotransmission has been implicated in personality since long ago. Particularly, personality dimensions as described by Cloninger, and later by the FFM, may be directly linked to dopaminergic, serotonergic, and noradrenergic neurotransmissions [ 85 , 86 , 87 ].

Dopamine dysfunctions, for example, have been associated to three specific dimensions of BPD: impulsivity, emotional dysregulation, and cognitive impairment [ 88 ]. Specific genetic polymorphisms of the dopamine transporter gene (DAT1) have been peculiarly associated with increased risk of BPD in MDD patients [ 89 ]. Moreover, the same polymorphism has been associated to angry-impulsive traits in comorbid BPD-MDD patients [ 90 ]. On the other hand, both serotonin transporter (5HTT) and serotonin A1 receptor (5HT1A) genes have been associated with BPD [ 91 , 92 ]. Specifically, 5HT1A gene alterations have ben correlated to abnormal amygdala structure and emotional responses in BPD-MDD comorbid patients [ 91 ]. Serotonin alterations seem to be tightly correlated to the “impulsivity color” of MDD, when comorbid with BPD, as well as with an increased risk of suicide [ 93 , 94 ]. Recent studies demonstrated that serotonin and dopamine neurotransmissions closely interact in defining the personality traits underlying BPD, and the simultaneous presence of both dysfunctions may interplay in favoring the risk of BPD development [ 95 ]. Norepinephrine, along with cortisol, has been associated to dissociative responses in BPD [ 96 ].

Targeting depression in BPD: clinical clues on the use of antidepressants. Focus on trazodone

BPD patients, with their pleiotropic symptomatologic manifestations, represent a huge burden for health systems. In fact, as above mentioned, BPD is frequently associated to coexisting psychiatric disorders, above all MDD, anxiety, substance use, and it is as much as frequently misdiagnosed [ 97 ]. Due to their comorbidities, as well as to their over-endorsement of symptoms, BPD patients often tend to self-medicate (even with substances) or to access primary cares, where they are not often understood and well-treated [ 98 ]. Although BPD patients have been described to have good chances to remit over the long period [ 99 ], during the trajectory of the disorder, they have frequent relapses and serious outbursts, which lead to multiple accesses to mental health services for specialized cares or hospitalizations [ 100 ].

All the most recent guidelines for the treatment of BPD seems to agree on the fact that a specific regimen of psychotherapy should be the first line treatment, whereas medications should be used with caution for intense and disruptive symptoms during decompensation acuity, and only for the shortest possible time [ 101 , 102 , 103 , 104 ]. However, while European guidelines—which include NICE (National Institute for Health Care and Excellence) ones—suggest to pharmacologically treat only comorbid disorders in BPD [ 103 , 104 ], APA (American Psychiatric Association) and WFSBP (World Federation of Societies of Biological Psychiatry) suggest using specific classes of medications to treat specific symptom domains [ 101 , 102 ]: thus, antidepressants should be be used to treat emotional dysregulation and impulsivity, similarly to mood stabilizers, while antipsychotics should be used for dissociative and cognitive-perceptual symptoms.

Although scarce evidence exists on the efficacy of antidepressant treatments in BPD, SSRIs (Selective Serotonin Reuptake Inhibitors) are currently the most prescribed medications [ 105 ]. The most part of RCTs examining the efficacy of antidepressants in BPD are outdated, and they have not been replicated since 2010. The main antidepressants for which data are available in the treatment of BPD are: fluoxetine, fluvoxamine, sertraline, amitriptyline, phenelzine, venlafaxine, mianserin. A Cochrane review [ 106 ] reported that antidepressants had no significant effects on the overall BPD severity; no beneficial effects were noticed on impulsivity, as well as on suicidal behaviors, whereas a worsening of suicidal ideation was noticed with fluoxetine; affective instability was slightly ameliorated by fluvoxamine, while no significant effects were noticed for self-harming, feeling of emptiness, anger; the only significant effects on depression were found with amitriptyline.

Similar results were obtained in a comparative meta-analysis by Vita et al. [ 107 ], with a documented, although slight, effect of antidepressants only on affective dysregulation.

Significant results have been achieved on MDD comorbid to BPD when antidepressants were combined to mentalizing psychotherapies (DBT, IPT [Interpersonal Psychotherapy]) [ 108 , 109 ].

It is worth noting that all the antidepressant drugs chosen to be tested in BPD patients, as above described, were selected based on their well-documented efficacy on MDD, which is primarily due to serotonergic effects (i.e., serotonin re-uptake inhibition), with generally scarce impact on other neurotransmitters, such as dopamine or norepinephrine [ 110 ]. On the other hand, the most significant effects in reported RCTs were obtained by means of antidepressant drugs that involved more than the sole serotonin neurotransmission, such as phenelzine, amitriptyline and fluoxetine, or even by combined treatments (e.g. fluoxetine plus olanzapine), which were able to control—although slightly—the core affective/emotional instability, which is the typical signature of BPD [ 106 ].

As above described, BPD core depressive symptoms have been hypothesized to involve multiple neurobiological substrates, such as opioidergic and oxytocinergic neurotransmission, and specific monoamine receptors, such as dopamine D2 and serotonin 2A receptors, which interplay with each others to generate the symptoms of comorbid MDD-BPD. Thus, a more targeted pharmacological approach might help to relieve, if only partially, depressive symptoms in BPD.

In this light, a revision of “old” antidepressant treatments, relying on the enhancement of their possible efficacy, based on their peculiar pharmacodynamic properties, might represent a valuable approach. According to this view, trazodone may be a useful tool to address the unmet needs of MDD in BPD.

The history itself of trazodone appears intriguing, if envisioned in the light of the abovementioned neurobiological underpinnings of BPD. Indeed, it is a triazolopyridine derivative, which was developed in 1960s in Italy based on the “mental pain” hypothesis of MDD, correlating depressive states to altered pain interoception [ 111 ]. Along with nefazodone, trazodone represents the prototype of the so-called serotonin antagonist/reuptake inhibitor antidepressants (SARIs). It is a powerful antagonist at 5HT2A serotonin receptors, which are bound already at low doses, together with alpha1- and alpha2- adrenergic receptors and H1 histamine receptors, thus exerting potent anxiolytic and sedative/hypnotic effects at these doses [ 112 ]. Trazodone also weakly binds the serotonin transporter (SERT), 5HT2B and 5HT2C serotonin receptors, even if it is not clear if it acts as a full agonist, a partial agonist or an antagonist at these last receptors [ 112 ]. Another peculiar characteristic is the strong binding to 5HT1A serotonin receptors, where it acts as a partial agonist with high intrinsic activity [ 113 ]. Moreover, trazodone has an active metabolite, the meta-chlorophenylpiperazine (mCPP), which is known to exert pro-serotonergic psychoactive functions similar to fenfluramine and MDMA (“ecstasy”), in addition to being a well-recognized agonist to multiple serotonin receptors (e.g., 5HT1A, 5HT1B, 5HT1D, 5HT2A, 5HT2B, 5HT2C, 5HT3, and 5HT7 receptors) [ 114 , 115 ]. Thus, trazodone shapes up to be a peculiar multimodal antidepressant, which may exert differential functions at different doses. In fact, the progressive recruitment of serotonin receptors—in particular 5HT2A and 5HT1A—at incremental dosages has been described to exert incremental antidepressant effects by means of multiple—and not completely understood-- mechanisms: (1) 5HT1A receptors activation may mediate some neurotrophic factors’ genes expression, which has been associated to antidepressant actions; (2) 5HT1A receptors may progressively inhibit glutamate release from cortical pyramidal neurons, whose hyperactivity has been implicated in cognitive symptoms of MDD; (3) 5HT2A and 5HT2C serotonin receptors blockade has been associated to the increase in dopamine and noradrenaline cortical release, which are complementary to serotonin in relieving depressive symptoms [ 112 ].

Currently, trazodone is marketed in three different formulations: immediate release (IR), prolonged release (PR), and once-a-day extended release (OAD). Trazodone IR has a rapid plasma peak (1 h) and a short half-life (6.6 h); trazodone PR has a slower plasma peak (4 h) and a longer half-life (12 h), and trazodone OAD shows a plateau plasma level for the entire day, with longer antidepressant concentration as compared to the other formulations [ 113 ]. A large amount of data supports the fact that trazodone has similar efficacy to all the other antidepressants when compared to placebo [ 116 ]. Moreover, the OAD formulation has been described to grant a higher antidepressant efficacy than a placebo with a once-a-day administration, with side effects comparable to other antidepressants [ 117 ]. Finally, trazodone displays high tolerability, even when administered in patients with comorbid clinical conditions, thus granting a safety profile in poly-pharmaco-treated patients [ 118 ].

Several characteristics of trazodone may let lean forward its valuable use in comorbid BPD-MDD patients.

As previously described, the concurrent blockade of 5HT2A/2C receptors and of SERT, the partial agonist activity at 5HT1A receptors, and the antagonism at 5HT7 receptors may boost the antidepressant action of trazodone by increasing serotonin postsynaptic action and the subsequent disinhibition of dopamine and noradrenaline cortical release, together with glutamate-modulated neurotrophic factors’ gene expression [ 112 , 119 ]. Indeed, some studies have described the rapid onset of trazodone antidepressant effects. Sheehan et al. [ 117 ] demonstrated that trazodone OAD (150-225 mg/day) may induce a substantial reduction in depressive symptoms within a week of treatment, and that these effects may persist until 56 weeks. Fagiolini et al. [ 120 ] reported a faster antidepressant response (within 7 days) in patients treated with trazodone OAD (150 mg/die) as compared to venlafaxine XR (75 mg/die). This faster antidepressant effects of trazodone were not only exerted, as mainly expected, on the sleep component of depressive symptoms, but also on the cognitive aspects of depression [ 121 ].

The rapid antidepressant action of trazodone could be really useful during the fast emotional outbursts of BPD patients, which often lead to hospitalization. Peculiarly, this fast action seems not to be accompanied by a heightened risk of suicidal behaviors, even in high-risk patients treated with trazodone [ 122 ].

Trazodone has been demonstrated to exert antinociceptive effects even at low dosages, possibility via a µ-opioid receptors-mediated mechanism [ 123 , 124 ]. These properties may be helpful in manage the altered pain interoception of BPD patients—their “mental pain”—, as well as in treating their susceptibility to auto-medication with analgesics or substances. Indeed, diverse studies provided evidence of a good efficacy of trazodone in the treatment of alcohol, benzodiazepines, and opioid abuse [ 125 , 126 ].

The off-label clinical use of trazodone as hypnotic is well-established [ 126 ]. Some BPD patients have been described to have particularly disrupted sleep, with frequent nightmares, which in turn have been correlated to an increased risk of dissociative experiences and suicidal behaviors [ 127 ], above all if related to childhood traumatic events [ 128 ]. Trazodone has been demonstrated to be particularly effective in improving the quality of sleeping and reducing nightmares in post-traumatic stress disorders-affected war veterans [ 129 ].

Conclusions

BPD is a devastating personality disorder, with multiple symptomatologic presentations, and often comorbid with mood disorders, particularly with MDD, thereby making it substantially treatment resistant. SSRIs have been demonstrated to be scarcely efficacious on BPD-MDD patients. However, the neurobiological underpinnings of BPD may suggest that a more targeted antidepressant approach may helpful in relieving BPD-MDD coexisting symptoms. Since its multimodal action on serotonin, dopamine, noradrenalin, opioid and glutamate neurotransmissions, as well as its incremental effectiveness, trazodone seems to embody all the characteristics which may make it a clinical valuable tool to be used in BPD-MDD patients. More specifically designed studies are warranted to corroborate these clinical clues.

Data availability

No datasets were generated or analysed during the current study.

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Carmine Tomasetti

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G. Autullo & V. Villari

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Tomasetti, C., Autullo, G., Ballerini, A. et al. Treating depression in patients with borderline personality disorder: clinical clues on the use of antidepressants. Ann Gen Psychiatry 23 , 21 (2024). https://doi.org/10.1186/s12991-024-00507-z

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Received : 28 January 2024

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DOI : https://doi.org/10.1186/s12991-024-00507-z

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