TERMINOLOGY

1. MONOZYGOTIC (MZ) TWINS: Also known as identical twins, they originate from a single fertilised egg (zygote) that splits into two embryos. MZ twins share 100% of their genetic material, making them valuable in studies exploring the genetic basis of traits or disorders, as any differences between them are primarily due to environmental factors.

2. ALLELE: An allele is a variant form of a gene. Different alleles can result in different traits, such as eye colour or blood type. In the context of genetic disorders, specific alleles may carry a risk for conditions like schizophrenia.

3. DIZYGOTIC (DZ) TWINS: Also known as fraternal twins, they develop from two separate eggs fertilised by two different sperm. DZ twins share about 50% of their genetic material, similar to regular siblings. Comparing the concordance rates of a trait in MZ and DZ twins helps researchers understand the genetic versus environmental contribution to that trait.

4. CONCORDANCE RATE: This is the probability that both individuals in a pair (such as twins or family members) will display a particular trait or disorder if one of them does. In genetic research, a higher concordance rate in MZ twins compared to DZ twins suggests a stronger genetic influence on the trait or disorder.

5. FAMILY STUDY: This type of study examines the prevalence of a specific trait or disorder within a family. It helps determine whether close relatives of individuals with a condition, like schizophrenia, have a higher risk of developing the same condition, indicating a possible genetic component.

6. PEDIGREE: A pedigree is a diagram that shows the occurrence and appearance of a particular trait within a family over multiple generations. It is used to track the inheritance patterns of genetic conditions and can help identify whether a disorder is likely to be monogenic (caused by a single gene) or polygenic (influenced by multiple genes).

7. MONOGENIC: Refers to traits or disorders caused by a mutation in a single gene. Monogenic disorders often follow simple inheritance patterns, such as dominant or recessive. Examples include Huntington's disease and cystic fibrosis. Schizophrenia is not considered monogenic, as it does not result from a mutation in just one gene.

8. POLYGENIC: Refers to traits or disorders that are influenced by multiple genes, each contributing a small effect. Schizophrenia is considered polygenic, involving many genetic variations spread across the genome, along with environmental influences.

9. META-ANALYSIS: A statistical method that combines the results of multiple independent studies on a particular topic to provide a more comprehensive understanding. In genetic research, a meta-analysis can pool data from various studies to better estimate the genetic risk factors associated with disorders like schizophrenia

GENETIC THEORY INTRODUCTION

Schizophrenia is a serious mental illness, which causes great distress to its sufferers and family. Many attempts have been made to find its cause so that successful treatment and preventative measures can be applied.

One of the main theories of schizophrenia is that it has a strong genetic component.

METHODS OF GENETIC RESEARCH
To gain further insights into the heritability and risk factors of schizophrenia, researchers use various methods such as pedigree analysis, family studies, and twin studies. These approaches help explore how both genetic and environmental factors contribute to the disorder.

RESEARCH USED IN THIS ESSAY SCHIZOPHRENIA

FINDING THE SCHIZOPHRENIC GENE

Early genetic research sought to identify a single gene or a few genes responsible for the disorder, a concept known as the "monogenetic" theory. However, extensive studies have since ruled out this possibility. Behavioural genetics expert Robert Plomin notes that, apart from a handful of conditions like Alzheimer's disease and Huntington's disease, no single gene has been identified as playing a critical role in any mental illness, including schizophrenia. He suggests that there is no clear evidence that individuals with schizophrenia have distinct genetic material that significantly differs from those without the disorder. Moreover, according to Plomin, without pinpointing specific genes, it remains difficult to understand how genetic risk translates into schizophrenia symptoms.

POLYGENIC THEORY OF SCHIZOPHRENIA
The current understanding of schizophrenia and most mental illnesses is that they are not linked to just one or two genes. Instead, schizophrenia is considered a "polygenic" disorder, meaning it is influenced by many genes, each contributing a small effect. Therefore, the risk of developing schizophrenia is spread across thousands of common genetic variations (known as common alleles) and a few rare, high-impact variants.

Large-scale studies, like genome-wide association studies (GWAS), have identified multiple genetic risk loci throughout the human genome. This research indicates that numerous small genetic factors, in combination with environmental influences, shape the risk of schizophrenia.

Some of the key genes and pathways involved in schizophrenia affect brain development, synaptic transmission (communication between nerve cells), neuronal signalling, and immune system function. This diversity suggests that schizophrenia is not a single disease but a spectrum of conditions influenced by various genetic and biological factors.

CRITICISMS OF THE POLYGENIC MODEL A03
Despite advances in understanding schizophrenia's polygenic nature, the model faces several criticisms:

• Lack of Specific Causal Pathways: With thousands of genes involved, each with a small effect, identifying how these variations directly cause schizophrenia is challenging. Critics argue that the polygenic model is too broad and lacks the specificity needed to guide treatment or diagnosis effectively.

• Diagnostic Difficulties: The polygenic model blurs the lines between schizophrenia and other mental health conditions, such as bipolar disorder and depression, as many genetic risk factors overlap. This overlap raises questions about the accuracy of current diagnostic categories.

• Clinical Application Challenges: While many risk genes have been identified, applying this information in clinical practice remains difficult. Since each genetic factor contributes only a small amount of risk, predicting who will develop schizophrenia based solely on genetics is unreliable.

• Overemphasis on Genetics: Focusing primarily on genetic factors can overlook the crucial role of non-genetic influences, like social environment, trauma, and lifestyle. Schizophrenia's development involves a complex interaction between genetics and these factors, suggesting the need for a more holistic approach to management and prevention.

FAMILY STUDIES

Another common way to investigate genes is to study the frequency of schizophrenia in family members, i.e., to see if a positive correlation coefficient for schizophrenia increases with relatedness. Zimbardo, 1987 and Gottesman, 1991 meta-analysed the concordance rates of schizophrenia in 1st, 2nd, and 3rd-degree relatives. Their data was collected from European countries between 1920 and 1987.

Their results are summarised below.

ZIMBARDO AND GOTTESMAN’S META-ANALYSIS F FAMILY STUDIES WITH SCHIZOPHRENIA

The meta-analyses show the following concordance rates: There is a 1 per cent chance that any person in the population could develop schizophrenia, Siblings have a 7-9 per cent concordance rate, Monozygotic (MZ) twins have a 44% - 48% concordance rate for developing the disorder compared to a 12- 17% concordance in Dizygotic (DZ) twins.

Proponents of the genetic model believe the above research findings show that the closer the genetic relatedness, the higher the risk for developing schizophrenia. Of special relevance is the 31% discrepancy between DZ and MZ twins’ concordance rates, which can be interpreted as evidence for genes as MZ twins are genetically identical.

Moreover, Gottesman’s 2010 study shows that children with two parents who have schizophrenia (they inherit two sets of faulty DNA) constitute a super-high-risk sample of psychosis. This implies a strong role of genetics when explaining schizophrenia.

ANALYSIS OF FAMILY STUDIES RESEARCH IN SCHIZOPHRENIA

Overall, there are many problems with using family and twin studies, including Gottesman, 2010.

Firstly, they are often retrospective and therefore unreliable because they cannot be checked; for example, we cannot go back to 1920 when the data was first collected and check if a person has schizophrenia by current definitions of DSM and ICD. This means the internal validity is undermined, and less credibility can be determined from the results.

Furthermore, the higher concordance in MZ twins does not necessarily mean genetics; MZ twins may be treated more alike than DZ twins and siblings because MZ twins are harder to tell apart and are always of the same gender. DZ twins’ studies rarely control for gender. This means we cannot be certain the higher concordance is down to genes.

More importantly, though, cause and effect are difficult to establish with this method as similarities in concordance may be due to the environment. Significantly, geneticists have failed to account for why fifty-two per cent of MZ twins do not get schizophrenia. Why don’t they? If schizophrenia is transmitted genetically, there should be a hundred per cent concordance rate in MZ twins! It is feasible that the relatives of Schizophrenics develop the disorder more often because they are exposed to the same environmental influences.

Especially relevant to this nature-nurture argument is Gottesman’s assumption that the 27-39% concordance rate for children with two schizophrenic parents is genetic.  As Tienari showed, children of schizophrenics are often adopted away because of the profound influence of their parent’s disorder on their cognitive and emotional development. Studies on Romanian orphans (Rutter) show that neglect and abuse can have permanent effects on emotional well-being if the child is adopted later than six months of age. This may be because negative experiences and lack of stimulation are hard-wired into the brain as a form of negative plasticity - if the damage happens during critical periods of early development. Indeed, many psychologists (R.D Laing, Oliver James) claim that living with a schizophrenic must be incredibly stressful and confusing to children as schizophrenics have greatly impaired cognition, language, and emotions. Furthermore, delusions and hallucinations might be frightening. It is, therefore, logical to propose that the child of a Schizophrenic would not be able to have rational conversations or expect support when the disorder is active. A parent(s) mental illness may cause mental illness in their children.  Environment and genes are impossible to untangle.

A closer inspection of some of the other concordance rates also suggests nurture is causal rather than nature. For instance, the concordance rates of dizygotic (DZ) twins and normal siblings. Dizygotic twins are no more similar genetically than normal siblings, yet they have a much higher concordance rate (roughly, 17% compared to 9%). If schizophrenia was purely genetic, then DZ twins and normal sibling’s incidence of schizophrenia should be identical as they both only share 50% of their DNA.

DZ twin’s higher concordance rate could be interpreted as environmental and/or psychological then because as DZ twins live in the same zeitgeist they are more likely to assess their social and emotional world from the same level of maturity. For example, parents arguing may be perceived negatively by an older sibling and remain unnoticed by a younger sibling but DZ twins may conclude similar disturbed observations about their parent’s relationship simply because they are the same age. Moreover, family dynamics/hierarchies continually change (e.g., things like family economics, job satisfaction, being the oldest, youngest, family stresses/illness) and thus may be interpreted differently to siblings of differing ages.

SEPARATED MZ TWIN RESEARCH

Separated twin studies offer a way of separating nature and nurture as if both twins are concordant for schizophrenia, then their environment cannot be blamed. Gottesman and Shields, 1982 have shown that the concordance rate of schizophrenia for twelve pairs of MZ twins reared apart was 58% (7 out of 12 twins) despite differing environments. This percentage is even higher than for MZ twins reared together.

A03 RESEARCH ANALYSIS ON SEPARATED MZ TWINS

Very few separated twin studies were conducted (as separated MZ twins are so difficult to find), so generalisability may be an issue. And 12 twin pairs are not enough samples for inferential statistics and thus probability calculations. And why were the twins separated? Wouldn’t events leading up to the separation of twins have been traumatic? Also, what about trauma post-separation?

Lastly, and perhaps crucially, there are serious doubts over the validity of twin studies as a method ( Jay Joseph's The Gene Illusion) , where he states most of the separated twins were in contact with each other. This means genetics cannot be inferred as the cause if the twins were in regular contact.

The Gene Illusion is a 2003 book by clinical psychologist Jay Joseph, in which the author challenges the evidence underlying genetic theories in psychiatry and psychology. Focusing primarily on twin and adoption studies, he attempts to debunk the methodologies used to establish genetic contributions to schizophrenia, criminal behaviour, and IQ. In the nature and nurture debate on the causes of mental disorders, Joseph's criticisms of genetic research in psychiatry have found their place among those who argue that the environment is overwhelmingly the cause of these disorders. Some of the conclusions of The Gene Illusion have been criticised in book reviews.

 RESEARCH ON THE FIVE REMAINING NON-CONCORDANT TWINS.

Gottesman and Shields then researched the remaining five non-concordant twins. Remember, five out of 12 twins did not develop schizophrenia when their MZ twin did. The researchers theorised that if any of the non-schizophrenic twins had a child who developed schizophrenia, then this would solve the nature-nurture debate. For example, it could not be argued that such a child could been affected by the experience of having a schizophrenic mother as their mothers were not ill. Therefore, if any child of a non-concordant twin did develop schizophrenia, it had to be genetic and inherited from the maternal lineage (e.g., their Mum’s MZ twin).

Results of this longitudinal study showed that nine per cent of children born from non-schizophrenic twins developed schizophrenia. As the general risk for developing schizophrenia is 1%, this supports a genetic basis for the disorder.

A03 RESEARCH ANALYSIS ON NON-CONCORDANT TWINS.

This statistic seems promising until you remember there were only five twins in the study; this would mean only one child out of any ten children born to non-Schizophrenic mothers would have developed the disorder. The numbers are not big enough to prove a statistically significant result.

ADOPTION STUDIES  RESEARCH

The most effective way of separating the effects of genes from the environment is to look at adopted children who later develop schizophrenia and compare them with their biological and adoptive parents.

Tienari began the Finnish adoption study in 1969. He followed 112 adopted children who had been separated from Schizophrenic mothers anytime from infancy to four years of age. He also had a matched control group of 135 adopted children who did not have Schizophrenic mothers.

TIENAR’S ADOPTION STUDIES RESEARCH

APFC: A01 RESEARCH
AIMS: To evaluate the genetic contribution to schizophrenia using an adoption design that disentangles genetic and environmental factors.
PROCEDURE/METHOD: 112 adopted children with mothers who had been diagnosed with paranoid schizophrenia. Control was 135 children adopted from parents with no mental illness. The schizophrenic group adoptees ranged from 5-7 years at the start of the study and had been separated from their mothers before 4. The control group were adopted earlier.
RESULTS: 7% of the schizophrenic group developed schizophrenia compared to 1.5% of the control group.
Conclusion: The higher concordance rate in the schizophrenic adoptees is inferred as genetic.

A03 RESEARCH ANALYSIS ADOPTION STUDIES

Similar studies have been carried out by Kety (1976, 19994) and Heston, 1976 which showed similar results. This adds validity to Tienari’s findings.

Adoption studies have been the most promising method yet and reveal that the adopted offspring of mothers with schizophrenia have a seven per cent chance of developing the disorder despite growing up with adoptive parents. This is compared to a 1.5% rate in children who are adopted from non-schizophrenics. Many psychologists believe that adoption studies show a very clear link that genetics are a risk factor for schizophrenia.

Additionally, Tienari’s study was a prospective longitudinal, natural/quasi-experiment, so it did not lack the problems associated with the retrospective, correlational studies used in the family and twin research (e.g., poor memory of participants, no cause-and-effect relationship, etc.).

There are, however, issues with Internal validity, specifically individual differences between the participants. Tienari claimed to have matched his experimental and control groups. The schizophrenic adoptees were removed from their mothers before four years of age; it is not known precisely when. The schizophrenic adoptees were adopted between the ages of 5 and 7 years. Where did they spend the intervening year in an institution?

It is not known if the schizophrenic adoptees had suffered deprivation, privation, or abuse in their first four years of life. It seems more likely that the children of schizophrenic mothers would have been adopted because of family problems. In contrast, the control group did not have such late adoptions or disruptions in early infanthood. This means that important extraneous variables were not controlled. Studies of children neglected in their early years show they have problems with language, friendships, and emotions throughout their lifespan (Rutter, Hodges, and Tizard). Disruption in care and family discord could have significant implications for a child’s future mental health. Can we, therefore, conclude that the results of Tienari’s study

are purely due to genetics?  Interestingly, Tienari noticed that adoptees were more likely to develop schizophrenia if their new families were disturbed.  This finding supports the idea that schizophrenia is a disorder that has both biological and psychological causes (e.g., both nature and nurture).  See the diathesis-stress Model.

 ETHICS FOR TIENARI

Tienari has been criticised as unethical because he studied children who were probably taken from their parents without their informed consent.  If the mothers were schizophrenic, then they would have been unable to consent to their child being adopted because they were mentally ill and would have been considered to have diminished responsibility for any actions or decisions made during active periods of their illness. Some researchers believe that Tienari was wrong to study their children if he were benefitting from an immoral decision.

VALIDITY OF RESEARCH METHODS

VALIDITY OF EARLY SCHIZOPHRENIA RESEARCH: A CRITICAL OVERVIEW

Early research into the genetics of schizophrenia, including meta-analyses, twin studies, and adoption studies, faces significant validity issues due to changes in diagnostic criteria over time. Most of these studies were conducted before the DSM-III (1980) introduced a more standardised approach to diagnosing schizophrenia, leading to inconsistent and outdated classifications.

• Meta-Analyses (e.g., Zimbardo, Gottesman): These analyses included data from studies conducted as far back as the 1920s, using broad definitions of schizophrenia that often encompassed conditions not classified as schizophrenia today. For instance, subtypes like "paranoid schizophrenia," common in earlier research, are no longer recognised in the current DSM-5. Therefore, participants in these meta-analyses might not meet today's criteria, undermining the validity of conclusions about genetic influences.

• Twin Studies (e.g., Gottesman and Shields): Twin studies from the mid-20th century often relied on clinical judgment or earlier versions of the DSM, such as DSM-I and DSM-II, which focused mainly on positive symptoms and included various psychotic conditions under the umbrella of schizophrenia. This lack of specificity likely inflated concordance rates for monozygotic (MZ) twins, as not all participants would meet the stricter DSM-5 criteria used today.

• Adoption Studies (e.g., Tienari): Similar issues are found in adoption studies, where shifting diagnostic criteria over the study periods meant that some participants initially labelled as schizophrenic may not align with current definitions. This inconsistency casts doubt on conclusions regarding the genetic transmission of schizophrenia.

SUMMARY

In all these studies, the use of broad and outdated definitions—often including subtypes and symptoms no longer recognised by DSM-5—challenges the validity of their findings. As diagnostic practices have evolved, it is crucial to interpret the results of early genetic research cautiously within the context of modern criteria

BIOLOGICAL EXPLANATION FOR SCHIZOPHRENIA:

KEYWORDS

NEUROTRANSMITTERS: A neurotransmitter is a chemical that allows neurons in the brain to communicate; they do this by producing a bridge across the synapse between the axon terminals and dendrites; this process allows the continuation of the nerve impulse to progress.

DOPAMINE: A neurotransmitter.

DOPAMINE FUNCTION: Dopamine has many functions in the brain, including important roles in behaviour and cognition (thinking), voluntary movement, motivation, punishment and reward, pleasure and focus.

AGONISTS/STIMULANTS: These drugs increase the availability of a neurotransmitter in the brain. There are many illegal agonists, e.g., street drugs: cocaine, crack, and PCP. LSD, amphetamines (speed), ecstasy cannabis, heroin, and crack, etc. Legal agonists are L-dopa, methadone, Prozac, and Valium. L-dopa is often used in Parkinson’s patients to increase dopamine availability in the brain.

ANTAGONISTS/BLOCKERS: These drugs block the availability of a neurotransmitter in the brain. There are not any street drugs that do this. Antagonists used to block dopamine are known as antipsychotics and neuroleptics (phenothiazines such as chlorpromazine (Thorazine), Risperidone and Clozapine are some examples.

HYPO AND HYPER: These two prefixes are easily confused as they sound similar, but they have, in fact, more or fewer opposite meanings. Hyper- means over, excessive, more than normal, as in such words as hyperbole (extravagant and obvious exaggeration) and hyperactive (abnormally or pathologically active). Hypo means low, under, beneath, down, or below normal, as in hypoglycemia (low blood sugar) and hyposensitivity (under sensitivity). About neurotransmitters, a hyperneurotransmitter system means too many neurotransmitters are being secreted into the synapses within a certain neural circuit. Because of this, it produces over-stimulation of the cells and causes an exaggeration of functions.

NEURAL CORRELATES: THE ORIGINAL DOPAMINE HYPOTHESIS

AO1 OUTLINE OF THE THEORY

It should be noted that biochemical theories do not compete with genetic theories. They can be complementary, e.g., genes could cause a person to produce too much dopamine.

The dopamine hypothesis was discovered accidentally after it was found that giving patients antihistamines before surgery reduced surgical shock by making patients sleepier and less fearful about their impending operations. This breakthrough finding encouraged pharmaceutical companies to re-examine antihistamines and find out why they had tranquilising effects.

Research soon showed that it was the nucleus of the antihistamines (phenothiazine) that was causing this sedative effect in patients.  Shortly after that, the French chemist Paul Charpentier prepared a new phenothiazine derivative, which he called chlorpromazine; thus, the first typical antipsychotic was created.

At first, chlorpromazine was given to a variety of patients who had disturbed and agitated behaviour. Still, it was soon discovered that it was very effective in calming patients with schizophrenia and psychosis. 

As phenothiazines derive their therapeutic properties by blocking dopamine receptors in the brain, it was hypothesised that Schizophrenia might be caused by excess dopamine. As a result, the original dopamine hypothesis was born.

The original dopamine hypothesis was put forward by Van Rossum in 1967. He hypothesised that there was a was hyperactivity of dopamine transmission, which resulted in the symptoms of schizophrenia, i.e., the unusual behaviour and experiences associated with schizophrenia (sometimes extended to psychosis in general) can be fully or largely explained by hyperactivity of dopamine D2 receptor neurotransmission in subcortical and limbic regions of the brain.

Schizophrenia is associated with poor attention and an inability to stay focused on one thing (knight’s move thinking and clang associations, for example); this is because dopamine’s role is to mediate motivation and attention and thereby gives a person the ability to determine what stimulus grabs their attention and drives the subsequent behaviour.

Overstimulation of the dopamine system ultimately leads to irrelevant stimuli becoming more prominent, which provides a basis for psychotic phenomena such as ‘delusions of reference’, where everyday occurrences may be layered with a heightened sense of bizarre significance. Furthermore, this misattribution of focus can lead to paranoid behaviour and persecutory delusions. This is because excess dopamine has a profound influence on thought, feelings and behaviour. 

A01: RESEARCH ANTI-PSYCHOTICS

The main evidence used to support the dopamine hypothesis is the theory behind the success of typical and atypical antipsychotic drugs such as Thorazine (chlorpromazine), e.g., as they reduce dopamine firing, schizophrenia must be caused by excess dopamine. Activity. Moreover, not only do anti-psychotic drugs (dopamine antagonists) reduce positive symptoms (hallucinations, delusions) in type one schizophrenics, but when the same individuals are given drugs with a dopamine agonist, e.g., drugs such as L-dopa that increase dopamine availability, then their symptoms became much worse.  According to Kapur, dopamine inflames the cognitive tendencies that people with schizophrenia exhibit even before they become ill. He says: ‘If you could test patients before they were psychotic, you’d probably find they tend to jump to conclusions or choose extreme explanations. When you add to this a biochemical fuel – excess dopamine – you inflame this way of thinking; that is what dopamine does. The antipsychotic drugs douse the flames and take away the fuel – they do not fundamentally change the patients’ tendencies, and that’s why relapse usually occurs when medication is stopped.

A03: RESEARCH ANALYSIS: ANTI-PSYCHOTICS

Also adding support to the theory is research on Parkinson’s sufferers and dopamine agonists. A lack of dopamine causes Parkinson's disease. As a result, Parkinson’s patients are treated with synthetic legal agonists to increase their dopamine availability (e.g., L-Dopa). However, if Parkinson’s patients are given high levels of L-dopa, they can suffer from positive symptoms, e.g., they can experience psychotic side effects which mimic the symptoms of schizophrenia. Conversely, Type 1 schizophrenics can suffer from Parkinson’s symptoms when on antipsychotic drugs.

A01: RESEARCH ILEGAL STREET DRUGS

This conclusion is further supported by the research of drug addicts who use street drugs with dopamine agonist properties, such as LSD, cocaine, amphetamine, methamphetamine and other similar substances, as all illegal drugs dramatically increase the levels of dopamine in the brain. Indeed, drug addicts often have symptoms that resemble those present in psychosis, particularly after large doses or prolonged use. This type of addiction is often referred to as "amphetamine psychosis" or "cocaine psychosis," which may produce experiences virtually indistinguishable from the positive symptoms associated with schizophrenia. In the early 1970s, several studies experimentally induced amphetamine psychosis in ordinary participants to better document the clinical pattern of schizophrenia.

It is also worth noting that when schizophrenics abuse street drugs (it should be noted that schizophrenia is comorbid with drug addiction), positive symptoms become much worse. For example, up to 75% of patients with schizophrenia have increased signs and symptoms of their psychosis when given moderate doses of amphetamine or other dopamine-like compounds/drugs, all given at doses that neuro-typical volunteers do not have any psychologically disturbing effects. Lastly, repeated exposure to high doses of antipsychotics (dopamine antagonists gradually reduced paranoid psychosis in these neurotypical participants. There are ethical issues with the above studies.

A03: RESEARCH ANALYSIS ILEGAL DRUGS

However, this type of research has also fallen out of favour with the scientific research community, as drug-induced psychosis is now thought to be qualitatively different from schizophrenia psychosis. Differences between the drug-induced states and the typical presentation of schizophrenia have now become clearer, e.g., euphoria, alertness, and over-confidence. Some researchers believe these symptoms are more reminiscent of mania (manic side of bipolar depression) than schizophrenia.

A01: RESEARCH RATS

Chemical stimulation in rats is thought to support the dopamine hypothesis. In brief, rats are given dopamine antagonists (e.g., antipsychotic drugs such as chlorpromazine) and dopamine agonists (e.g., L-dopa, PCP and amphetamines). The behaviour that rats show when given agonists is thought to be like the positive and negative symptoms of schizophrenia in humans. For example, several animal models of schizophrenia are based on the experimental observation that phencyclidine (PCP) and amphetamines can induce behavioural changes that include locomotor hyperactivity, stereotyped behaviour, and social withdrawal (Murray and Horita 1979).

A03: RESEARCH ANALYSIS RATS

Of course, rats are not comparable to humans; not only do they not have a language, which is one of the key problem areas in schizophrenics, but psychologists do not have a viable way of assessing how disorganised or hallucinogenic a rat’s thoughts are whilst on L-dopa as they can’t ask a rat if it is hallucinating or delusional. Moreover, as the clinical interview is the only valid way of assessing schizophrenia in humans, one wonders how the researchers got over that problem when assessing the rats ‘supposedly’ positive schizophrenic symptoms; schizophrenia may be unique only to humans.

On the other hand, there are many similarities between rats and humans, including comparable hormonal and nervous systems. Plus, we have almost identical hind, mid-, and forebrains. More importantly, rats and humans share similar mesolimbic systems, the pathway dopamine is processed in, so the research would be valuable in assessing how antagonists and agonists affect dopamine receptors.

ANALYSIS SPECIFIC TO THE ORIGINAL DOPAMINE HYPOTHESIS.

An important observation is that schizophrenia is not the only disorder associated with dopamine; bipolar I, II (manic depression), schizoaffective disorder and acute transient psychosis are just some of the disorders associated with this neurotransmitter. This means that excess dopamine might have more to do with psychosis than schizophrenia and is, therefore, only a partial explanation.

Also relevant is the fact that current research shows that one-third of individuals with schizophrenia do not respond to antipsychotics despite high levels of D2-receptor occupancy. In other words, they fit the criteria for dopamine hypothesis 1, but drugs that reduce dopamine activity do not alleviate their positive symptoms. This finding undermines the idea that excess dopamine causes schizophrenia. On the other hand, some health professionals believe that this result occurs when patients start chemotherapy too long after the start of their symptoms.

More importantly, a large subset of schizophrenics do not suffer from positive symptoms and instead present with “negative” symptoms. In these cases, antipsychotics do not affect type-two negative symptoms whatsoever. But interestingly, if dopamine agonists such as L-dopa are given, then these symptoms can improve. Thus, a major problem with the original dopamine hypothesis is that dopamine is not implemented in type 2 schizophrenia, where negative symptoms predominate.

THE REFORMULATED DOPAMINE HYPOTHESIS: DOPAMINE 2 AND THE HYPO AND HYPER THEORIES

Over the years, the awareness of the importance of understanding negative symptoms (flattening of affect, apathy, poverty of speech, anhedonia, and social withdrawal) and cognitive symptoms (deficits in attention, working memory, and executive functions) in this illness and of their resistance to D2 receptor antagonist drugs led to a reformulation of the classical DA hypothesis.

Thus a second dopamine hypothesis was formulated. This hypothesis postulated that negative and cognitive symptoms of the disorder can be attributed to hypo or hyperfunctionality of D1 and D2 dopamine receptors. In other words, some schizophrenics have under-functioning dopamine receptor activity (hypo systems), and some schizophrenics have over-functioning or hyper dopamine systems (as per the original dopamine hypothesis). This finding would not only explain the antipsychotic resistance in persons with negative symptoms, but it would also explain why they had underactive D2 receptors.

NEURAL CORRELATES

A03: RESEARCH ANALYSIS OF DOPAMINE 2 HYPOTHESIS

If schizophrenia is caused by dopamine imbalance, then there would be evidence of unusual dopamine activity in the brain. Many studies have shown increased dopamine receptors in the brains of schizophrenics. However, historical methods of measuring dopamine receptors relied on post-mortems.

Post-mortem research is problematic because real-time’ dopamine activity cannot be measured in the deceased. Also relevant here is that researchers often failed to control for participants who had a history of being medicated with antipsychotics. Taking any drug can affect brain chemistry, and the above results may have been a result of taking antipsychotics.

Moreover, case studies are not generalisable to other schizophrenic populations as the individuals studied might have had unique brain configurations. Most importantly, other studies have not always replicated the above findings. There have been tremendous problems with the classification of schizophrenia. Thus, it seems reasonable to suppose that many of the samples used in historical studies before DSM V might be invalid; for example, samples might have had patients with bipolar or catatonia. Significantly, the sample may have contained individuals with negative and positive symptoms. As researchers back then were looking at evidence for the original dopamine hypothesis, having individuals with negative symptoms would have skewed the results for the hyperdopamine theory. This would explain why studies in the past have had mixed findings.

NEURAL CORRELATES: However, today, there are much better ways of investigating dopamine density, such as PET and fMRI imaging. Neural correlates are measurements of the structure or function of the brain that occur in parallel with an experience or behaviour, in the case of schizophrenia, there is growing evidence that schizophrenia is down to structural and neurotransmitter abnormalities in the brain. Brain scanning techniques have made it possible to investigate living brain images.

Both positive and negative symptoms have neural correlates in the brain.  

RESEARCH ON BRAIN IMAGERY AND POSITIVE SYMPTOMS SHOWS THAT SCHIZOPHRENICS:

• There is an excess of dopamine receptors in the mesolimbic system, caudate nucleus, and amygdala, but there are also a significant number of schizophrenics that have hypo dopamine systems.

• Generally have faster dopamine metabolism.

• Show greater levels of dopamine release (particularly in the striatum) than non-psychotic individuals after taking amphetamine, patients diagnosed with schizophrenia

• Reduced activity in the superior temporal gyrus and anterior cingulate gyrus has been linked to the development of auditory hallucinations. Patients experiencing auditory hallucinations showed lower activation levels in these areas than controls. Therefore, reduced activity in these brain areas is a neural correlate of auditory hallucinations.  

RESEARCH ON BRAIN IMAGERY AND NEGATIVE SYMPTOMS

• Activity in the ventral striatum has been linked to the development of avolition (loss of motivation)

• The ventral striatum is believed to be particularly involved in the anticipation of a reward for certain actions; therefore, if areas are abnormal such as the ventral striatum, then this would result in a lack of motivation (avolition)  

• Many studies show how important D1 receptors are to optimal functioning in the pre-frontal cortex (the home of personality, planning, initiation, etc). Those with negative symptoms show under-functioning in the prefrontal cortex (PFC).

POSITIVE AND NEGATIVE NEURAL CORRELATES

These findings are known as neural correlates because the observed behaviour correlates with the cortex's damaged area. Together, these findings have led to the hypothesis that the activity of dopamine (D1) receptors in the prefrontal cortex might be implicated in the cognitive impairments and negative symptoms of schizophrenia. In contrast, the excess dopamine (d2) transmission may be related only to the core or "positive" symptoms (hallucinations, delusions).

A03 FOR BOTH DOPAMINE HYPOTHESES AND NEURAL CORRELATES

Schizophrenia could be interpreted as a form of brain damage to various regions in the brain that are concerned with language and thought. For example, areas in the brain occupied by Dopamine D2 receptors are hypo and hyper in Broca’s area. This may account for the differences found in language between patients with positive and negative symptoms.

Overall, both hypotheses shed some light on the disorder, and many different research methods clearly demonstrated a dopamine link. What is not clear, however, is which way around the cause-and-effect link is. To put it simply, which came first, schizophrenia or the hyper or hypo dopamine system - chicken and egg analogy? Does schizophrenia cause disruption or change in the dopamine system, or does an imbalance of dopamine receptors cause schizophrenia? Each is a valid proposition. Behaviour can cause a neurochemical change; for instance, smiling has been shown to affect serotonin production.

Brain chemistry is still in its infancy. It is believed that dopamine is part of a very complicated jigsaw of neurotransmitters involved in the aetiology of schizophrenia. This idea is supported by the fact the new class of atypical drugs, such as clozapine, have shown that dopamine is not the only neurotransmitter associated with schizophrenia, as atypical drugs work on serotonin receptors, too. Also, antipsychotic drugs do not have a therapeutic effect until weeks after taking them, although they immediately block dopamine receptors. Dopamine may influence other neurotransmitters.

THERE ARE OTHER NEURAL CORRELATES

APFC BRAIN VENTRICLE STUDY IN. SCHIZOPHRENICS

Many neural correlates do not involve dopamine; for example,

• AIMS: People with schizophrenia have abnormally large ventricles in the brain. Ventricles are fluid-filled cavities.

• PROCEDURES: Researchers compared 16 patients with "large" ventricles (ventricles more than I SD above the control mean) with 16 patients with the smallest ventricles from a sample of 52 schizophrenic patients.

• FINDINGS: Patients with ventricular enlargement showed some impairment in the sensorium and had a preponderance of "negative" symptoms (e.g., alogia, affective flattening, avolition, anhedonia), while those with small ventricles were characterized by "positive" symptoms (e.g., delusions, hallucinations, positive formal thought disorder, bizarre behaviour).

• CONCLUSIONS: These findings suggest that combining a measure of brain structure with the clinical picture may provide a useful new approach to classifying schizophrenia. This means that the brains of schizophrenics are lighter than normal.

• A03: Enlarged ventricles may be the result of taking anti-psychotic medication.

A03 FOR ALL BIOLOGICAL THEORIES - GENETIC AND NEURAL CORRELATES

DETERMINISM

All biological theories of schizophrenia are deterministic and suggest that you have no free will against developing or personally overcoming Schizophrenia. There are negative and positive aspects to this. On the plus side, parents will not be blamed for causing schizophrenia in their offspring, and individuals will not be perceived to be at fault either, as their illness is a result of their genes and/or neurotransmitters. There will, therefore, be less social stigma about being schizophrenic. However, other people may not want to procreate with schizophrenics because subsequent kids might inherit the gene.

On the negative side, excuses, excuses, excuses! Individuals and families may see it pointless to try to change their behaviour and rely on drugs to alleviate symptoms. Individuals may believe they are predestined to have Schizophrenia, which is very depressing.

PHYSIOLOGICAL REDUCTIONISM & NATURE V NURTURE

Biological explanations of schizophrenia are reductionist as they attempt to explain a complex, multi-faceted disorder at the level of genes and dopamine. Their rationale is that humans are biological organisms, reducing even complex behaviours to neurophysiological components should be possible.  As a result, biological theories disregard the importance of looking at a person holistically, e.g., how biology, parenting and stress, for example, might combine as risk factors in developing the disorder.

It is now known that biology is not the only case, as only 48% of MZ twins are concurrent for schizophrenia, so psychological processes must also contribute. For example, highly expressed emotion in families has been shown to cause relapse. This demonstrates that complex phenomena cannot easily be explained simply by reference to physiological imbalance.  The influence of these brain chemicals is indisputable, but to argue that they only cause schizophrenia is to neglect all other potential influences during this disorder.  It may well be that, for example, stress is the ultimate cause of the disorder, creating physiological imbalances – the proximate cause. 

Indeed, DSM V now believes that Schizophrenia is an aetiologically heterogeneous disorder and has thus renamed it a “spectrum” disorder. In other words, schizophrenia is a disorder that has not only a multitude of different things that can cause it, but it is also a disorder with no defining features. The addition of the term “spectrum” and the less stringent guidelines show that the DSM 5 acknowledges that it sees schizophrenia as an umbrella term and acknowledges that any risk factor for developing Schizophrenia will combine biology and the environment. Therefore, the cause of it is no longer seen as a fight between nature and nurture.

The Diathesis-Stress Model (DSM) interprets schizophrenia as a result of brain impairment in areas responsible for language and cognition. It suggests that certain brain regions, particularly those with dopamine D2 receptors, like in Broca's area, may be underactive or overactive. This could explain the linguistic differences in patients exhibiting positive versus negative symptoms. According to the DSM, the origins of such brain impairments in schizophrenia are multifaceted, involving a blend of genetic factors, exposure to pathogens or viruses, complications during birth, etc., all of which may interact with external stressors like abuse, bullying, or family discord.

This comprehensive perspective defines the diathesis-stress model (DS), offering a nuanced view that combines biological predispositions with environmental pressures.