Biological Basis of Schizophrenia and Antipsychotics

During the 1950s.

Increased dopamine in the brain & reduced tremors and slow; imprecise movements.

Some showed behaviours similar to individuals with schizophrenia = a link between increased dopamine & schizophrenia.

In the 1950s; also called typical/first-generation antipsychotics.

Bind strongly to dopamine receptors & block dopamine transmission. The notes describe sustained blockade as 'permanent'; with the annotation 'as long as half-life allows it'.

The next dose arrives while receptors remain blocked = no gap in blockade & dopamine transmission is consistently affected.

Late 1990s; also called unconventional/second-generation antipsychotics.

Lower affinity & weaker binding = drugs 'let go' quicker; temporarily disrupting dopamine transmission & allowing a gap in blockade.

Serotonin; they block 5-HT2A receptors.

Typical = phenothiazines & butyrophenones; atypical = diverse chemical structures.

Typical = block D2 receptors & reduce positive symptoms. Atypical = block D2 & 5-HT2A receptors; among others; & reduce positive and negative symptoms.

Typical = increased EPS & slightly increased risk of TD and NMS. Atypical = increased risk of weight gain & diabetes.

Abnormally high dopamine activity in the brain accounts for schizophrenia; particularly positive symptoms.

Hypersensitivity/high density of postsynaptic D2 receptors = excessive firing of dopaminergic neurons across the subcortex.

Positive symptoms; e.g. hallucinations; delusions & disorganised thinking.

- Original hypothesis = schizophrenia explained by abnormally high dopamine activity; based mainly on positive symptoms linked to dopamine. One symptom group used to explain whole disorder -> reductionist/too simplistic; negative symptoms remain unexplained.

- Drugs reducing dopamine activity -> little/no improvement in individuals with mainly negative symptoms = evidence against excessive dopamine explaining schizophrenia as a whole.

- Revised hypothesis: excess mesolimbic dopamine -> positive symptoms; reduced mesocortical/prefrontal dopamine -> negative & cognitive symptoms = accounts for both symptom groups.

Induced psychosis in volunteers without schizophrenia by giving large amounts of amphetamines; increasing dopamine in the brain.

Paranoid delusions & cold; unemotional responses.

To test the dopamine hypothesis by seeing whether induced psychosis mimicked schizophrenia's symptoms & could explain naturally occurring schizophrenia.

D1-D5; distributed across the cerebral cortex & limbic system.

Investigated antipsychotic effects on D2 receptors & linked these receptors mainly to subcortical regions of the limbic system = groundwork for the revised dopamine hypothesis.

Emotional regulation; arousal & memory.

Ventral tegmental area -> nucleus accumbens.

Too much dopamine = positive symptoms. Antipsychotic drugs reduce dopaminergic neurotransmission = reduce positive symptoms.

Emotional responses/personality; motivation & cognition.

Ventral tegmental area -> frontal lobe/prefrontal cortex.

Too little dopamine activity at D1 receptors in the frontal lobe.

Original = mainly D2 hypersensitivity/overabundance. Revised = both D1 receptors in the prefrontal cortex & D2 receptors.

Original = general subcortical dopamine overactivity. Revised = mesolimbic overactivity & mesocortical underactivity.

Original = dopamine alone; viewed as an overall excess. Revised = dopamine excess/deficit in different regions & interactions with serotonin and glutamate.

Hyperdopaminergia in the mesolimbic pathway = positive symptoms; e.g. hallucinations/delusions. Hypodopaminergia in the mesocortical pathway/prefrontal cortex = negative & cognitive symptoms; e.g. avolition; speech poverty and cognitive deficits.

- Cause & effect criticism: dopamine imbalance may not be root cause of schizophrenia = possible intermediate step arising from genetic predisposition.

- Dopamine dysregulation does not occur in isolation. Inherited predisposition -> abnormal dopamine regulation -> imbalance. Dopamine abnormality itself therefore needs explaining.

- Twin & family studies: genetic similarity linked to schizophrenia -> supports inherited biological vulnerability behind dopamine imbalance; rather than isolated brain abnormality.

- Dopamine hypothesis describes neurochemical mechanism through which symptoms may arise; but not its origin. Identifying an intermediate step = incomplete explanation of why schizophrenia develops.

- Gottesman (1991): examined schizophrenia across many families. Greater genetic similarity -> greater probability both individuals have schizophrenia = higher concordance among genetically similar relatives.

- Concordance = both members of a pair sharing a condition. Schizophrenia concordance: identical twins = about 48%; non-identical twins = 17%.

- Higher identical-twin concordance -> supports inherited biological vulnerability. If abnormal dopamine activity were an isolated brain problem unrelated to inheritance; genetic closeness would not consistently predict whether relatives developed schizophrenia.

- Annotation: without genetic involvement; identical & non-identical twins would have similar concordance. Different rates -> supports genetic involvement; genes may explain origin of dopamine dysregulation.

- SWGPGC (2014): large genome study identified 108 separate genetic loci associated with schizophrenia -> complex genetic contribution; not just a few abnormal dopamine genes.

- Polygenic = many genes involved; rather than one alone. Numerous associated loci -> complicated genetic vulnerability rather than single-gene explanation.

- Some associated loci linked to dopamine receptors; others linked to glutamate function & synaptic plasticity. Handwritten annotations also identify serotonin.

- Genetic associations across several systems -> a few abnormal dopamine genes cannot fully explain schizophrenia. Suggests complicated neuronal network & possible dysregulation of an entire neuronal system.

- Inherited influences may affect several interacting systems -> explanation extends beyond dopamine imbalance. Dopamine activity = only part of biological account.

- Direct measurement of neurotransmitters at active synapses in living human brain = difficult. Researchers measure breakdown products instead of dopamine at synapses -> indirect method.

- Metabolites = substances remaining after neurotransmitter breakdown. Enzymes break dopamine down into HVA (homovanillic acid) = indicator of dopamine activity.

- Cerebrospinal fluid collected through lumbar puncture/spinal tap -> HVA in fluid measured.

- High HVA assumed to indicate high dopamine activity because HVA = dopamine breakdown product. Indirect measurement used as evidence when investigating dopamine involvement in schizophrenia.

- Criticism targets methodology & validity of supporting evidence: researchers investigate dopamine in living brain using breakdown products -> indirect evidence; open to extraneous influences.

- HVA in cerebrospinal fluid may vary with food/drink intake; medical drugs; recreational drugs & dietary variation -> differences need not reflect schizophrenia-related dopamine activity.

- Stress & physical activity = potential extraneous variables. Lumbar puncture = invasive & stressful -> procedure may affect neurotransmitter levels & distort HVA readings.

- Confounding variables difficult to control completely across patients -> HVA may reflect diet; drug use or stress rather than underlying schizophrenia-related processes.

- Metabolite-based conclusions require caution. Until neurotransmitters can be measured more accurately; indirect HVA measurements & uncontrolled influences limit validity of evidence supporting dopamine hypothesis.