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Neurochemical Disorders Schizophrenia

Neurochemical Disorders II: Schizophrenia
Schizophrenia is a syndrome characterized by specific psychological manifestations, including auditory hallucinations, delusions, thought disorders and behavioural disturbances. It is a common disorder with a lifetime prevalence of 1% and an incidence of 2–4 new cases per year per 10 000 population. It is more common in men and typically presents early in life. Like all psychiatric disorders there is no diagnostic test for this condition, which is defined by the existence of key symptoms.

·       Positive symptoms:
      delusions: abnormal or irrational beliefs, held with great conviction and out of keeping with an individual’s sociocultural background;
      hallucinations: perceptions in the absence of stimuli.
·       Negative symptoms:
      blunting of mood, apparent apathy, lack of spontaneous speech and action;
      disordered speech.

Neurochemical Disorders II: Schizophrenia, delusions, hallucinations, The dopamine hypothesis of schizophrenia,

A distinction used to be made between type 1 and 2 schizophrenia but this has fallen out of fashion as it may relate more to the length of time that the individual has had the condition. The cause of schizophrenia is unknown but a number of aetiological factors have been suggested:
       Genetic factors: first-degree relatives of people with schizophrenia have a greatly increased risk of developing the disease; around 10% for siblings, 6% for parents and 13% for children. Concordance rates in twins are relatively high with figures varying from 42% to 50% for monozygotic twins and between 0 and 14% for dizygotic twins. Recent Genome Wide Association Studies (GWAS) have also confirmed a genetic basis for the condition.
    Environmental factors: e.g. infections during pregnancy also may have a role, with adoption studies demonstrating the importance of both genetic and environmental factors. In these studies gene–environment interactions have been demonstrated in children of schizophrenic parents adopted into good versus disturbed adoptive families. In this latter respect one influential theory relating to a family cause appeals to high levels of ‘expressed emotion’ (hostility, lack of emotional warmth, over-involvement) as a risk for relapse.

The dopamine hypothesis of schizophrenia
Basic model
Simply stated, this embodies the idea that schizophrenia is caused by up-regulation of activity in the mesolimbic dopamine system. The evidence for this theory comes from:
·       Dopamine-blocking drugs show an antipsychotic effect.
·  Drugs that up-regulate dopamine can produce positive symptoms of psychosis (e.g. amphetamines).
·       Some neuroimaging studies in patients have found evidence of dopamine up-regulation.
The dopamine hypothesis has been criticized for the lack of direct evidence in its favour and for certain inconsistencies:
·       Dopamine agonists do not produce all of the symptoms of schizophrenia (notably, they do not produce negative symptoms);
·   Dopamine-blocking drugs do not act immediately – there may be a long period before symptoms begin to resolve.

Revised model
The above inconsistencies led to the revision that both dopamine up-regulation and down-regulation must be invoked to account for the core features of schizophrenia, with the positive symptoms arising from up-regulation of mesolimbic dopamine function and the negative symptoms from down-regulation of mesocortical function.
However, many still think this as an inadequate explanation of such a complex disorder, and there is a view that schizophrenia is associated with N-methyl-D-aspartate (NMDA) (glutamate) receptor hypofunction. This arose from observations that NMDA blockers such as phencyclidine (‘Angel Dust’) and ketamine (widely used in anaesthesia) produce a psychotic state (including negative symptoms) that is held to be more strongly redolent of schizophrenia than the psychosis produced by dopaminergic agents. There- fore, it has been proposed that glutamate hypofunction may account for both up-regulation of the mesolimbic dopamine system, from a diminished excitatory drive of GABAergic inhibition (i.e. an attenuation of the ‘brake’ system), and down-regulation of the mesocortical system because of diminished direct drive (the ‘activating’ system).

Cognition in schizophrenia
Whilst schizophrenia is traditionally described in terms of psychotic symptoms, there is increasing evidence of cognitive deficits, particularly in the memory domain, that may accompany (and perhaps precede) the onset of these symptoms.

The mainstay of therapy in schizophrenia remains the use of drugs that block dopamine receptors, of which there are at least five subtypes in the brain (D1–D5 receptors; see Chapter 19). These agents (e.g. chlorpromazine) are called antipsychotics or neuroleptics. Most neuroleptics block D1 receptors but there is a close correlation between the clinical dose of antipsychotic drugs and their affinity for D2 receptors, suggesting that blockade of this receptor subtype may be particularly important. D2 receptors are found in the limbic system and in the basal ganglia, and D3 and D4 receptors are found mainly in the limbic areas.
Antipsychotic drugs (eg chlorpromazine, haloperidol) require several weeks to control the symptoms of schizophrenia and most patients require maintenance treatment for many years. Relapses are common even in drug-maintained patients. Unfortunately, neuroleptics also block dopamine D2 receptors in the basal ganglia, often producing distressing and disabling movement dis- orders (e.g. parkinsonism, acute dystonic reactions, akathisia [motor restlessness] and tardive dyskinesia [orofacial and trunk movements]) which may be irreversible; see Chapter 42). Blockade of D2 receptors in the pituitary gland causes an increase in prolactin release and endocrine effects (e.g. gynaecomastia, galactorrhoea; see Chapter 11). Many neuroleptics also block muscarinic receptors (causing dry mouth, blurred vision, constipation), ╬▒-adrenoceptors (postural hypotension) and histamine H1 receptors (sedation).

Atypical drugs
Some newer drugs have a reduced tendency to cause movement disorders and are referred to as atypical agents (e.g. clozapine, risperidone, olanzapine, quetiapine). With the possible exception of clozapine, these drugs are not more efficacious than the older antipsychotic drugs. Clozapine is restricted to patients resistant to other drugs because it causes neutropenia or agranulocytosis in about 4% of patients. Risperidone and other newer atypical agents are increasingly used in the treatment of schizophrenia because they are more acceptable to patients.
It is not clear why some neuroleptics are ‘atypical’. Clozapine may be atypical because in addition to being a dopamine D2 antagonist it is a potent blocker of 5-HT2 receptors.