Transmethylation hypothesis

This early view held that schizophrenia might be related to excess methylated biogenic amines. Dimethyltryptamine (DMT), for example, was used as a snuff on Haiti to induce mystical states; an injection causes a transient schizophrenia-like psychosis. Mescaline, a methylated substance related to dopamine and noradrenaline, does not cause symptoms that closely resemble schizophrenia. Methionine, a methyl donor, may exacerbate symptoms.

Dopamine

Although subjected to modification, the dopamine (DA) theory of schizophrenia refuses to lie down. However, while implicated, DA does not act in a vacuum.

Preferential D2 antagonism, as with sulpiride and haloperidol, is equally efficacious as when non-selective D1 and D2 antagonists, like flupentixol and fluphenazine, are used. As assessed using positron emission tomography (PET), degree of DA receptor blockade does not distinguish between antipsychotic drug responders and non-responders. While amphetamine psychosis may mimic paranoid schizophrenia to some extent, it is characterised by over-responsiveness rather than emotional blunting, thought disorder is uncommon, and tactile and olfactory hallucinations are more likely to be reported than in schizophrenia. In one study, ketamine and amphetamine produced positive symptoms and euphoria in healthy subjects, but perceptual changes were caused only by ketamine whereas only amphetamine caused hostility, grandiosity and somatic concern. Both drugs produced conceptual disorganisation but only ketamine induced concrete thinking and strange mannerisms. Reduction over some weeks in circulating plasma levels of HVA (chief DA metabolite) that correlates with clinical response to antipsychotic drugs can be viewed as favouring a role for DA in schizophrenia in particular, psychosis in general, or just as a non-specific drug effect. Amphetamines exacerbate schizophrenia even when the patient is compliant with medication. Amphetamine challenge leads to greater release of DA in schizophrenia patients than in healthy controls: this may mean that stress causes excess DA release in schizophrenia.

Functional imaging studies have not consistently demonstrated an excess of D2 receptors in drug-naive schizophrenia. Efforts to link schizophrenia with the D2 dopamine receptor gene region on chromosome 11 have been problematic. Similar difficulties apply to the D3 receptor gene. Nevertheless, functional imaging suggests that D2 receptors may be overactive in some cases of schizophrenia, particularly during periods of active psychosis, and such cases may be more responsive to antipsychotic medication. It has been suggested that D2 receptor up-regulation in the caudate nucleus is related to genetic risk for schizophrenia.

The D4 receptor was reported to be increased in the brains of schizophrenia cases in the early 1990s. Haloperidol has a higher affinity for D4 receptors than clozapine and D4-selective drugs have not demonstrated antipsychotic activity. 

Methamphetamine users who become psychotic tend to have a family history of schizophrenia and are more likely to possess early-onset schizotypal characteristics; and these two factors determine the duration of psychosis.

Negative symptoms may be due to mesocortical hypodopaminergia, and positive symptoms may arise from mesolimbic hyperdopaminergia. One hypothesis states that reduced prefrontal DA, due to pre-existing prefrontal pathology, leads to up-regulation of subcortical DA activity and hence psychosis. Prenatal lesions in rodents leads to delayed release of excess DA into adulthood. Does this explain the time of onset of schizophrenia?

It was recently suggested that delusions, irrespective of diagnosis, may be due to dysregulated DA release from pathways rising from the midbrain coupled with bias in reasoning; negative symptoms may be due to DA dysregulation; and the exact combination of positive and negative symptoms depends on relative involvement of different mesocorticolimbic circuits. An fMRI BOLD study found that severity of delusions in schizophrenia, as measured with the PANSS, correlated with inappropriate midbrain activation in response to neutral stimuli. Are positive symptoms Jacksonian ‘release phenomena’ with excess limbic D2 and D4 activity and increased frontal 5-HT2 and reduced DA activity? Basic research suggests 5-HT2 blockade might increase DA activity in the frontal cortex.

Perhaps DA exerts a pathogenic effect during adolescence by disturbing the balance of excitatory and inhibitory inputs to pyramidal cells in the cortex or by affecting information processing by the cortex during puberty. One version of the DA hypothesis states that genes and/or prenatal insults to the mesocortical pathway reduces the amount of cortical, particularly frontal, DA; this causes loss of corticolimbic glutamatergic transmission and loss of inhibitory feedback of the ventral tegmental area from the cortex; there is decreased inhibition of the mesolimbic system and increased mesolimbic DA transmission. 

It is postulated that clozapine ameliorates negative symptoms by blocking serotonin receptors, increasing mesocortical DA. Phencyclidine (PCP) reduces DA turnover in monkeys. Clozapine then normalises pre-frontal cortex (PFC) dopaminergic turnover. The DA hypothesis is less appropriate with clozapine than the older antipsychotics. Amphetamine challenge improves cognitive functioning in schizotypy without affecting other psychotic symptoms. There is as yet no definite link between schizophrenia and any DA receptor.

Serotonin 

Serotonin (5-HT) modifies DA release. Activity of 5-HT2 receptors in the cerebral cortical receptors diminishes as we age.

The stimulant meta-chlorophenylpiperazine is a recreational drug of the piperazine class. This 5-HT partial agonist exacerbates the positive symptoms of schizophrenia. PCP causes symptoms that resemble the positive and negative symptoms of schizophrenia (including catatonic features); with negative symptoms there is decreased dopaminergic terminal activity in the frontal cortex that can be normalised by 5-HT2 antagonists. 5-HT2 antagonism indirectly activates midbrain dopaminergic activity and increases DA release in the frontal cortex. A combination of 5-HT2 and DA receptor antagonists causes selective enhancement in the PFC with resulting correction of the regional imbalance between cortical and midbrain dopaminergic mechanisms. 5-HT2 antagonism may partly explain the beneficial effects of clozapine on negative symptoms. Adding an antidepressant such as an SSRI to an antipsychotic drug may moderately improve negative symptoms. Neuroleptic-naive schizophrenia cases have reduced 5-HT2A receptors in the parietal and frontal cortex on PET.

Glutamate

Normal mesolimbic glutamatergic neurones inhibit the mesolimbic dopaminergic pathways. PCP is a non-competitive inhibitor of NMDA receptor-mediated transmission and may block this controlling effect. In sub-anaesthetic dosage, ketamine, an NMDA receptor antagonist, may produce thought disorder not unlike that found in schizophrenia. Antipsychotic drugs may increase glutamatergic activity.

In schizophrenia, specific loss of mRNA encoding for non-NMDA glutamate receptors was reported in the hippocampus, perhaps due to reduced glutamate production. Never-treated first-episode schizophrenic patients have increased glutamate levels in the anterior cingulate and thalamus – thalamic glutamate was significantly decreased after 30 months, some grey matter reductions were seen at 10 months, becoming widespread at 30 months, and parietal and temporal lobe grey matter loss correlated with loss of thalamic glutamate, the researchers speculating about neurodegeneration or a plastic response to reduced subcortical activity. In a murine model, a reduction in glutaminase (converts glutamine to glutamate) may have antipsychotic-like properties. A recent follow-up of patients with schizophrenia from diagnosis found the sum of thalamic glutamate and glutamine levels decreased over 80 months and correlated negatively with a measure of social functioning; thalamic glutamine and loss of grey matter were significantly correlated in many brain areas; and these findings were considered to reflect an underlying neurodegeneration.

Complexins I and II (presynaptic proteins involved in fusion of storage vesicles with cell membranes – markers for inhibitory and excitatory neurones, respectively) may be relevant. There may be excessive loss of complexin II in the medial temporal lobe in schizophrenia and complexin II gene polymorphisms may influence current cognitive performance in patients with schizophrenia.

D-cycloserine is a partial agonist at the glycine modulatory site of NMDA receptors and might improve negative symptoms in schizophrenia, as might the adjuvant use of glycine. These substances may have the opposite effect, an increase in negative symptoms, when added to clozapine. A 2003 study found significantly lower serum levels of D-serine in schizophrenia than in controls while a 2005 study found plasma glycine levels and glycine-serine ratios that were lower and homocysteine levels that were higher in schizophrenia than in controls, low glycine levels correlating with more negative symptoms. A more recent study found no significant difference between placebo and either glycine or D-cycloserine in terms of change in negative or cognitive symptoms of schizophrenia. Increased third-trimester maternal homocysteine levels may increase the risk for schizophrenia in offspring at least twofold.

N-methylglycine (sarcosine), a potent endogenous inhibitor of glycine transporter 1, added to stable antipsychotic drug regimens, may improve the negative and cognitive symptoms of stable chronic schizophrenia. D-serine and sarcosine can improve positive symptoms in chronic schizophrenic cases on stable antipsychotic drug regimens. Also, sarcosine especially may also benefit acutely ill patients with schizophrenia when given with an antipsychotic drug.

LY2140023, a pro-drug with antipsychotic activity, is a highly selective agonist at group II metabotropic glutamate receptors and has no significant affinity for dopamine receptors. 

Hypoxia renders neurones susceptible to glutamate-induced damage. Early damage of this type might lead to schizophrenia in adolescence or later when abnormal circuitry comes under increased cortical control with resultant increased DA activity. Alternatively, the original hypoxia/glutamate insult reduces NMDA receptor availability with decreased inhibitory modulation via glutamate-dependent γ-aminobutyric acid (GABA) activity, causing over-stimulation of some brain pathways.

An in situ hybridisation study found a decrease in the NR1 subtype of the NMDA receptor in the hippocampus. It is possible that changes in cortical glutamatergic transmission lead to dopaminergic changes as a secondary phenomenon.

Neuregulin-1 (chromosome 8p) is highly expressed in brain and signals through tyrosine kinase receptors, thereby being involved in neurodevelopment. Neuregulin-1 (at 8p12) might play a role in influencing susceptibility to schizophrenia and bipolar disorder. 

GABA

Significant non-treatment-related reduction in glutamic acid decarboxylase (needed for GABA synthesis) mRNA levels in schizophrenic PFC in the absence of significant cell loss has been noted. Recently, researchers reported lower levels of mRNA for the delta subunit of the GABA-A receptor in the dorsolateral PFC in schizophrenia. The authors suggested that this may add to deficient tonic inhibition and PFC dysfunction. The density of chandelier neurone axon terminals (distinctive axon terminal arrays [‘cartridges’] providing inhibitory input to the initial axonal segment of pyramidal cells) immunoreactive for the GABA membrane transporter (GAT-1) is reduced in most people with schizophrenia. There may be down-regulation of glycoproteins secreted preferentially by cortical GABAergic prefrontal neurones in schizophrenia and psychotic bipolar affective disorder.

Treatment of chronic schizophrenia cases with MK-0777 (a benzodiazepine-like drug that is selective for GABA-A receptors containing α-2 or α-3 subunits) may hold promise in alleviating cognitive deficits. Are changes involving GABA in PFC neural circuitry important in cognitive dysfunction in schizophrenia?

Parvalbumin, calbindin and calretinin are calcium-binding proteins. Parvalbumin-containing GABA neurones develop between three to six months of pregnancy and reduced numbers of parvalbumin cells were recently reported in the frontal cortex and hippocampus in patients with schizophrenia. Also, while others did not find reduced numbers of hippocampal neurones in the pyramidal cell layer in schizophrenia they reported reductions in numbers of somatostatin- and parvalbumin-positive interneurones and decreased levels of somatostatin, parvalbumin and glutamic acid decarboxylase mRNA expression. Inhibitory interneurones containing parvalbumin may be reduced in number and there may be reduced expression of the GABA-synthesising enzyme glutamic acid decarboxylase, findings suggesting a functional PFC GABA deficit.

Acetylcholine

Acetylcholine is important for cognition. Muscarinic and nicotinic receptor numbers may be reduced in schizophrenia. A functional polymorphism of the α-7 nicotinic receptor has been linked to this condition. Acetylcholine modulates striatal and cortical dopamine. People with schizophrenia are known to smoke heavily. The muscarinic receptor agonism of clozapine may be important for its effects on both positive and negative symptoms.

Xanomeline, an M1 and M4 agonist and M5 antagonist but also with agonism at 5-HT1A and 1B and antagonism at 5HT2 receptors, may have some role in improving verbal learning and short-term memory in schizophrenia. DMXB-A, a cholinergic nicotinic partial agonist for the α-7 receptor, may improve negative symptoms.

Free radicals

These are chemical species with an unpaired electron in one of their orbits. Enzymes such as superoxide dismutase and other substances defend against oxidative injury. Starvation, heavy smoking, and heavy alcohol intake increase oxidative tone and oxyradical production. Vitamins E and C and fish or vegetable fats may offer some protection but there are basic research data suggesting a neuroprotective role for nicotine and a methodologically challengeable study of Swedish conscripts found that cigarette smoking at ages 18-20 was associated with a reduced risk for schizophrenia. It is still not clear if antipsychotic drugs are neuroprotective against oxidative stress. Microglial cells produce various pro-inflammatory cytokines (eg. TNF-α) and free radicals (eg. nitric oxide). Various typical and novel antipsychotic drugs inhibit cytokine and free radical release from activated microglia. Cytokines and free radicals might inhibit neurogenesis and cause white matter abnormalities in schizophrenia. Stress non-specifically might cause IFN-γ and other chemicals to activate microglia leading to release of cytokines and free radicals that then lead to the neuropathology of schizophrenia.

Viral infections

Do winter and early summer peaks of schizophrenia births reflect an infectious cause? It should be noted there have been a number of studies that did not favour an infectious aetiology.

If viruses are the cause of schizophrenic illnesses they only account for a small number of cases. Schizophrenia may not be caused by a specific infectious agent as such but rather result from an immune reaction in the central nervous system.

There may be a shift from type I (cellular) to type II (humoral) immune response in schizophrenia: impaired type I response was suggested by a small study where IFN-γ and TNF-α expression was comparatively diminished in schizophrenia.

Lipid metabolism

Levels of arachidonic acid in the frontal lobes, platelet conversion of arachidonic acid to prostaglandins, red cell membrane arachidonic acid and docosahexaenoic acid, and platelet membrane polyunsaturated fatty acid are reduced in schizophrenia. Brain phosphodiester concentration is increased in first-episode schizophrenia, which may relate to increased breakdown of phospholipase A2. Phosphomonoesters are less plentiful, perhaps due to decreased synthesis of phospholipids. Calcium-independent phospholipase A2 activity is increased in schizophrenia, whereas calcium-dependent activity is normal. In late childhood/early adolescence a normal pruning in synaptic density occurs; it is possible that increased phospholipase A2 activity could cause this to fail. Lipid peroxidase and vitamin E concentrations are increased in schizophrenia, especially in smokers. Long-chain omega-3 fatty acids might have potential for preventing full-blown psychosis in young people with subthreshold psychotic states. Researchers have suggested that antipsychotics change the ratio of polyunsaturated to saturated fatty acids and cholesterol content leading to changes in neuronal connectivity.

Secondary schizophrenia

Certain drugs may precipitate paranoid-hallucinatory psychoses: anticholinergics; bromocriptine; LDOPA; psychostimulants (eg. amphetamine); hallucinogens (eg. LSD and PCP); ACTH and steroids; disulfiram; indomethacin; digoxin; vigabatrin (GABA transaminase inhibitor); and anti-malarial and anti-TB agents.

Certain conditions may be associated with a schizophrenia-like presentation: brain injury or tumour; cerebrovascular disease; frontotemporal dementia; Parkinson’s disease (contradictory evidence); encephalitis; central syphilis; Sydenham’s chorea; temporal lobe epilepsy; Huntington’s disease; Wilson’s disease; narcolepsy (some cases may be due to amphetamine); Fahr’s disease (familial idiopathic basal ganglia calcification, an autosomal dominant condition); and demyelinating disorders.

Is there a shared genetic basis between schizophrenia and coeliac disease and does abnormal intestinal permeability in schizophrenia permit passage of exorphins that cause behavioural problems, and can gluten precipitate schizophrenia in a few cases? A genetic marker (6p23-p22.3) in coeliac disease is close to the dysbindin locus (implicated in schizophrenia). Of note, immune reaction to gliadin has recently been reported in bipolar disorder.

Schizotypal disorder

This quasi-schizophrenic, chronic disorder (or personality type) is characterised by magical thinking, eccentricity, circumstantiality, excess use of metaphors, and over-elaboration but no gross incoherence of thought. There are suspiciousness, paranoid thinking, unresisted obsessionality, illusions, depersonalisation and derealisation, with occasional transient exacerbations. There is impairment of working memory and difficulty in correctly interpreting facial expressions and in producing facial expressions that are socially attractive or with specific emotions. Only some cases develop schizophrenia but a family history of schizophrenia is not uncommon. It is often considered as part of a ‘schizophrenic spectrum’. Aspects of this disorder can commonly be seen in relatives of patients with other disorders, especially in association with mood disorder.

Some concluding remarks

There is growing, albeit incomplete and sometimes contradictory, evidence that the brain in schizophrenia is primed by a host of genes of individual small effect leading to abnormal ‘wiring’. When the psychosis becomes overt there may be some further neurological deterioration. Biochemical pathology certainly involves dopamine and the effects of other chemicals are only beginning to receive adequate research attention. The brain is a neurochemical orchestra in which each component interacts with others in complex ways. Poor methodology (eg. including schizoaffective disorder in studies of schizophrenia) and the problem of validity (as distinct from reliability) of diagnoses are major hurdles to overcome in research in this area. Endophenotype/intermediate phenotype (eg. dysfunctional smooth-pursuit eye movement or face emotion recognition delineation), as yet in its infancy, may answer some of these conundrums. 

As a working clinical model, the author still relies heavily on the psychoanalytical and filter theories of schizophrenia: people with this devastating problem have been robbed of their protective barrier between ‘us’ and ‘them’; they are psychologically naked, exposed and vulnerable; their brains play bizarre tricks on ‘them’ and we see ‘them’ as being ‘bizarre’.

See part one of this series.

See part two of this series.

Declaration of interest: none.