Dopamine is the most extensively investigated neurotransmitter system in schizophrenia. In 1973 it was proposed that schizo-phrenia is related to hyperactivity of dopamine. This proposition became the dominant pathophysiological hypothesis for the next 15 years. Its strongest support came from the fact that all com-mercially available antipsychotic agents have antagonistic effects on the dopamine D2 receptor in relation to their clinical potencies (Creese et al., 1975). In addition, dopamine agonists, such as am-phetamine and methylphenidate, exacerbate psychotic symptoms in a subgroup of patients with schizophrenia. Moreover, as noted earlier, the most consistently reported postmortem finding in the literature of schizophrenia is elevated D2 receptors in the striatum.
The dopamine hyperactivity hypothesis and the primacy of D2 antagonism for antipsychotic drug action were seriously ques-tioned largely because of the advent of clozapine, an atypical an-tipsychotic drug. Clozapine has proved to be the most efficacious treatment for chronic schizophrenia and yet it has one of the lowest levels of D2 occupancy of all antipsychotic drugs. This started an extensive search for explanations underlying the extraordinary ef-ficacy of clozapine. However, new information from PET studies has once again highlighted the central role that the dopaminergic system plays in treatment of psychosis. The typical and atypical antipsychotics are effective only when their D2 receptor occupancy exceeds 65%, reinforcing the importance of D2 antagonism in pro-ducing antipsychotic effects. However, an important difference between typical and atypical antipsychotics is in their affinity for the D2 receptors. Medications like clozapine attach loosely to and dissociate rapidly from the dopamine D2 receptors compared with typical antipsychotic agents (like haloperidol) which have strong affinity for and bind tightly to these receptors.
Five subtypes of dopamine receptor have now been dis-covered, D1, D2, D3, D4 and D5, and interest in dopamine recep-tors other than the D2 receptor has arisen. Reduced levels of D1-like dopamine receptors in the prefrontal cortex of patients with schizophrenia including in those never exposed to antipsy-chotic agents have been reported. The D1 receptors are expressed predominantly by pyramidal neurons on their dendritic spines, where they possibly modulate glutamate-mediated inputs to these neurons – inputs that mainly come from other pyramidal and thalamic neurons. Thus the reduced D1-like receptors seen in the prefrontal cortex of schizophrenia patients may underlie aspects of cognitive dysfunction and severity of negative symp-toms (Nestler, 1997).
Clinical trials of dopamine agonists have resulted in im-provements in the negative symptoms of schizophrenia. A new model of dopamine dysfunction was proposed which stated that deficits in dopamine, perhaps in the prefrontal cortex, may result in negative symptoms and that concomitant dopamine dysregula-tion in the striatum, perhaps related to faulty presynaptic control of dopamine release, may be involved in positive symptoms. This bidirectional model is under investigation.
The DA hypothesis of schizophrenia has been critical in guiding schizophrenia research for several decades. Until re-cently, a main shortcoming of this hypothesis was absence of di-rect evidence linking DA dysfunction to schizophrenia. Sophis-ticated in vivo techniques have provided fascinating data directly implicating dopamine in developing psychosis. It is also becom-ing clear that dopamine works closely with serotonin, glutamate and other systems such that changes in one system affects the balance of the other systems too.
Clozapine has a relatively high affinity for specific serotonin (5-hydroxytryptamine [5-HT]) receptors (5-HT2A and 5-HT2C) and risperidone, has even greater serotonin antagonistic properties. Clozapine, risperidone, olanzapine, quetiapine and ziprasidone, the novel antipsychotic agents, have a greater ratio of serotonin 5-HT2A to dopamine D2 binding affinity. This has led to the hypoth-esis that the balance between serotonin and dopamine may be altered in schizophrenia. Serotonin 5-HT2A (and other serotonin) receptor occupancy by the antipsychotic drugs, depending on the areas of the brain involved, could be associated with improve-ment in cognition, depression and D2 receptor mediated EPS.
There has been an explosion of new information about the structure and function of 5-HT receptors. To date, 15 serotonin receptor subtypes have been identified. Two receptors, 5-HT6 and 5-HT7, have been proposed as candidates for atypical drug ac-tion and are therefore reasonable targets for pathophysiological studies of schizophrenia. It is clear that the field is in the early stages of understanding the possible involvement of serotonin in schizophrenia.
Glutamate is a major brain excitatory amino acid neurotrans-mitter and is critically involved in learning, memory and brain development. Interest in glutamate and the NMDA receptor in schizophrenia arose because of the similarity between phencycli-dine (PCP) psychosis and the psychosis of schizophrenia. PCP is a noncompetitive antagonist of the NMDA receptor and produces a psychotic state that includes conceptual disorganization, audi-tory hallucinations, delusions and negative symptoms. PCP pro-duces more symptoms that are similar to those of schizophrenia than most other pharmacological agents.
PCP and other highly potent NMDA receptor antagonists cause neuronal damage and therefore are not used as research tools in clinical populations. However, ketamine, a widely used dissociative anesthetic, is another noncompetitive NMDA antag-onist and, at subanesthetic doses, produces a PCP-like psychosis resembling schizophrenia. The glutamate hypothesis of schizo-phrenia is one of the most active areas of research currently. The NMDA receptor is reported to play a critical role in guiding axons to their final destination during neurodevelopment. Also, abnormalities with glutamate transmission is reported in many areas of the brain such as frontal cortex, hippocampus, limbiccortex, striatum and thalamus. Moreover, there are changes re-ported in the gene expression in these areas, Hypoglutamatergia in schizophrenia may have very important downstream modu-latory effects on catecholaminergic neurotransmission and play a critical role during neurodevelopment. It also plays an impor-tant role in synaptic pruning and underlies important aspects of neurocognition.
GABA is the major inhibitory neurotransmitter in brain. Sup-port for GABA’s involvement in schizophrenia comes from two lines of investigation. First, clinical trials have demonstrated that benzodiazepines, administered both in conjunction with antipsychotic drugs and as the sole treatment, are effective at reducing symptoms in subgroups of schizophrenia patients. Benzodiazepines are agonists at GABAA receptors. Secondly, postmortem studies have found a deficit in GABA interneurons in the anterior cingulum and prefrontal cortex and decreased GABA uptake sites in the hippocampus. GABAergic neurons are especially vulnerable to glucocorticoid hormones and also to glutamatergic excitotoxicity.
Several peptides have been hypothesized to play a pathophysi-ological role in schizophrenia. Interest in neurotensin arose be-cause of the discovery that it is colocalized in some dopaminergic neurons and acts as a neuromodulator of this and other neuro-transmitters. In preclinical studies, neurotensin was found to have effects that resembled those of antipsychotic drugs (Kasckow and Nemeroff, 1991. In addition, schizophrenia patients were found to have lower cerebrospinal fluid neurotensin levels than healthy control subjects and other patients with neuropsychiatric disor-ders. Other peptides that are under consideration for a patho-physiological role in schizophrenia are somatostatin, dynorphin, substance P and neuropeptide Y.
Heightened noradrenergic function has been implicated in psychotic relapse in subgroups of schizophrenia patients (van Kammen et al., 1990). In addition, clozapine, but not other neu-roleptic drugs, consistently produces increases in central and pe-ripheral indices of noradrenergic function, and one study found
significant relationship between increases in plasma norepine-phrine and improvement in positive symptoms.
Carlsson and colleagues (2001) provide a multineurotransmitter theory of schizophrenia which improves upon previous biochem-ical theories of schizophrenia. Accumulating evidence suggests that hyperdopaminergia in schizophrenia is probably second-ary to some other phenomena. The data involving glutamater-gic system suggests that NMDA receptor antagonism enhances the spontaneous and amphetamine-induced release of dopamine and thus raises the possibility that hypoglutamatergia could be related to the hyperdopaminergia. Carlsson and colleagues propose that psychotogenesis depends on an interaction between dopamine and glutamate pathways projecting to the striatum from the lower brain stem and cortex respectively. These neu-rotransmitters are predominantly antagonistic to each other, the former being inhibitory and the latter stimulatory when acting on striatal GABAergic projection neurons. These GABAergic neurons belong to striatothalamic pathways, which exert an inhibitory action on thalamocortical glutamatergic neurons, thereby filtering off part of the sensory input to the thalamus to protect the cortex from a sensory overload and hyperarousal. Hyperactivity of dopamine or hypofunction of the corticostriatal glutamate pathway should reduce this protective influence and could thus lead to confusion or psychosis. As a result, the in-direct striatothalamic pathways have an inhibitory influence on the thalamus with the corresponding direct pathways exerting an opposite and excitatory influence. Both pathways are controlled by glutamatergic corticostriatal pathways enabling the cortex to regulate the thalamic gating in opposite directions. Thus, accord-ing to Carlsson and colleagues they appear to serve as brakes and accelerators.
It has been suggested that the activity of the direct path-ways is predominantly phasic and of the indirect pathways is mainly tonic. This difference could have important consequences for a different responsiveness of the direct and indirect pathways to drugs. Thus the NMDA receptor antagonists are behavioral stimulants. AMPA receptor antagonists act in the same direction as NMDA antagonists in some and opposite direction in other experiments. The relationship between glutamate and serotonin is very important and interesting. Serotonin appears to play a more important role than dopamine in the behavioral stimula-tion induced by hypoglutamatergia. Serotonin may play a more prominent role than dopamine in the behavioral stimulation in-duced by hypoglutamatergia. Schizophrenia is a syndrome of heterogeneous etiology and pathology. If one neurotransmitter is disturbed, it will inevitably have an impact on other neurotrans-mitters (Carlsson et al., 2001).
Neurodevelopmental hypotheses of schizophrenia posit that a disruption in normal development causes the illness (Wein-berger, 1987). Thus, the “lesion” occurs well before the onset of the illness and interacts with maturation events such as neu-ronal precursor, glial proliferation and migration; axonal and dendritic proliferation; myelination of axons; programmed cell death and synaptic pruning and is in all likelihood a nonpro-gressive disease process. Support for the neurodevelopment hypothesis includes the fact that the majority of patients with schizophrenia do not have a course of illness marked by progres-sive deterioration such as found in dementias. In addition, brain morphological abnormalities commonly found in this illness, such as enlarged ventricles and reduced mesolimbic structures, do not appear to be progressive and, in fact, are present at the on-set of the illness. Moreover, gliosis, which occurs during active pathological processes as part of the cellular reparative process in mature brains, is not commonly found in postmortem studies of schizophrenia.
That illness onset typically occurs in the teenage years and early twenties, as opposed to earlier in life when the pro-posed pathogenic insult occurs, has been explained by the fact that brain regions implicated in this illness, such as prefrontal cortex, are still undergoing myelination during the adolescent years and are therefore not fully functional until that time. Thus, an early lesion involving this region could remain silent until adolescence, when its normal functional capacity is expected to be realized. However, these assumptions have proven to be controversial.