Changing Views of Schizophrenia and Antipsychotic Agents

By | February 4, 2015

In the years following the introduction of the first antipsychotic drugs (the mid-1950s), their most clinically salient effect was suppression of the symptoms of acute psychosis, including delusions, hallucinations, thought disorder, agitation, and gross disorganization. The past several years of research on the outcome of pharmacotherapy for schizophrenia have seen an emphasis on the domains of functioning where the neuroleptics fall short, most particularly, negative symptoms, deficit states, and cognitive and neuropsychological impairments. In addition, there has been much study of response to atypicals by people who are known to be unresponsive to typicals. As of this writing, most of the published studies contrast clozapine (Clozaril), the first widely available atypical, with haloperidol (Haldol), a first-generation typical. There is a considerable amount of information on risperidone (Risperdal), the second widely available atypical, and on olanzapine (Zyprexa). Data on the remaining approved atypicals — quetiapine (Seroquel) and ziprasidone (Geodon) — are just beginning to appear.

There is broad agreement that about half of the people diagnosed with schizophrenia who are unresponsive to typicals show a fair to good response to clozapine and that clozapine produces substantially fewer side effects at standard therapeutic dose levels. There is controversy as to whether clozapine has differentially greater effects on negative symptoms. The problem appears to be that the term negative symptoms represents a heterogeneous category of clinical expressions, probably linked to different neurophysiological and developmental mechanisms. Some may be primary, directly linked to the etiology of the disorder, whereas others are secondary, arising from incidental factors such as drug side effects or individuals’ responses to the primary expressions. For example, some of the differential effectiveness of atypicals for negative symptoms (lack of motivation or feeling) may be attributable to their lower levels of extrapyramidal side effects. There is some evidence that secondary negative symptoms show more differential response than primary negative symptoms.

Both clozapine and risperidone are superior to typicals in reducing the degree of neurocognitive impairment that remains in the severe and persistent residual phase of the disorder, after the recipient has been determined to be medicated optimally. There is some preliminary evidence that olanzapine also improves cognitive functioning. However, no atypical returns cognition to pre-morbid or normal levels, and the impact of the atypicals’ superior cognitive effects on overall outcome is not clearly established.

It is not obvious why atypicals benefit neurocognition. One possibility is that they are simply more effective at resolving acute psychosis and the severe cognitive impairments attendant to that condition. Another possibility is that typical antipsychotics have detrimental effects on cognition during the residual phase, whereas atypicals lack these effects. Residual-phase impairments could be partly caused by the typicals’ anticholinergic (interference with the action of acetylcholine in the brain) properties, as is suspected for some negative symptoms (it is noteworthy in this regard that, as discussed above, neurocognitive impairments are associated with negative symptoms). A third possibility is that, in addition to their anti-psychotic action, atypicals affect other neurochemical systems that produce cognitive impairments in the residual phase of the disorder. In this regard, candidate mechanisms include selective acetylcholine agonism, downregulation of 5-hydroxytryptamine Type 2a receptors, and enhanced glycine modulation of the N-methyl-D-aspartate receptor, a component of the glutamate transmitter system. It is entirely possible that different atypicals affect neurocognition in different ways.

Clozapine appears to moderate some dimensions of affective dysregulation, in the domains of hostility and irritability. This may prove an important advantage for managing aggression, mania, and depression when they co-occur with the more pathognomic characteristics of schizophrenia. Clozapine has been found to reduce aggression in particularly violent and treatment-resistant individuals. Risperidone was found to be no more effective than typicals in this regard.

The atypicals are considerably more expensive than the typicals. However, cost-effectiveness analyses indicate that the greater cost is more than offset by the reduced costs consequent to atypicals’ greater clinical efficacy.