Greater attention has been given to the cognitive dimension in schizophrenia in recent years. This has resulted from increased recognition that cognitive impairment and negative symptoms of the disease have a greater impact on quality of life (QOL) compared to positive symptoms. Successful treatment of positive symptoms in patients with schizophrenia has not been shown to robustly translate into improvements in employment status or social relationships, while cognitive improvements are strongly associated with these important aspects of QOL and independence. These findings are based on extensive testing with standard cognitive tests for measuring executive function, verbal learning and memory, word recall, verbal working memory, spatial working memory, attention, and vigilance. Verbal learning and executive function, in particular, have been found to be valid predictors of employment success independent of the degree of severity of positive symptoms.

From the perspective of efficacy, the main advantages of the group of new antipsychotic drugs, including ziprasidone, clozapine, quetiapine, olanzapine, and risperidone, are their ability to improve cognitive function. Other advantages are more selective, eg, clozapine in treatment-resistant schizophrenia, while the advantages for positive and negative symptoms in neuroleptic responsive patients are modest and sometimes difficult to demonstrate. The advantage for cognitive function is important because of abundant evidence that cognitive function is a key predictor of work and social function acquisition. The drug-induced cognitive improvement can synergize with typical rehabilitation programs and more experimental cognitive retraining programs to optimize these areas of improvement. Improved cognition also has implications for better compliance and decreased caretaker burden. It is also important to consider the efficacy of antipsychotics to improve mood and negative symptoms and to provide a biological framework for their ability to achieve these advantages over typical neuroleptic drugs. This article will provide new data on efficacy of this class of drugs relative to each other and to typical neuroleptics. Current theories linking efficacy in cognition to unique effects on cortical dopaminergic and cholinergic function and improved patterns of connectivity in the brain during cognitive task performance will be discussed. Finally, pharmacologic strategies to augment affect and cognitive improvements due to the new antipsychotic drug therapies will be discussed.

Clozapine is a prototype atypical antipsychotic drug and displays efficacy in 30% to 60% of schizophrenia patients who do not respond to traditional antipsychotics. There is considerable evidence supporting a concentration-response relationship for clozapine. A plasma clozapine concentration >200 to 420 ng/mL increases the probability of antipsychotic effects. Approximately 70% to 80% of variability in clozapine plasma concentration can be attributed to variability in cytochrome P450 1A2 activity. Measurement of caffeine metabolites in plasma or urine can be used as an in vivo index of cytochrome P450 1A2 activity, since caffeine is primarily eliminated by oxidative metabolism through this cytochrome P450 enzyme. Caffeine-based tests may contribute to individualization of clozapine dosages and optimization of its antipsychotic effects in schizophrenia patieents There are several lines of evidence suggesting the potential involvement of the dopamine D4 receptor in pharmacodynamic effects of clozapine. Clozapine has a 10-fold higher affinity for the dopamine D4 receptor in comparison to the D2 and the D3 receptors. Moreover, the free plasma fluid concentration of clozapine is comparable to its binding affinity for the D4 receptor in vitro. Blockade of the D4 receptor in the mesocorticolimbic region, a brain area implicated in the pathogenesis of schizophrenia, may contribute to efficacy of clozapine in negative symptoms. Moreover, the dopamine D4 receptor gene (DRD4) displays an unusual degree of genetic variation (polymorphism). In a recent preliminary study, investigated the (G)n mononucleotide repeat polymorphism within the first intron of the D4 gene in 50 schizophrenia patients refractory to traditional antipsychotics. These patients were prospectively followed for antipsychotic response during clozapine treatment. Analysis of variance found significant differences in antipsychotic response as demonstrated by mean change in Brief Psychiatric Rating Scale scores among the genotype panels for this polymorphism F[3,49]=4.1 (P=0.01). Future studies investigating the mechanistic basis of variability in response to clozapine should focus on both pharmacokinetic and pharmacodynamic factors.

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial was an effectiveness/”pragmatic” clinical trial designed to compare the efficacy, tolerability, and cost-effectiveness of four atypical antipsychotics (olanzapine, quetiapine, risperidone and ziprasidone) and a conventional antipsychotic (perphenazine) for an 18-month period in patients with schizophrenia. The study randomized 1,460 patients with fewer exclusion criteria than in most trials in hopes that this would allow for a more representative sample of outpatients in “real world” practice. Olanzapine demonstrated significant superiority in time to discontinuation for all cause and for lack of efficacy, as well as likelihood of hospitalization for relapse; however, it was associated with a significantly higher rate of metabolic side effects. Perphenazine exhibited comparable effectiveness with quetiapine, risperidone, and ziprasidone, and appeared to be as well tolerated as the atypicals. However, it had the highest rate of drop out due to extrapyramidal symptoms and was restricted to patients who did not have tardive dyskinesia (TD). This article examines the phase 1 CATIE results to guide the clinician in understanding how to interpret the findings, which were intended to be a guide for clinical practice. The nature of the patient population, the doses of drugs relative to one another, inclusion of patients who were treatment resistant, and exclusion of patients with TD from randomization to perphenazine were potential sources of bias in the study. In particular, the use of a higher-than-usual peak dose of olanzapine may have led to the superior results achieved with it. Practical suggestions are given for choice of antipsychotic medication in patients with chronic schizophrenia.

The primary basis for the action of neuroleptic drugs has been suggested to be a blockade of D2 receptors in the mesolimbic system, with subsequent decrease in the firing rate of ventral tegmental (A10) dopamine neurons by the process of depolarisation inactivation (Matthyssee, 1974; Bunney et al, 1991). The main evidence for this hypothesis is that: the affinities for the D2 receptor of all effective antipsychotic drugs are positively correlated with their average clinical dose (Seeman & Lee, 1975; Creese et al, 1976); and chronic administration of antipsychotic drugs produces nearly complete inhibition of the firing of ventral tegmental (A10) dopamine neurons that project to the limbic forebrain (Chiodo & Bunney, 1983). Clozapine, the prototypical atypical antipsychotic drug, also satisfies both criteria (Seeman & Lee, 1975; Chiodo & Bunney, 1985). However, the demonstration that clozapine is more effective than other neuroleptics for the treatment of both schizophrenic patients who are responsive to typical neuroleptics (Meltzer, 1992) as well as those who are resistant (Kane et al, 1988) suggests that this simple dopamine hypothesis of neuroleptic drug action is insufficient. Indeed, there is evidence that clozapine at clinically effective doses produces less D2 receptor occupancy and, hence, less antagonism of D2 receptors in the striatum, and probably also in the limbic system, than typical neuroleptic drugs (Farde et al, 1992); this further challenges the adequacy of the dopamine hypothesis to explain the greater efficacy of clozapine. This leaves the need to consider what else besides a D2 receptor blockade may explain the action of clozapine and, indeed, whether limited blockade is superior to a more complete one.

The use of items from the Schedule for Affective Disorders and Schizophrenia and from the Present State Examination scales for assessing positive and negative symptoms in schizophrenia was examined using factor analysis. The factorial structure of the items which putatively assess positive and negative symptoms was examined. A three-factor solution was obtained with factors identified as: a negative symptom factor (factor 1); a positive symptom factor (factor 2); a ‘disorganisation’ factor (factor 3), consisting primarily of items related to disordered thinking. A solution which was highly similar in important loadings was obtained with an independent sample of patients. High correlations of the rotated factors with the external criteria supported the interpretations of the factors. The results indicate that symptoms generally classified as negative or positive are factorially independent. Furthermore, a disorganisation factor, consisting of items previously included in positive and negative symptoms factors, is necessary for a full representation of the factor structure.

A schedule is described for rating the symptoms of mental illness over a period of time which includes several episodes. The reliability was measured in a study involving six raters. The sources of information required were studied, in 20 patients, by comparing an interview with the patient, a similar interview with an informant and an analysis of the case records. A synopsis of interview and record data are necessary to obtain adequate information about longitudinal psychopathology and ‘lifetime’ diagnosis.

Various outcome measures following clozapine administration to neuroleptic-resistant schizophrenic patients are considered. The importance of a multidimensional perspective is emphasised. There was significant improvement in positive symptoms, some negative symptoms, quality of life, some types of cognitive function (e.g. semantic memory), extrapyramidal function, and tardive dyskinesia. Readmission to hospital, and family burden were markedly reduced, which achieved significant savings in the cost of treatment. Compliance with clozapine and weekly blood testing can be achieved in the majority of treatment-resistant cases. These benefits may occur independently of each other.

Clozapine has an affinity for the dopamine (DA) D2 receptor which is relatively weak but is in line with its average clinical dose when compared with typical neuroleptic drugs. A few atypical antipsychotic drugs may have high absolute affinities for the D2 receptor, but most are weak D2 blockers. The atypical antipsychotic drugs also differ from the typical antipsychotic drugs by a relatively high affinity for the serotonin (5-HT2) receptor. This is evident on both in vitro and in vivo binding to cortical 5-HT2 receptors. The atypical antipsychotics are best distinguished from the typical antipsychotics on the basis of the relationship between strong 5-HT2 and weak D2 affinities. High D1 receptor binding is not characteristic of the group of atypical drugs. A new group of putative atypical antipsychotic drugs with high affinities for 5-HT2 compared to D2 receptors is under study.

Using structured psychiatric interviews, we searched for differences between depressed patients with bipolar affective disorder, and with other types of depression. The patients were taken from 2 large series, collected in London and Chicago. Some differences were found, but few more than would be expected by chance, in view of the large number of variables examined. The possible reasons for this failure are discussed. They include contamination of the groups, and the insensitivity of structured mental state inventories.

Platelet monoamine oxidase (MAO) activity was studied in 33 in-patients with bipolar and schizoaffective disorder who were treated with lithium. Platelet MAO activity was found to increase following 10–41 days of lithium treatment compared to a prior drug free period, and the increase was positively correlated with the duration of lithium treatment. The increase in platelet MAO activity was not correlated with clinical improvement as measured by the Brief Psychiatric Rating Scale (BPRS) and the Global Assessment Scale (GAS). The number of platelets per unit of blood was also significantly correlated with the number of days of lithium treatment. However, the increase in the number of platelets in lithium-treated patients was not correlated with the increase in MAO activity and thus appears not to account for it. These results indicate that studies relating platelet MAO activity to psychiatric diagnosis should be interpreted cautiously if patients are receiving lithium carbonate.

The rate of recovery of the H-reflex, an electrical evoked monosynaptic spinal cord reflex, was abnormally high (fast) in over 20% of unmedicated psychotic patients of all major diagnostic classes. A few patients had significantly lower H-reflex recovery curves. Chronic neuroleptic treatment produced relatively lower recovery curves, whereas fluoxetine, a specific serotonin uptake blocker, produced relatively higher curves.

Motor activity, monitored by a wrist motion transducer, was related to serum CPK activity the following morning in a group of psychiatric in-patients. In 4 of 10 patients, studied for periods exceeding one week, total 24-hour activity was significantly correlated with morning serum CPK activity. Motor activity during the night was unrelated to serum CPK activity. In a larger group of 30 patients, studied for one or two-day periods, inter-individual differences in activity level were not related to serum CPK activity, although both sex and race were significantly related to variance between subjects in that activity.