Since the introduction of chlorpromazine and throughout the development of the new-generation antipsychotic drugs (APDs) beginning with clozapine, the D(2) receptor has been the target for the development of APDs. Pharmacologic actions to reduce neurotransmission through the D(2) receptor have been the only proven therapeutic mechanism for psychoses. A number of novel non-D(2) mechanisms of action of APDs have been explored over the past 40 years but none has definitively been proven effective. At the same time, the effectiveness of treatments and range of outcomes for patients are far from satisfactory. The relative success of antipsychotics in treating positive symptoms is limited by the fact that a substantial number of patients are refractory to current medications and by their lack of efficacy for negative and cognitive symptoms, which often determine the level of functional impairment. In addition, while the newer antipsychotics produce fewer motor side effects, safety and tolerability concerns about weight gain and endocrinopathies have emerged. Consequently, there is an urgent need for more effective and better-tolerated antipsychotic agents, and to identify new molecular targets and develop mechanistically novel compounds that can address the various symptom dimensions of schizophrenia. In recent years, a variety of new experimental pharmacological approaches have emerged, including compounds acting on targets other than the dopamine D(2) receptor. However, there is still an ongoing debate as to whether drugs selective for singe molecular targets (that is, 'magic bullets') or drugs selectively non-selective for several molecular targets (that is, 'magic shotguns', 'multifunctional drugs' or 'intramolecular polypharmacy') will lead to more effective new medications for schizophrenia. In this context, current and future drug development strategies can be seen to fall into three categories: (1) refinement of precedented mechanisms of action to provide drugs of comparable or superior efficacy and side-effect profiles to existing APDs; (2) development of novel (and presumably non-D(2)) mechanism APDs; (3) development of compounds to be used as adjuncts to APDs to augment efficacy by targeting specific symptom dimensions of schizophrenia and particularly those not responsive to traditional APD treatment. In addition, efforts are being made to determine if the products of susceptibility genes in schizophrenia, identified by genetic linkage and association studies, may be viable targets for drug development. Finally, a focus on early detection and early intervention aimed at halting or reversing progressive pathophysiological processes in schizophrenia has gained great influence. This has encouraged future drug development and therapeutic strategies that are neuroprotective. This article provides an update and critical review of the pharmacology and clinical profiles of current APDs and drugs acting on novel targets with potential to be therapeutic agents in the future.

When nonpharmacological strategies alone are insufficient, and switching antipsychotics to relatively weight-neutral agents is not feasible, the literature supports the use of concomitant metformin as first choice among pharmacological interventions to counteract antipsychotic-induced weight gain and other metabolic adversities in schizophrenia.

Drug monitoring in psychiatry is of increasing interest due to compliance problems, side effects of psychoactive drugs and the search for adequate dosage. In the present study, plasma levels of clozapine, as determined by high performance liquid chromatography, were investigated in 148 patients receiving a daily dose between 12.5 and 700 mg clozapine. Regression analysis revealed a linear relationship between dose and plasma concentrations. Plasma concentrations at a given dose (level divided by dose and body weight) in male patients reached only 69.3% of the concentrations in female patients (Mann-Whitney U Test P less than 0.001). When the patients were divided into smokers and non-smokers, the corresponding plasma levels were also found to be linearly dose dependent in each of the two groups. However, the average plasma concentration at a given dose was only 81.8% in smokers, compared to non-smokers. This difference was statistically significant (variance analysis P = 0.022). Dividing female patients into smokers and non-smokers, the smokers reached nearly the same plasma levels as the non-smokers. Male smoking patients reached average plasma concentrations which were only 67.9% of those of non-smokers. This difference was statistically significant (Mann-Whitney U Test P = 0.0083). The plasma levels of the different age groups at a given dose per kg body weight were compared using the Mann-Whitney U Test. Significant differences were found between group 1 (18-26) and group 4 (45-54) (P less than 0.01) and group 2 (27-35) and group 4 (P less than 0.01) showing higher plasma levels in the older age group.(ABSTRACT TRUNCATED AT 250 WORDS)

Second-generation antipsychotic agents (SGAs) are increasingly replacing first-generation antipsychotic agents due to their superior activity against the negative symptoms of schizophrenia, decreased extrapyramidal symptoms and better tolerability. However, some SGAs are associated with adverse metabolic effects as significant weight gain, lipid disorders and diabetes mellitus. The pathogenesis of SGA-induced disturbances of glucose homeostasis is unclear. In vivo studies suggest a direct influence of SGAs on peripheral insulin resistance. To this end, we analyzed whether olanzapine might alter glycogen synthesis and the insulin-signaling cascade in L6 myotubes. Glycogen content was diminished in a dose- and time-dependent manner. Within the insulin-signaling cascade IRS-1 tyrosine phosphorylation was induced several fold by insulin and was diminished by preincubation with olanzapine. IRS-1-associated PI3K activity was stimulated by insulin three-fold in L6 myotubes. Olanzapine inhibited insulin-stimulated IRS-1-associated PI3K activity in a dose-dependent manner. Protein mass of AKT, GSK-3 and GS was unaltered, whereas phosphorylation of AKT and GSK-3 was diminished, and pGS was increased. Finally, we compared olanzapine with amisulpride, an SGA clinically not associated with the induction of diabetes mellitus. Glycogen content was diminished in olanzapine-preincubated L6 cells, whereas this effect was not observed under the amisulpride conditions. We conclude that olanzapine impairs glycogen synthesis via inhibition of the classical insulin-signaling cascade and that this inhibitory effect may lead to the induction of insulin resistance in olanzapine-treated patients.

A multicenter randomized 4-week interindividual double-blind study was carried out in 58 hospitalized patients with major depressive disorder (DSM III 296.23,296.22,296.33,296.32,296.53 and 296.52) to test the dose-effect relationship of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram: 3 × 0.25 mg, 3 × 0.50 mg and 3 × 1.00 mg rolipram/day. With respect to the desired effect, the 3 × 0.50 mg dosage stood out from the others in almost all relevant parameters. With respect to the response rate, the efficacy of the 3 × 0.25 mg dosage was about the same as that reported in the literature for placebo. The inferior performance of the 3 × 1.00 mg dosage compared to the 3 × 0.50 mg dosage might indicate a reverse U-shaped dose-effect relationship. There was good tolerance to all three dosages. There were no findings that might cast doubt on the safety of the dosages tested.