The next generation of "atypical" antipsychotics: the role of positron emission tomography

Almost fifteen years of research with Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) have led to a profound understanding of the relationships between antipsychotic doses and plasma levels on the one hand and occupancy of (striatal) D2 -like dopamine receptors on the other hand as well as with the associated clinical effects and side effects. Furthermore, with the development of clinically "atypical" antipsychotics PET studies helped to generate hypotheses regarding the essential pharmacological properties of this heterogeneous class of drugs. Possible mechanisms of action include combined D2 -/5-HT2 antagonism, preferential mesolimbic binding, and fast dissociation from the D2 -receptor. Our recently published PET study on the in vivo characterization of the partial dopamine receptor agonist, aripiprazole, suggests a novel mechanism of action, which leads to clinically "atypical" properties of an antipsychotic. Aripiprazole, of which the antipsychotic efficacy has been proven in various multicenter clinical trials, leads to almost complete saturation of D2 -like dopamine receptors at clinically used doses; however, the incidence of extrapyramidal side effects under aripiprazole is not higher than under placebo. PET like no other method is suitable to display in vivo a novel mechanism of "atypicality" of a new class of antipsychotics.     

Antipsychotic and antidepressive effects of second generation antipsychotics

Second generation antipsychotics display antidepressive effects in schizophrenic patients that are more pronounced than those of traditional neuroleptics and that go beyond antidepressive effects secondary to the reduction of positive symptoms. The antidepressive potential of second generation antipsychotics is presumably related to their pharmacological mechanisms, which differ from those of traditional neuroleptics. Among others, 5-HT_2A antagonism is of special relevance for most of the new antipsychotics in this respect. But also special interactions with the dopaminergic system, as is the case with amisulpride and aripiprazole, or noradrenalin- and/or serotonin-reuptake-inhibition, as with ziprasidone and zotepine, should be considered. It can be summarised that the antipsychotic and antidepressive effects of second generation antipsychotics are mostly based on different pharmacological mechanisms. This might be especially true for direct antidepressive effects, i. e. antidepressive effects that are not mediated by the reduction of positive symptoms.     

Neuroleptics, atypical antipsychotics and "awakening"

Clinical response to the treatment of schizophrenic patients with atypical antipsychotics is sometimes labeled as "awakening". However, there is no general agreement what this term specifically means. The wide range of definitions starts from withdrawal of side effects of classical neuroleptics and goes through psychological phenomena to the definition that postulates arresting of the psychotic process. The paper presents a review of different points of view on "awakening" phenomena as well as problems that are connected with it. Some own experiences and attempts at generalization are presented. They deal with new problems and challenges connected with treatment of patients with acute and chronic schizophrenia with atypical antipsychotics.     

Treatment strategies for dosing the second generation antipsychotics

Background: The second generation antipsychotics now have clinical approvals for the treatment of schizophrenia, bipolar depression, bipolar mania, autism, major depressive disorder and are used furthermore off‐label to treat other mental disorders. Each agent is unique in its pharmacodynamic profile and allows for unique dosing strategies to be employed when treating these different disorders. Aims: To review relevant data regarding the second generation antipsychotics and their empirical dosing strategies. To further review and comment theoretically in these areas where substantial, definitive data are lacking. Materials and Methods: A MEDLINE and recent textbook review was conducted regarding each second generation antipsychotic and cross‐referenced with searches for major mental disorders. The findings are compiled in the review below. Discussion: The second generation antipsychotics are clearly delineated in the treatment of psychosis and mania and share similar mechanisms of action to achieve these results: dopamine‐2 receptor antagonism for efficacy and serotonin‐2a receptor antagonism for EPS tolerability. From here, each agent has a unique pharmacodynamic and pharmacokinetic profile where some agents carry more, or less antidepressant, anxiolyic, or hypnotic profiles. Choosing an agent, and dosing it in low, middle, or high ranges may result in differential effectiveness and tolerability. Conclusion: The second generation antipsychotics have many clinical applications in psychiatric practice. This article serves to review this and also suggests ways clinicians may optimize treatment based upon patient diagnosis and utilizing appropriate dosing of each individual second generation antipsychotic.     

Effects of second generation antipsychotics on leptin and ghrelin

BACKGROUND: Weight gain is a major side effect of antipsychotic treatment. Some atypical antipsychotic agents have profound effects on weight. Body weight is regulated by a complex system, including both peripheral and central factors. Two of the hormones that seem to play an important role in the regulation of food intake, energy metabolism, and body weight are leptin and ghrelin. Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss. Ghrelin on the other hand is a fast-acting hormone, seemingly playing a role in meal initiation. In this present study it is aimed to compare the effects of five different atypical antipsychotic medications on leptin and ghrelin. METHOD: 112 patients who were treated either with clozapine (n=20), olanzapine (n=28), risperidone (n=22), quetiapine (n=20) or amisulpride (n=22) as monotherapy for at least one year and age, gender, and body mass index (BMI) matched control group (n=23) were assessed cross-sectionally. Ghrelin and leptin levels were measured with enzyme-immunoassay. RESULTS: When fasting serum leptin levels were compared between groups, control group had the highest mean value (9.2+/-6.7) and amisulpride group had the lowest mean value (3.7+/-2.1) but still there was no statistically significant difference between six groups (F=1993, p=0.084). In the comparison of the mean values of fasting serum ghrelin levels there was a statistically significant difference between groups (F=11,473, p=0.00). In post-hoc analysis it was seen that the control group had the lowest ghrelin level (194.5+/-86.8). Quetiapine treated group (378.1+/-260.4) had similar fasting serum ghrelin levels to control group. All the other antipsychotic treatment groups had significantly higher levels of fasting serum ghrelin compared to control group, highest in amisulpride treated group (597.0+/-150.0). CONCLUSION: The weight-gain side effect of atypical antipsychotics can be related with the orexigenic effect of elevated serum ghrelin rather than leptin deficit. Among the five widely used atypical antipsychotics quetiapine is the only one which does not elevate the ghrelin level.     

Influences of second generation antipsychotics on the course of schizophrenia

Although there were multiple initiatives to modify course and outcome of schizophrenia by optimizing present psychopharmacologic strategies many unsolved problems still exist. There is no doubt that first generation antipsychotics reduce positive symptoms of psychosis but the impact on negative symptoms or disturbances of affect or cognition remains very poor. In contrast second generation antipsychotics show significantly a better tolerability, especially less extrapyramidal side effects. However, they may initiate strong individual side effects. This article reflects advantages and disadvantages of modern antipsychotics on the course of schizophrenia.     

Time to rehospitalization in patients with schizophrenia discharged on first generation antipsychotics, non-clozapine second generation antipsychotics, or clozapine

Rehospitalization is an important outcome of drug effectiveness in schizophrenia. In this study, the hypothesis that clozapine and some second generation antipsychotics (SGA) were superior to first generation antipsychotics (FGA) in preventing rehospitalization of patients with schizophrenia discharged from a university hospital in Brazil was tested. A retrospective observational study was conducted designed to evaluate time to rehospitalization of patients with schizophrenia discharged on a regimen of oral FGA, depot FGA, risperidone, olanzapine and amisulpride, other SGA, or clozapine, during a three-year follow-up period. Risk factors associated with rehospitalization were examined. Of the 464 patients with schizophrenia discharged from hospital, 242 met criteria for study entry. Higher rehospitalization rates were observed in patients treated with depot FGA (30%), risperidone (30%) and other SGA groups (28.5%), respectively. Clozapine was significantly associated with lower rehospitalization risk compared with risperidone. The risk of rehospitalization in patients on olanzapine and amisulpride, and oral FGA, was similar to that of patients in use of clozapine. These results however, are limited by the heterogeneity of illness severity across the groups.     

Optimal dosing of atypical antipsychotics in adults: a review of the current evidence

This review describes dosing strategies used to optimize the beneficial effects of atypical antipsychotic medications. Differences between manufacturers' recommended dosing and actual clinical practice are reconciled using evidence from pivotal double-blind randomized registration studies, other randomized clinical trials, case series, and case reports. With clozapine and perhaps olanzapine, plasma levels are correlated with therapeutic response; with risperidone, plasma levels are not correlated with therapeutic response but may be related to the occurrence of extrapyramidal symptoms. Information related to optimal dosing of quetiapine and ziprasidone is more limited. In clinical practice, the mean daily dose of risperidone has decreased, whereas that for olanzapine is increasing. The percentage of patients receiving quetiapine at doses above the manufacturer's recommended maximum is higher than would be expected, further illustrating that dosing ranges established during registration studies may not reflect the needs of day-to-day practice.     

Antidepressive effects of traditional and second generation antipsychotics: a review of the clinical data

For a long time,in the context of depressive symptoms in schizophrenia traditional neuroleptics were mostly discussed with respect to possible depressiogenic side effects, although some studies argued that they may also have certain antidepressive effects. However, this was not proven at that time in placebo-controlled studies. Placebo-controlled studies performed in recent years have shown that second generation antipsychotics have antidepressive effects which are significantly stronger than those of the traditional neuroleptics. In addition, it was demonstrated that this antidepressive effect can only partially be explained as being secondary to the improvement of positive and negative symptoms, and is apparently predominantly due to a direct (primary) effect on depressive symptoms. It is of special relevance in this context that the antidepressive effect of second generation antipsychotics was recently demonstrated in depression. The positive results from some studies in bipolar depression are especially impressive and underline the antidepressive potencies of novel antipsychotics beyond the spectrum of schizophrenia.     

Emerging evidence for the use of atypical antipsychotics in borderline personality disorder

BACKGROUND: The availability of new atypical antipsychotics provides new opportunities for the treatment of borderline personality disorder (BPD). METHODS: Original papers on this topic were sought. Our study reviewed and discussed 14 papers. RESULTS: 2 RCTs, 4 non-controlled open-label studies and 8 case reports. The patient populations studied were highly diverse and the dropout rate after a long follow-up period was high. All of the articles reported positive effects of olanzapine, clozapine, quetiapine and risperidone. CONCLUSION: BPD patients with psychotic-like, impulsive or suicidal symptoms might benefit from atypical antipsychotics. Since the methodological quality of the reviewed articles is poor, further randomised placebo-controlled studies with longer follow-ups are needed before any firm conclusions can be drawn.     

Treatment of "the premonitory state of schizophrenia" with atypical antipsychotics]

"Premonitory symptoms and signs" before the full-blown stage of schizophrenia are recognized as abnormal expressions (signs) and symptoms of "early schizophrenia", as described by Nakayasu (1990). The following conclusions were derived from my examination of the effects of atypical antipsychotics on six patients suffering from 'the premonitory symptoms and signs' in 'the premonitory state of schizophrenia'. 1) Even though hyperventilation, fatigue and a depressive state existed in the foreground at the first medical examination, we suspected 'the premonitory state of schizophrenia', and investigated symptoms of 'early schizophrenia' as described by Nakayasu, in cases in which abnormal expressions such as stiff facial expression and specific tense and perplexed attitude were observed. 2) In cases in which 'the premonitory symptoms and signs' were observed, we introduced treatment with atypical antipsychotics as soon as possible. Hyperventilation and a depressive state, which were considered to be induced by 'the premonitory state of schizophrenia', disappeared as a result of the improvement of 'the premonitory symptoms and signs' by the atypical antipsychotics. 3) Risperidone, perospirone, and olanzapine were effective for so-called "positive early symptoms". Risperidone, which is expected to have an acute effect, was effective in cases in which early intervention was necessary. When a depressive state was secondarily induced by risperidone, a change to perospirone was useful. Furthermore, when risperidone and perospirone were not sufficiently effective, olanzapine improved 'the premonitory symptoms and signs'. 4) In cases in which so-called "negative early symptoms" and a decrease in the energy-potential, such as emotional blunting, were observed, olanzapine induced improvement. 5) In 'the premonitory state of schizophrenia', treatment with atypical antipsychotics should be maintained, for both the improvement of 'the premonitory symptoms and signs' and the prevention of progression to the full-blown stage. The dose and duration of the treatment with antipsychotics should be carefully modified, with consideration for the specificity of the life cycle and life events for each patient. In conclusion, treatment with atypical antipsychotics was useful for both the improvement of 'the premonitory symptoms and signs of schizophrenia' and the prevention of the development of pathogenesis.