Current Psychopharmacology - Volume 1, Issue 2, 2012

Objective: This study investigated gender differences in clozapine prescription in Australia as a proxy measure of treatment resistant schizophrenia. Method: Patients (n=9383) were identified retrospectively from the Hospira ClopineConnect database ranging from October 1992 to September 2009. Data collected included patients’ date of birth, gender, daily dose of clozapine and commencement date of clozapine. Results: The majority (69%) of patients on clozapine were male. The mean dose for males (433.6 mg, SD = 187.6 mg) was significantly higher than for females (376.1 mg, SD = 184.0 mg), p<0.001. The mean dose per age group was higher for males than females in all age groups. The mean age at which female patients started clozapine was 36.3 years (SD = 12.5 years) and for male patients was 31.7 years (SD = 9.9 years), with the difference significant (p<0.001). The male to female ratio of patients commencing clozapine was 2.6:1 below the age of 45, and 0.9:1 above the age of 45. The overall ratio of male to female patients was 2.2:1 which was higher than noted in other naturalistic clozapine databases in different regions of the world. Conclusions: Men are 2.2 times more likely to be prescribed clozapine and begin at an earlier age than females. The gap of several years in age of commencement of clozapine between males and females is comparable to a gap seen in age of first diagnosis of schizophrenia. This suggests that men are more likely to develop a more severe form of illness (treatment resistant schizophrenia) than women despite equal prevalence of schizophrenia. The gender difference in clozapine prescription is more marked in Australia when compared with other countries.

Background: Aripiprazole is an atypical antipsychotic that was approved, relatively recently, for use in adolescents with schizophrenia. Objective: The aim was to discuss efficacy and tolerability issues of aripiprazole in adolescents suffering from schizophrenia. Method: A Medline search identified only three studies and one post hoc analysis for one of them, concerning the use of aripiprazole in adolescents with schizophrenia. Finally, one of the studies was excluded because of the small number of cases treated with aripiprazole. Results: Based on the clinical evidence, including data from two short-terms clinical trials and one post-hoc analysis of one of the abovementioned studies, aripiprazole seemed generally safe and well tolerated in children and adolescents. Aripiprazole at doses of 10 to 30 mg/day was more efficacious in ameliorating the symptoms (including hostility) of schizophrenia than was placebo. It was associated with low number and mild-to-moderate intensity of adverse events, and with no clinically relevant findings in ECGs, vital signs, and clinical laboratory tests. The most common adverse events were extrapyramidal disorder, somnolence, and tremor. Also aripiprazole is unlikely to be associated with hyperprolactinemia and clinically significant weight gain. Conclusion: Scant information exists to evaluate the use of aripiprazole in early-onset schizophrenia, due to the lack of published studies. The initial encouraging results provide further support and point out the necessity for systematic research on the efficacy and tolerability of aripiprazole in pediatric patients suffering from schizophrenia.

The Psychobiological Model of Temperament and Character (also known as the Seven Factor model) is described in detail in this review, in terms of its neurophysiological underpinnings, psychometric properties, and clinical applications in the diagnosis and treatment planning of personality disorder (PD). The Temperament and Character Inventory (TCI), a self-report test developed to assess temperament and character traits, is used to evaluate bio-genetic (temperament) and adaptive (character) aspects of personality. Diagnosis of PD is a 2-step process that involves both character assessment (character is essential to assess mal-adaptation, as the core impairment shared by all subtypes of PD) and temperament assessment (temperament is used to distinguish specific symptomatic presentations in differential diagnosis of PD). We advocate that the Seven Factor Model of Temperament and Character provides a theoretical framework for more productive research, assessment, and treatment of normal personality and PD. In addition, pharmacotherapy and psychotherapy of PD are discussed in some detail, including pharmacological management of temperament and psychotherapy of character based on TCI scores. Finally, congruence between the Seven Factor model and the expected DSM-5 classification of and approach to PD are discussed in some detail.

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene that codifies the protein huntingtin. The disease is characterized by neurodegeneration of certain areas of the brain, particularly the striatum and the cortex. The first symptoms usually appear in mid-life and include cognitive deficits and motor disturbances that progress over time. The disease is invariable fatal and there is currently no cure for individuals affected with this disorder. HD transgenic mouse models have served as useful tools not only to elucidate the mechanisms underlying neurodegeneration in the HD brain, but also to test a number of therapeutic strategies for this disease. As a consequence of the promising results obtained in some of these preclinical studies, various pharmaceutical compounds have now been used in clinical trials. However, in most cases, the benefits observed in the clinical setting have been somewhat limited and, as such, the search for effective treatments still continues. In this review we present an overview of the various therapeutic strategies for HD that have received attention during the past decades, including the use of essential fatty acids, creatine, co-enzyme Q10, remacemide, riluzole, memantine, cystamine, minocycline, and tetrabenazine. We compare their efficacy in mitigating the neuropathology and symptoms of HD transgenic mouse models with the results that have been obtained with these compounds in clinical trials. Finally, we outline some recommendations that should be considered when designing future preclinical and clinical trials for the screening of potential therapeutic strategies for HD.

γ-Secretase was first identified as a protease that cleaves amyloid precursor protein (APP) and produces Aβ peptides, which are thought to be pathogenic in Alzheimer's disease (AD). However, the physiological functions of this enzyme remain to be clarified. In the canonical Notch signaling pathway, ligands bind to the extracellular domain of Notch and trigger sequential proteolytic cleavage. Finally, the intracellular domain (ICD) of Notch is released from the cell membrane by γ-secretase and translocates to the nucleus where it modulates gene expression through binding to transcription factors. Thus, γ-secretase plays a central regulatory role in the Notch signaling pathway. Recently, it was demonstrated that many type 1 transmembrane proteins, including APP and Notch, are substrates for γ-secretase, and the ICDs of these substrates are released from the cell membrane by γ-secretase. These processes are very similar to those that occur in Notch signaling. Thus, the common enzyme, γ-secretase, modulates proteolysis and the turnover of possible signaling molecules, suggesting that mechanisms similar to Notch signaling may contribute widely to γ-secretaseregulated signaling pathways, including APP signaling which leads to AD. Indeed, we have shown that ICD of APP induces dynamic changes in gene expression and neuron-specific apoptosis. Our findings suggest that APP signaling responds to the onset of AD. Here, we focus on γ-secretase-regulated signaling hypothesis and discuss the possibility that APP signaling may be closely correlated with the onset of AD.

Depression is the most common mental disorder, affecting a large population worldwide. Of the psychiatric syndromes which present mood disorders, major depressive disorder (MDD) is one of the most severe due to the long periods of depressed mood, somatic symptoms, cognitive disturbances, clinically significant distress and impairment in everyday functioning. The causes of MDD are complex and associated with environmental and biological aspects. Treatment comprises structured forms of psychotherapy and antidepressant medication but remission rates are low and justify the implementation of an alternative effective treatment. Various authors have associated physical exercise with the treatment of depression and different biological and psychological hypotheses have been proposed. Several clinical trials have been performed and, while some authors report no apparent association, the majority of the published data demonstrates a positive effect of physical exercise on both depressive symptoms and Quality of Life (QoL). In this review, the current status of exercise associated treatment of MDD is addressed, relevant data and models are discussed, and an updated view of the current situation is presented.

Autism Spectrum Disorders (ASD) are characterized by dysfunction in three core symptom domains: social impairments, communication impairments, and repetitive behaviours with restricted interests. Oxytocin (OXT) and the structurally similar peptide arginine vasopressin (AVP), may play a role in the etiology of these disorders, especially in the social difficulties domain. Oxytocin is involved in milk let-down and uterine contractions at a peripheral level, while in the brain it predominantly has a neuromodulatory function on affiliative and social behavior. Abnormalities of OXT in ASD are herein reviewed, using blood studies, neuroimaging, and translational research. Genetic abnormalities in OXT have also been consistently reported in ASD. Clinical trials with OXT are currently aimed at reducing social impairments and repetitive behaviours. Finally, the current limitations and prospects for the future of OXT treatment in ASD are discussed.

There has long been a concern that all psychotropics may have adverse cardiac effects including prolongation of the QT interval. The recent expanded use of the atypical antipsychotics has increased these concerns. This is a selective review of the effect of the major classes of psychotropic drugs on the QT interval. The review also includes a review of methadone given the high co-morbidity between major psychiatric disorders and substance use disorders.