Emerging evidence from genome-wide association studies (GWAS) support the association of polymorphisms in the alpha 1C subunit of the L-type voltage-gated calcium channel gene (CACNA1C) with bipolar disorder. These studies extend a rich prior literature implicating dysfunction of L-type calcium channels (LTCCs) in the pathophysiology of neuropsychiatric disorders. Moreover, calcium channel blockers reduce Ca(2+) flux by binding to the α1 subunit of the LTCC and are used extensively for treating hypertension, preventing angina, cardiac arrhythmias and stroke. Calcium channel blockers have also been studied clinically in psychiatric conditions such as mood disorders and substance abuse/dependence, yielding conflicting results. In this review, we begin with a summary of LTCC pharmacology. For each category of disorder, this article then provides a review of animal and human data. In particular, we extensively focus on animal models of depression and clinical trials in mood disorders and substance abuse/dependence. Through examining rationale and study design of published clinical trials, we provide some of the possible reasons why we still do not have definitive evidence of efficacy of calcium-channel antagonists for mood disorders. Refinement of genetic results and target phenotypes, enrollment of adequate sample sizes in clinical trials and progress in physiologic and pharmacologic studies to synthesize tissue and isoform specific calcium channel antagonists, are all future challenges of research in this promising field. © 2010 Wiley-Liss, Inc.

Variations in voltage-dependent calcium channel L-type, alpha 1C subunit (CACNA1C) gene have been associated with bipolar disorder in a recent meta-analysis of genome-wide association studies [Ferreira et al., 2008]. The impact of these variations on other psychiatric disorders has not been yet investigated. Caucasian non-Hispanic participants in the STAR*D study of treatment for depression for whom DNA was available (N = 1213) were genotyped at two single-nucleotide polymorphisms (SNPs) (rs10848635 and rs1006737) in the CACNA1C gene. We examined putative phenotypic indicators of bipolarity among patients with major depression and elements of longitudinal course suggestive of latent bipolarity. We also considered remission and depression severity following citalopram treatment. The rs10848635 risk allele was significantly associated with lower levels of baseline agitation (P = 0.03; beta = -0.09). The rs1006737 risk allele was significantly associated with lesser baseline depression severity (P = 0.04; beta = -0.4) and decreased likelihood of insomnia (P = 0.047; beta = -0.22). Both markers were associated with an increased risk of citalopram-emergent suicidality (rs10848635: OR = 1.29, P = 0.04; rs1006737: OR = 1.34, P = 0.02). In this exploratory analysis, treatment-emergent suicidality was associated with two risk alleles in a putative bipolar liability gene.

Objective Some studies suggest that depressive subtypes, defined by groups of symptoms, have predictive or diagnostic utility. These studies make the implicit assumption of stability of symptoms across episodes in mood disorders, which has rarely been investigated. Methods We examined prospective data from a cohort of 3,750 individuals with bipolar I or II disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder study, selecting a subset of individuals who experienced two depressive episodes during up to two years of follow-up. Across-episode association of individual depressive or hypomanic/mixed symptoms was examined using the weighted kappa measure of agreement as well as logistic regression. Results A total of 583 subjects experienced two prospectively observed depressive episodes, with 149 of those subjects experiencing a third. Greatest evidence of stability was observed for neurovegetative features, suicidality, and guilt/rumination. Loss of interest and fatigue were not consistent across episodes. Structural equation modeling suggested that the dimensional structure of symptoms was not invariant across episodes. Conclusion While the overall dimensional structure of depressive symptoms lacks temporal stability, individual symptoms including suicidality, mood, psychomotor, and neurovegetative symptoms are stable across major depressive episodes in bipolar disorder and should be considered in future investigations of course and pathophysiology in bipolar disorder.

We present the history of four bipolar patients who developed neuroleptic malignant syndrome (NMS) after antipsychotic treatment, focusing on the relationship between NMS and catatonia. In all cases, the administration of antipsychotics has been suspended as soon as fever and autonomic disturbances occurred. A supportive therapy was initiated to stabilize general conditions, then every patient started electroconvulsive therapy (ECT) in combination with benzodiazepines (BDZ). The risk of complications was reduced by the quick adoption of supportive care, whereas the combination of ECT and BDZ was effective in resolving the clinical picture. These cases may provide further support to the hypothesis that catatonia and NMS are disorders pertaining to the same spectrum of illness because the onset or exacerbation of catatonic symptoms coincided with the administration of antipsychotics. Our experience confirms the efficacy and safety of ECT in combination with BDZ as treatment of NMS and residual catatonia.

aripiprazole has proven to be an effective medication for the acute treatment of manic and mixed episodes, as well as for the prophylactic-maintenance phase of bipolar disorder in patients recovering from a manic/mixed episode. Choosing the appropriate dosing and tapering strategy, addressing the side effects, controlling withdrawal symptoms from previous medications and using adjunctive medications when necessary are key to successful treatment with aripiprazole.

BackgroundAlthough manic episodes in older adults are not rare, little published data exist on late-life manic episodes. Resistance to treatment and concomitant neurological lesions are frequent correlates of elderly mania. The aim of this study was to investigate the prevalence of hospitalizations due to mania in patients older than 64 years through a period of 5 years in an Italian public psychiatric ward. Moreover, we aimed at describing clinical presentation of elderly manic episodes.MethodsA retrospective chart review was conducted in order to describe clinical presentation of 20 elderly patients hospitalized for manic episode; moreover, we compared age at onset, the presence of family history for mood disorders, psychosis and irritability between the elderly group and a matched group of 20 younger manic inpatients.ResultsSeven percent of the whole inpatient elderly people suffered from mania. Half of those patients had a mood disorder age at onset after 50 years and 5 patients were at their first manic episode. Geriatric- and adulthood mania showed similar clinical presentation but younger people had more frequently a mood disorders family history.ConclusionHalf of our older manic inpatients consisted of "classic" bipolar patients with an extension of clinical manifestations into later life; the other half of our sample was heterogeneous, even though it was not possible to identify clearly which patients may have had vascular lesions related to the onset of mania.

Aim: To evaluate the efficacy and safety of the augmentation of clozapine with aripiprazole in patients with treatment-resistant schizoaffective and psychotic bipolar disorders in a retrospective manner. Pharmacodynamic and pharmacokinetic interactions between the two drugs were also investigated.Patients: Three men and 4 women (median age 36 and 40 years, respectively) who had mean scores at BPRS and CGI-Severity of 59.1±12.0 and 5.4±0.5, respectively, were treated with clozapine (mean dose 292.9±220.7 mg/day). Patients received an adjunctive treatment with aripiprazole (mean dose 6.8 ± 3.7 mg/day). Clozapine, norclozapine and aripiprazole plasma levels were measured by means of a high performance liquid chromatograpy with UV detection.Results: Total scores at BPRS decreased significantly (from 59.1±12.0 to 51.1±15.6, p=0.007) after aripirazole augmentation. In particular, the factors “thought disorder” (from 10.4±4.4 to 9.0±4.5, p=.047) and “anergia” (from 10.0±2.7 to 8.0±2.4, p=.018) significantly improved. Concomitant administration of aripiprazole and clozapine did not result in an increase in side effects over the period of treatment. Dose-normalized plasma levels of both clozapine and norclozapine and the clozapine/norclozapine metabolic ratio in all patients did not vary as well.Conclusion:The augmentation of clozapine with aripirazole was safe and effective in severe psychotic schizoaffective and bipolar disorders which failed to respond to atypical antipsychotics. A possible pharmacokinetic interaction between clozapine and aripiprazole does not account for the improved clinical benefit obtained after aripiprazole augmentation.

A sensitive and reproducible screening analytical method is described for the determination of six pyrethroids (phenothrin, permethrin, cyfluthrin, cypermethrin, deltamethrin, fenvalerate) in egg and meat samples by gas chromatography and electron capture detection (GC-ECD). A fast cleanup procedure, based on solid-phase extraction has been used, ensuring reduced solvent consumption and time and allowing the simultaneous preparation of multiple sample extracts. Under the optimal chromatographic conditions, an efficient separation was obtained with a total analysis time of less than 60 min, including the extraction-purification steps. Good responses for the six pyrethroids were obtained in a range of 50-500 μg L, with linear coefficients higher than 0.9992. Instrumental limits of detection were between 0.22 and 0.63 μg L, corresponding to 0.04 and 0.13 μg kg in the matrix. Detection limits in chicken eggs and various meat samples, calculated on spiked samples, were in the range 0.05-0.25 μg kg and 0.07-0.23 μg kg, respectively. The validation results confirmed that the proposed GC-ECD method can be used as a reliable screening tool for the determination of pyrethroids in official check analyses. The method was extensively validated following the European directives, demonstrating its conformity in terms of selectivity, sensitivity, recovery, precision, and measurement uncertainty.