Calcium Channel Antagonists for Mood Disorders.

PURPOSE: Development of new thymoleptic medications has primarily centered on anticonvulsants and antipsychotic drugs. Based on our studies of intracellular calcium ion signaling in mood disorders, we were interested in the use of novel medications that act on this mechanism of neuronal activation as potential mood stabilizers. METHOD: We reviewed the dynamics of the calcium second messenger system and the international body of data demonstrating increased baseline and stimulated intracellular calcium levels in peripheral cells of patients with bipolar mood disorders. We then examined studies of the effect of established mood stabilizers on intracellular calcium ion levels and on mechanisms of mobilization of this second messenger. After summarizing studies of calcium channel blocking agents, whose primary action is to attenuate hyperactive intracellular calcium signaling, we considered clinical experience with this class of medications and the potential for further research. FINDINGS: Established mood stabilizers normalize increased intracellular calcium ion levels in bipolar disorder patients. Most case series and controlled studies suggest an antimanic and possibly mood stabilizing effect of the calcium channel blocking medications verapamil and nimodipine, with fewer data on isradipine. A relatively low risk of teratogenicity and lack of cognitive adverse effects or weight gain suggest possible applications in pregnancy and in patients for whom these are considerations. IMPLICATIONS: Medications that antagonize hyperactive intracellular signaling warrant more interest than they have received in psychiatry. Further experience will clarify the applications of these medications alone and in combination with more established mood stabilizers.

Benzodiazepines Remain Important Therapeutic Options in Psychiatric Practice.

Benzodiazepines and medications acting on benzodiazepine receptors that do not have a benzodiazepine structure (z-drugs) have been viewed by some experts and regulatory bodies as having limited benefit and significant risks. Data presented in this article support the use of these medications as treatments of choice for acute situational anxiety, chronic anxiety disorders, insomnia, alcohol withdrawal syndromes, and catatonia. They may also be useful adjuncts in the treatment of anxious depression and mania, and for medically ill patients. Tolerance develops to sedation and possibly psychomotor impairment, but not to the anxiolytic effect of benzodiazepines. Sedation can impair cognitive function in some patients, but assertions that benzodiazepines increase the risk of dementia are not supported by recent data. Contrary to popular opinion, benzodiazepines are not frequently misused or conduits to misuse of other substances in patients without substance use disorders who are prescribed these medications for appropriate indications; most benzodiazepine misuse involves medications that are obtained from other people. Benzodiazepines are usually not lethal in overdose except when ingested with other substances, especially alcohol and opioids. Benzodiazepines comprise one of the few classes of psychotropic medication the mechanisms of action of which are clearly delineated, allowing for greater precision in their clinical use. These medications, therefore, belong in the therapeutic armamentarium of the knowledgeable clinician.

Psychotic Depression: Diagnosis, Differential Diagnosis, and Treatment.

Psychotic depression was initially considered to be at one end of a continuum of severity of major depression. Subsequent experience demonstrated that psychosis is an independent trait that may accompany mood disorders of varying severity. While much has been learned about the impact of severe mood congruent delusions and hallucinations on the course and treatment response of depression, less is known about fleeting or mild psychosis, mood incongruent features, or psychotic symptoms that reflect traumatic experiences. Acute treatment of psychotic unipolar depression generally involves the combination of an antidepressant and an antipsychotic drug or electroconvulsive therapy. There is inadequate information about maintenance treatment of unipolar psychotic depression and acute and chronic treatment of psychotic bipolar disorder. Decision-making therefore still must rely in part on clinical experience.

Executive Function and Personality Predict Instrumental Activities of Daily Living in Alzheimer Disease.

OBJECTIVE: Previous research shows that executive function (EF) and personality independently predict functional decline. Our objective was to determine whether personality traits predict independence with instrumental activities of daily living (IADLs), after accounting for executive dysfunction, in a mixed sample of patients with amnestic mild cognitive impairment (MCI) and Alzheimer disease (AD). METHODS: In a cross-sectional analysis at a university medical center, 63 healthy older adults (median age: 67.6 years; 71% women) and 119 patients (median age: 75.0 years; 58% women) with varying degrees of AD (probable AD: 85; possible AD: 3; amnestic MCI: 31) were studied. Standardized neuropsychological measures, NEO Five-Factor Inventory (NEO-FFI), and informant-report Lawton and Brody IADL scales were used. All participants underwent neuropsychological evaluation, including administration of self- and informant-report NEO-FFI. Patients additionally underwent neurologic examination, and their informants completed the Lawton and Brody IADL scale. RESULTS: When testing the association between EF and personality on IADLs in the patient sample, conceptual card sorting, informant-report Openness, and informant-report Conscientiousness all significantly predicted IADLs, after accounting for age, education, and depression. In addition, a significant interaction showed that low Conscientiousness and executive dysfunction, in combination, can predict impairment of IADLs. CONCLUSION: Personality has a unique association with IADLs in patients with AD pathology that is not explained by EF. The findings confirm prior speculation that personality, in addition to cognitive dysfunction, is a risk factor for functional decline. Early identification of vulnerable individuals may allow for intervention to prolong functional independence.

Levetiracetam, Calcium Antagonism, and Bipolar Disorder.

Hyperactive intracellular calcium ion (Ca) signaling in peripheral cells has been a reliable finding in bipolar disorder. Some established mood stabilizing medications, such as lithium and carbamazepine, have been found to normalize elevated intracellular Ca concentrations ([Ca]i) in platelets and lymphocytes from bipolar disorder patients, and some medications the primary effect of which is to attenuate increased [Ca]i have been reported to have mood stabilizing properties.Hyperactive intracellular Ca signaling has also been implicated in epilepsy, and some anticonvulsants have calcium antagonist properties. This study demonstrated that levetiracetam, an anticonvulsant that has been shown to block N and P/Q-type calcium channels in animal studies does not alter elevated [Ca]i in blood platelets of patients with bipolar disorder. Review of published clinical trials revealed no controlled evidence of efficacy as a mood stabilizer.This study underscores the possibility that pharmacologic actions of a medication in animals and normal subjects may not necessarily predict its pharmacologic or clinical effects in actual patients. Effects of treatments on pathophysiology that is demonstrated in clinical subtypes may be more likely to predict effectiveness in those subtypes than choosing medications based on structural similarities to established treatments.

RNA-Seq analysis implicates dysregulation of the immune system in schizophrenia.

BACKGROUND: While genome-wide association studies identified some promising candidates for schizophrenia, the majority of risk genes remained unknown. We were interested in testing whether integration gene expression and other functional information could facilitate the identification of susceptibility genes and related biological pathways. RESULTS: We conducted high throughput sequencing analyses to evaluate mRNA expression in blood samples isolated from 3 schizophrenia patients and 3 healthy controls. We also conducted pooled sequencing of 10 schizophrenic patients and matched controls. Differentially expressed genes were identified by t-test. In the individually sequenced dataset, we identified 198 genes differentially expressed between cases and controls, of them 19 had been verified by the pooled sequencing dataset and 21 reached nominal significance in gene-based association analyses of a genome wide association dataset. Pathway analysis of these differentially expressed genes revealed that they were highly enriched in the immune related pathways. Two genes, S100A8 and TYROBP, had consistent changes in expression in both individual and pooled sequencing datasets and were nominally significant in gene-based association analysis. CONCLUSIONS: Integration of gene expression and pathway analyses with genome-wide association may be an efficient approach to identify risk genes for schizophrenia.

Short-term safety and pharmacokinetic profile of asenapine in older patients with psychosis.

OBJECTIVES: The aim of this study was to assess the short-term tolerability of two titration schedules of sublingual asenapine in older patients with psychosis, not associated with organic brain disease, and to compare asenapine pharmacokinetics in older patients versus younger adults with schizophrenia. METHODS: Patients ≥ 65 years with psychosis without dementia were randomized for 6 weeks to two dose-escalation regimens: 2 days at 2 mg twice daily (BID), 2 days at 5 mg BID, and 10 mg BID thereafter (slow escalation); or 4 days at 5 mg BID and 10 mg BID thereafter (rapid escalation). Clinical and pharmacokinetic assessments were performed in each group. RESULTS: Of 122 randomized patients, 76 (62.3%) completed the trial. The incidence of treatment-emergent adverse events (AEs) was comparable (72.1%) with both regimens. The most frequently reported AEs were hypertension, headache, and somnolence; incidence of extrapyramidal symptom-related AEs was 5.7%. Mean end point weight change was 0.4 kg. For asenapine 5 and 10 mg BID, median times to maximum concentration were 1.00 and 1.06 h, respectively; maximum concentrations (C(max) ) were 4.73 and 7.93 ng/mL; areas under the concentration versus time curve (0-12 h; AUC(0-12) ) were 32.1 and 56.3 ng∙h/mL. CONCLUSIONS: Despite 12-30% increases in asenapine C(max) and AUC(0-12) in older patients compared with previously published findings in younger schizophrenia patients, possibly as a result of slower drug clearance, asenapine was generally well tolerated during both dose-escalation schedules. No dose adjustment appears to be necessary in older patients.

Self-prescribed and other informal care provided by physicians: scope, correlations and implications.

BACKGROUND: While it is generally acknowledged that self-prescribing among physicians poses some risk, research finds such behaviour to be common and in certain cases accepted by the medical community. Largely absent from the literature is knowledge about other activities doctors perform for their own medical care or for the informal treatment of family and friends. This study examined the variety, frequency and association of behaviours doctors report providing informally. Informal care included prescriptions, as well as any other type of personal medical treatment (eg, monitoring chronic or serious conditions). METHOD: A survey was sent to 2500 randomly-selected physicians in Colorado, 600 individuals returned questionnaires with usable data. The authors hypothesised: (1) physicians would prescribe the same types of treatment at home as they prescribed professionally; and (2) physicians who informally prescribed addictive medications would be more likely to engage in other types of informal medical care. RESULTS: Physicians who wrote prescriptions for antibiotics, psychotropics and opioids at work were more likely to prescribe these medications at home. Those prescribing addictive drugs outside of the office treated more serious illnesses in emergency situations, more chronic conditions and more major medical/surgical conditions informally than did those not routinely prescribing addictive medications. Physicians reported a variety of informal care behaviour and high frequency of informal care to family and friends. DISCUSSION: The frequency and variety of informal care reported in this study strongly argues for profession-wide discussion about ethical and guideline considerations for such behaviour. These areas are discussed in the paper.

Preliminary Assessment of a Novel Continuum-of-Care Model for Young People With Autism Spectrum Disorders.

Because of limited intermediate-care services, patients with autism spectrum disorders (ASDs) are increasingly being treated in emergency departments (EDs) and psychiatric hospitals. To address this growing problem, the authors developed a mobile outreach program, called Access to Psychiatry through Intermediate Care (APIC), for young (≤26 years) patients with ASD at risk for involvement with emergency medical services or the legal system. In its initial year, the average program duration per patient was 264.5 days. Clinical and Family Distress Scale scores indicated significant improvements for participating patients and caretakers. In the first year, among 40 patients with sufficient data for comparison, 13 (33%) went to the ED, and lengths of stay decreased up to 77% from pre- to postintervention. Given a cost per APIC-enrolled patient of $1,700, the net saving for the cost of ED treatment was $2,260-$2,559 per patient. The feasibility and cost-effectiveness of the APIC model has attracted additional state and county funding.

Psychopharmacology for neurologists.

Psychiatric disorders are common in neurological patients, and psychopharmacological agents are frequently used to treat agitation and other problems in neurological practice. Antidepressants are effective for depression caused by neurological illness, but they can interact with other medications. Antianxiety drugs can aggravate cognitive disorders and should be used cautiously in this context. Antipsychotic drugs can be useful for acute agitation, but they are being found to be neither effective nor safe for chronic nonpsychotic agitation. Other agents such as beta blockers and serotonergic agents are being found to be more useful. Uses, doses, adverse effects, and interactions of psychiatric medications in neurology are summarized in this article, and suggestions are provided for the practical application of these treatments.

Applications of calcium channel blockers in psychiatry: pharmacokinetic and pharmacodynamic aspects of treatment of bipolar disorder.

Introduction: Calcium channel blockers (CCBs) comprise a heterogeneous group of medications that reduce calcium influx and attenuate cellular hyperactivity. Evidence of hyperactive intracellular calcium ion signaling in multiple peripheral cells of patients with bipolar disorder, calcium antagonist actions of established mood stabilizers, and a relative dearth of treatments have prompted research into potential uses of CCBs for this common and disabling condition. Areas covered: This review provides a comprehensive overview of intracellular calcium signaling in bipolar disorder, structure and function of calcium channels, pharmacology of CCBs, evidence of efficacy of CCBs in bipolar disorder, clinical applications, and directions for future research. Expert opinion: Despite mixed evidence of efficacy, CCBs are a promising novel approach to a demonstrated cellular abnormality in both poles of bipolar disorder. Potential advantages include low potential for sedation and weight gain, and possible usefulness for pregnant and neurologically impaired patients. Further research should focus on markers of a preferential response, studies in specific bipolar subtypes, development of CCBs acting preferentially in the central nervous system and on calcium channels that are primarily involved in neuronal signaling and plasticity.