The Efficacy and Tolerability of Once-daily Controlled-release Trazodone for Depressed Mood, Anxiety, Insomnia, and Suicidality in Major Depressive Disorder

By David V. Sheehan, MD, MBA; Anna Rozova, MSc, MD; E. Roderich Gossen, PhD; Michael Gibertini, PhD

Abstract

Trazodone Contramid® once-a-day (TzCOAD) is a reformulation of trazodone hydrochloride that controls the release of trazodone over 24 hours. A standard effect size analysis (Cohen’s d) determined which items of the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Montgomery-Åsberg Depression Rating Scale (MADRS) showed the greatest improvement in patients with major depressive disorder (MDD), following up to 8 weeks of therapy with TzCOAD. An additional insomnia analysis assessed whether the efficacy of TzCOAD is influenced by improvements in insomnia or baseline severity of insomnia.  The analyses used data from a randomized study of 412 patients receiving 150–375 mg TzCOAD (N = 206) or placebo (N = 206). The results of the Cohen’s d analysis on the modified intent-to-treat population (LOCF) showed HAMD items with the greatest improvement were insomnia items (middle: -0.35, late: -0.24), feelings of guilt (-0.24), and depressed mood (‑0.23); for MADRS items they were reduced sleep (-0.31), inner tension (‑0.22), reported sadness (‑0.21), and suicidal thoughts (‑0.21).  An analysis of covariance showed no significant interaction between improvements in the HAMD Bech-6 core symptoms of depression and the baseline MADRS reduced sleep item or early changes in the HAMD-17 sleep disturbance factor. These results suggest that the antidepressant efficacy was independent of the baseline severity of insomnia and of the improvement in insomnia. Overall, the results elucidate the efficacy components and tolerability characteristics previously demonstrated for TzCOAD monotherapy for patients with MDD at the recommended daily dose of 300 mg.

 

Early Predictors of Weight Gain Risk During Treatment with Olanzapine: Analyses of Pooled Results from 58 Clinical Trials

By Ilya Lipkovich, PhD, Jennie G. Jacobson, PhD, Cathy Caldwell, MS, Vicki Poole Hoffmann, PhD, Ludmila Kryzhanovskaya, MD, Charles M. Beasley, Jr., MD

Abstract

This analysis evaluated the usefulness of different predictors in identifying patient risk of substantial weight gain (SWG) during olanzapine treatment. Data were from 58 studies with 3826 patients diagnosed with schizophrenia, schizophrenia spectrum disorders, bipolar mania, bipolar depression, or borderline personality disorder. The primary definition for SWG was gaining ≥12% of baseline weight by endpoint (30 weeks ±5 weeks); other definitions of SWG were also examined. Potential predictors of SWG included baseline patient characteristics, weight change, and percent weight change at Weeks 1, 2, 3, and 4 after olanzapine initiation. To facilitate model building and validation, the data set was randomly partitioned into training (N=1912), validation (N=1149), and test (N=765) sets and 2 complementary analytic techniques were used: logistic regression with stepwise variable selection followed by receiver operating characteristic analysis evaluation of resulting candidate models and decision trees. Approximately 24% of patients gained ≥12% of their initial weight, about 30% gained ≥10%, and 45% gained ≥7% or ≥5 kg by the 30-week endpoint. Baseline covariates significantly and positively associated with probability of SWG were lower baseline body mass index, younger age, female sex, United States residency, and African ethnicity. Early weight changes substantially improved the prediction of the risk for longer-term SWG. These results confirm that cut-offs for weight gain during the first 4 weeks of treatment may be useful in evaluating SWG risk for an individual patient.

AMISULPRIDE FOR CLOZAPINE INDUCED SIALORRHEA

By Ashish Aggarwal, MD, and Dinesh Dutt Sharma, MD

Abstract

Clozapine is an atypical and novel antipsychotic medication useful for patients with schizophrenia who are refractory to treatment. Its use is often associated with troublesome side effects like sialorrhea, sedation, weight gain, enuresis, dizziness, besides life threatening side effects like agranulocytosis.

Drug treatments used for Clozapine induced sialorrhea (CIS) like anticholinergic drugs and α 2 receptor antagonists have their own added side effects. A case of CIS responding to low dose of Amisulpride is reported.

Catatonia And CPK Elevation In Neurosyphilis: Role Of Plural Pharmacodynamic Mechanisms

By Lauterbach EC, Norris B, Carter WG, Shillcutt SD

Abstract

To report catatonia in neurosyphilis with elevated creatine phosphokinase (CPK) and to understand the pharmacodynamics of catatonia.  EXPERIMENTAL DESIGN: Case report.  PRINCIPAL OBSERVATIONS:  We encountered catatonia in a man with neurosyphilis after increasing aripiprazole and valproate (drugs reported to improve catatonia) and reducing doxycycline and temazepam dosages, consistent with identified dopamine D2, serotonin 5HT2, and 5HT1a (aripiprazole), GABA-B (valproate), glutamatergic NMDA (aripiprazole, valproate, doxycycline), and GABA-A (aripiprazole, temazepam) mechanisms of catatonia.  CPK was markedly elevated despite the absence of neuroleptic malignant syndrome (NMS) and responded to lorazepam, as did the catatonia. CONCLUSIONS: This appears to be the first case report of catatonia without NMS associated with each of the following: neurosyphilis, aripiprazole, and temazepam withdrawal. This case further adds to the emerging literature of catatonia arising with valproate and atypical antipsychotic co-administration, and of non-NMS catatonia associated with CPK elevations.  Plural simultaneously – operant pharmacodynamic mechanisms may explain catatonia of unclear etiology and reconcile a seemingly contradictory literature (e.g., the capacity of certain drugs (e.g., aripiprazole, valproate) to either relieve or precipitate catatonia depending on their pharmacological contexts). Besides reduced D2, 5HT2, and GABA-A and increased 5HT1a, GABA-B, and NMDA receptor stimulation appreciated in the clinical literature, stimulation of adenosine, muscarinic, and H1 histamine receptors may also have promoted catatonia in this case and others, whereas the alpha-2 agonist clonidine has alleviated it.  Multiple drugs in this regimen and our current reliance on mechanisms determined primarily in preclinical studies now indicate the need for clinical studies to determine the relative importance of each mechanism in human patients.

Ziprasidone Induced Tardive Cervical Dystonia

By Ayse Kutlu, Senem DĂ¼ndar, Nur S.Altun, Faik Budak

Abstract

Fifty years old female patient used 80 mg/day ziprasidone for 4 months after diagnosed as atypical depression. After 4 months of ziprasidone treatment, involuntary movements appeared in her neck region.  Ziprasidone was stopped in by tapering 20 mg/day, but the involuntary movements continued and even exacerbated. Then, oral clonazepam treatment was started but no improvement was observed.

Finally, she was administered Botulinum Toxin A (BTX-A) treatment. After the fourth  BTX-A injection therapy, significant reduction in neck pain and improvement of head deviation was observed.Â