Response and remission rates with adjunctive aripiprazole in patients with major depressive disorder who exhibit minimal or no improvement on antidepressant monotherapy.

BACKGROUND: The efficacy of adjunctive aripiprazole in patients with major depressive disorder (MDD) with no improvement after 8 weeks of prior antidepressant monotherapy has not been evaluated. METHODS: A post hoc analysis of three similarly designed, randomised, double-blind, placebo-controlled, phase III studies was conducted investigating the efficacy and safety of aripiprazole adjunctive to standard antidepressant treatment (ADT) in MDD patients with a prior inadequate response to one to three ADTs. Minimal improvement to antidepressant monotherapy was defined as a Clinical Global Impressions - Improvement (CGI-I) score of 3 and non-improvement as a CGI-I of 4 at weeks 6 and 8 of antidepressant monotherapy. RESULTS: The end-point response rate for ADT minimal improvers receiving adjunctive aripiprazole was 38.8% vs. 26.6% for adjunctive placebo (p < 0.05; number needed to treat [NNT] = 9 [95% confidence interval: 4.8-27.7]), and for ADT non-improvers receiving adjunctive aripiprazole was 24.0% vs. 10.3% for adjunctive placebo (p < 0.05; NNT = 8 [95% confidence interval: 4.4-21.5]). ADT minimal improvers and non-improvers demonstrated significant improvements in response vs. ADT alone as early as after 1 and 2 weeks of adjunctive treatment, respectively. The end-point remission rate for ADT minimal improvers receiving adjunctive aripiprazole was 34.2% vs. 21.0% for adjunctive placebo (p < 0.05; NNT = 8), and for ADT non-improvers receiving adjunctive aripiprazole was 16.0% vs. 5.9% for adjunctive placebo (p < 0.05; NNT = 10). The most common adverse events for ADT minimal improvers and non-improvers receiving adjunctive aripiprazole were akathisia, restlessness and insomnia. CONCLUSION: Patients with minimal or no improvement after 8 weeks of antidepressant monotherapy significantly benefited from adjunctive aripiprazole treatment, supporting the efficacy of this treatment for MDD patients with all levels of response to ADT.

Analysis of suicidality in pooled data from 2 double-blind, placebo-controlled aripiprazole adjunctive therapy trials in major depressive disorder.

OBJECTIVE: To assess the impact of adjunctive aripiprazole versus adjunctive placebo treatment on suicidality in patients with major depressive disorder. METHOD: Data were pooled from 2 identical aripiprazole augmentation studies. Patients with DSM-IV-TR-diagnosed major depressive disorder with an inadequate response to 8 weeks of prospective antidepressant treatment were randomly assigned to adjunctive placebo or adjunctive aripiprazole (2-20 mg/d) treatment for 6 weeks. Adverse events related to suicidality were identified in the adverse event database using the Medical Dictionary for Regulatory Activities-preferred term. Treatment-emergent suicidal ideation was defined using item 10 (suicidality) of the Montgomery-Åsberg Depression Rating Scale (MADRS) and item 18 (suicidality) of the Inventory of Depressive Symptomatology (IDS). RESULTS: In total, 737 patients were included in the safety database (aripiprazole n = 371; placebo n = 366). No suicides were reported. There were no treatment-emergent, suicide-related adverse events in the aripiprazole group; 2 patients in the placebo group had ≥ 1 adverse event related to suicide (both suicidal ideation). More placebo than aripiprazole patients > 25 years old experienced a 2-point (P < .01) or 1-point (P < .05) worsening of MADRS item 10 scores. For this age group, 2-point improvement in MADRS item 10 scores and 1-point improvement of IDS item 18 scores were significantly more common in aripiprazole patients than placebo patients (both P < .05). CONCLUSIONS: This post hoc analysis demonstrated that adjunctive aripiprazole treatment in patients with depression with a history of an inadequate response to antidepressant medication is associated with a decreased rate of suicidality in a group of subjects not at significant risk. Prospective trials directly assessing suicidality are needed to further understand the benefits of an adjunctive antipsychotic in an at-risk population. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758.

The pharmacokinetics of standard antidepressants with aripiprazole as adjunctive therapy: studies in healthy subjects and in patients with major depressive disorder.

Possible effects of the atypical antipsychotic aripiprazole on the pharmacokinetics of standard antidepressant therapies (ADTs) were assessed in two open-label, non-randomised studies in healthy subjects (Studies 1 and 2) and two placebo-controlled studies in patients with major depressive disorder (MDD) (Studies 3 and 4). Healthy subjects received venlafaxine 75 mg/day (Study 1; N = 38) or escitalopram 10 mg/ day (Study 2; N = 25) with the addition of aripiprazole 10-20 mg/day (10 mg/day fixed dose in Study 2) for 14 days. Patients with MDD (N = 498; Studies 3 and 4) received escitalopram (10-20 mg/day), fluoxetine (20-40 mg/day), paroxetine controlled-release (37.5-50 mg/day), sertraline (100-150 mg/day) or venlafaxine extended-release (150-225 mg/day) for 8 weeks plus placebo. Incomplete responders were randomised (1:1) to placebo or adjunctive aripiprazole 2-20 mg/day. Blood samples were collected for pharmacokinetic analysis of ADTs. Plasma concentration-time data from Studies 3 and 4 were combined for statistical analysis. In healthy subjects, point estimates [90% CI] for the ratios of geometric means of C( max) (venlafaxine 1.148 [1.083-1.217]; escitalopram 1.04 [0.99-1.09]) and AUC(TAU) (venlafaxine 1.183 [1.130-1.238]; escitalopram 1.07 [1.04-1.11]) indicated no meaningful increase in ADT exposure in the presence of aripiprazole. In patients, point estimates for mean plasma concentration ratios indicated no substantial effect of aripiprazole on any ADT escitalopram 0.970 [0.911-1.033], fluoxetine 1.177 [1.049-1.321], paroxetine 0.730 [0.598-0.892], sertraline 0.958 [0.887-1.035] or venlafaxine 0.966 [0.887-1.051]. Aripiprazole had no meaningful effects on the pharmacokinetics of standard ADTs in either healthy subjects or patients with MDD.

EEG monitoring in depressed patients undergoing repetitive transcranial magnetic stimulation.

To date, 33 subjects diagnosed with major depressive disorder have undergone transcranial magnetic stimulation (TMS) in the authors' clinic. Five of these patients showed minimal electroencephalogram (EEG) variants at baseline. The authors describe the course of treatment and serial EEGs in 3 of the 5 patients who did not show progressive EEG changes in association with active rTMS. These three cases suggest that minimal EEG anomalies at baseline need not serve as a contraindication to undergoing rTMS. Two patients with progressive EEG changes in association with sham rTMS in one and active rTMS in the other are also discussed.

Subtyping women with bulimia nervosa along dietary and negative affect dimensions: a replication in a treatment-seeking sample.

Recent cluster-analysis studies of women with bulimia nervosa (BN) have suggested two subtypes, a pure dietary subtype and a mixed dietary-negative affect. We aimed to replicate the subtyping findings in a clinical study group of 48 adult women with BN. Cluster analyses revealed a dietary-negative affect subtype (56% of cases) and a pure dietary subtype (44% of cases). The dietary-negative affect subtype was characterized by significantly greater eating-related attitudinal psychopathology and associated psychological disturbance. Our findings suggest that severe restraint is a central feature of BN and that affective disturbance, which occurs in roughly half of cases, is associated with greater eating-related attitudinal psychopathology and psychological symptomatology.

Electroencephalogram and repetitive transcranial magnetic stimulation.

Scalp recordings of the electroencephalogram (EEG) have been used in association with repetitive transcranial magnetic stimulation (rTMS) investigations as a safety measure in monitoring ongoing EEG activity and as a neurophysiologic tool in examining the specific effects induced by the magnetic stimulus on the EEG or evoked potentials (EPs). Medline review on the use of EEG or EPs with rTMS reveals that this area has been largely unexplored. Limited available studies attest to the potential for studies combining EEG/EPs and rTMS to be useful in further elucidating the normal brain physiology. Herein, we report on our experience with continuous EEG sampling combined with rTMS in patients with major depression (n = 14), schizophrenia (n = 7), and obsessive-compulsive disorder (n = 5). Our data support the practice of using continuous EEG monitoring when the stimulation parameters fall outside established safety guidelines.

No effect of light on basal glucagon levels in winter seasonal depressives and comparison subjects.

We explored the effect of light therapy upon basal fasting plasma glucagon in 15 patients with winter depression vs. 15 comparison subjects before and after at least 1 week of light treatment. No differences were seen between groups or conditions. There was no correlation between glucagon change and antidepressant response.

Transcranial magnetic stimulation and auditory hallucinations in schizophrenia.

12 patients with schizophrenia and auditory hallucinations received 1 Hz transcranial magnetic stimulation of left temporoparietial cortex. In a double-blind crossover trial, active stimulation significantly reduced hallucinations relative to sham stimulation.

Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists.

BACKGROUND: The cognitive, behavioral, and mood effects of N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine and ketamine, have been used to study the effects of NMDA receptor dysfunction. Pharmacological modulation of the effects of NMDA receptor antagonists, such as ketamine, may lead to development of novel therapeutic agents for psychiatric illnesses such as schizophrenia. Preclinical studies indicate that some ketamine effects may be mediated through increased glutamate release. In this study, we tested the hypothesis that lamotrigine, a drug reported to inhibit glutamate release, will reduce the neuropsychiatric effects of ketamine in humans. METHOD: Healthy subjects (n = 16) completed 4 test days involving the administration of lamotrigine, 300 mg by mouth, or placebo 2 hours prior to administration of ketamine (0.26 mg/kg by intravenous bolus and 0.65 mg/kg per hour by intravenous infusion) or placebo in a randomized order under double-blind conditions. Behavioral and cognitive assessments were performed at baseline and after administration of the medications. RESULTS: Lamotrigine significantly decreased ketamine-induced perceptual abnormalities as assessed by the Clinician-Administered Dissociative States Scale (P<.001); positive symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale positive symptoms subscale (P<.001); negative symptoms as assessed by the Brief Psychiatric Rating Scale negative symptoms subscale (P<.05); and learning and memory impairment as assessed by the Hopkins Verbal Learning Test (P<.05). However, lamotrigine increased the immediate mood-elevating effects of ketamine (P<.05). CONCLUSIONS: Glutamate release-inhibiting drugs may reduce the hyperglutamatergic consequences of NMDA receptor dysfunction implicated in the pathophysiologic processes of neuropsychiatric illnesses such as schizophrenia. Further study is needed.

A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression.

BACKGROUND: Multiple groups have reported on the use of repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant major depression. The purpose of this study is to assess the efficacy of rTMS in unmedicated, treatment-resistant patients who meet criteria for major depression. METHODS: Depressed subjects, who had failed to respond to a median of four treatment trials, were assigned in a randomized double-blind manner to receive either active (n = 10; 20 2-sec trains of 20 Hz stimulation with 58-sec intervals; delivered at 80% motor threshold with the figure-of-eight coil positioned over the left dorsolateral prefrontal cortex) or sham (n = 10; similar conditions with the coil elevated and angled 45 degrees tangentially to the scalp) rTMS. These sequences were applied during 10 consecutive weekdays. Continuous electroencephalogram sampling and daily motor threshold determinations were also obtained. RESULTS: The group mean 25-item Hamilton Depression Rating Scale (HDRS) score was 37.2 (+/- 2.0 SEM) points. Adjusted mean decreases in HDRS scores were 14.0 (+/- 3.7) and 0.2 (+/- 4.1) points for the active and control groups, respectively (p <.05). One of 10 subjects receiving active treatment demonstrated a robust response (i.e., HDRS decreased from 47 to 7 points); three other patients demonstrated 40-45% decreases in HDRS scores. No patients receiving sham treatment demonstrated partial or full responses. CONCLUSIONS: A 2-week course of active rTMS resulted in statistically significant but clinically modest reductions of depressive symptoms, as compared to sham rTMS in a population characterized by treatment resistance.

Antidepressant effects of ketamine in depressed patients.

BACKGROUND: A growing body of preclinical research suggests that brain glutamate systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. This is the first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression. METHODS: Seven subjects with major depression completed 2 test days that involved intravenous treatment with ketamine hydrochloride (.5 mg/kg) or saline solutions under randomized, double-blind conditions. RESULTS: Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion (i.e., mean 25-item Hamilton Depression Rating Scale scores decreased by 14 +/- SD 10 points vs. 0 +/- 12 points, respectively during active and sham treatment). CONCLUSIONS: These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression.

Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy.

BACKGROUND: Several lines of emerging evidence suggest that dysfunction of gamma-aminobutyric acid (GABA) systems is associated with major depression. However, investigation of this hypothesis is limited by difficulty obtaining noninvasive in vivo measures of brain GABA levels. In this study we used in vivo proton magnetic resonance spectroscopy to investigate the hypothesis that abnormalities in the GABA neurotransmitter system are associated with the neurobiologic processes of depression. METHODS: The GABA levels were measured in the occipital cortex of medication-free depressed patients meeting DSM-IV criteria (n = 14) and healthy control subjects with no history of mental illness (n = 18) using a localized difference editing proton magnetic resonance spectroscopy protocol. An analysis of covariance was employed to examine the effects of depression, sex, and age. RESULTS: The depressed patients demonstrated a highly significant (52%) reduction in occipital cortex GABA levels compared with the group of healthy subjects. While there were significant age and sex effects, there was no interaction of diagnosis with either age or sex. CONCLUSION: This study provides the first evidence of abnormally low cortical GABA concentrations in the brains of depressed patients.

Symptom provocation studies in psychiatric disorders: scientific value, risks, and future.

Several lines of investigation have contributed to the increasing recognition of the biological basis of psychiatric disorders. Symptom provocation studies have made important contributions toward this. With the emergence of novel methodologies, the role of symptom provocation studies has come under increasing scrutiny and debate. The scientific contributions and risks of symptom provocation studies are discussed using the psychostimulant paradigm in schizophrenia research as the prototypical study. The application of studies in other areas of medicine that carry risks similar to those associated with symptom provocation studies, are also reviewed. The authors draw on the parallel of cardiac stress testing to highlight risks: benefits issues. Finally, the authors discuss the future of symptom provocation studies and emphasize that these studies will need to meet the highest scientific standards, ethical standards and safeguards.

NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders.

Antagonists of the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors and agonists of the glycine-B coagonist site of these receptors have been important tools for characterizing the contributions of NMDA receptor pathophysiology to a large number of neuropsychiatric conditions and for treating these conditions. Among these disorders are Alzheimer's disease, chronic pain syndromes, epilepsy, schizophrenia, Parkinson's disease, Huntington's disease, addiction disorders, major depression, and anxiety disorders. This review will examine pathophysiological and therapeutic hypotheses generated or supported by clinical studies employing NMDA antagonists and glycine-B agonists and partial agonists. It will also consider ethical issues related to human psychopharmacological studies employing glutamatergic probes.

Bulimia nervosa and alcohol dependence. A case report of a patient enrolled in a randomized controlled clinical trial.

Bulimia nervosa and alcohol use disorders frequently co-occur. A review of the literature, however, reveals a paucity of information on treatment of patients with these comorbid conditions. We present a case report of a 34-year-old Caucasian female with a 20-year history of bulimia nervosa with co-occurring alcohol dependence, who participated in a randomized placebo-controlled medication augmentation trial for bulimia nervosa. The patient served as a pilot subject who met the exclusionary criterion of alcohol dependence, but received all the assessment and intervention procedures of the clinical trial for bulimia nervosa. Despite double-blind random assignment to a placebo condition, the patient's symptoms of bulimia nervosa substantially improved over the course of the 5-week efficacy trial. We hypothesize that this improvement was due to concurrent abstinence from alcohol rather than a placebo effect.

Models of antidepressant action.

Although immediate pharmacologic targets can be identified for most antidepressant treatments, elucidation of the critical biological mechanisms leading to symptom relief has defied decades of research. In this review, selected neurotransmitter, biochemical, and anatomic models of antidepressant action are considered with regard to their explanatory power and therapeutic applicability. Monoamine models have been a focus of research attention on antidepressant action, an appropriate emphasis in that virtually all antidepressant medications have high affinity for monoamine substrates. Furthermore, prevailing monoamine models have suggested some promising therapeutic strategies. Nevertheless, these models are ultimately incomplete and do not fully explain important clinical limitations of current treatment: delayed response, incomplete efficacy, and unsustained remissions. Continued therapeutic advancements will likely require the development of models of antidepressant action that extend beyond the monoamines.

Effect of catecholamine depletion on lithium-induced long-term remission of bipolar disorder.

BACKGROUND: This study investigated the effects of catecholamine depletion with alpha-methylparatyrosine (AMPT) on mood indices in patients with bipolar disorder who were in long-term remission with lithium therapy. METHODS: Eight subjects with DSM-IV bipolar disorder currently in remission for > 3 months on lithium were included in the study. Subjects were given either AMPT or placebo, in a randomized double-blind manner, in two test sessions of 4 days each. RESULTS: Subjects did not have any significant changes in mood during AMPT or placebo administration; however, 24-48 hours after the last active AMPT dose subjects had a transient relapse of hypomanic symptoms. Relapse of hypomanic symptoms did not correlate with increases in serum levels of homovanillic acid or 3-methoxy-4-hydroxyphenylglycol. CONCLUSIONS: These findings suggest that the mechanism of prevention of manic relapse by long-term lithium therapy may be dependent on stability of the catecholamine system.

Transcranial magnetic stimulation of left temporoparietal cortex in three patients reporting hallucinated "voices".

BACKGROUND: Prior studies suggest that auditory hallucinations of "voices" arise from activation of speech perception areas of the cerebral cortex. Low frequency transcranial magnetic stimulation (TMS) can reduce cortical activation. METHODS: We have studied three schizophrenic patients reporting persistent auditory hallucinations to determine if low frequency TMS could curtail these experiences. One hertz stimulation of left temporoparietal cortex was compared with sham stimulation using a double-blind, cross-over design. RESULTS: All three patients demonstrated greater improvement in hallucination severity following active stimulation compared to sham stimulation. Two of the three patients reported near total cessation of hallucinations for > or = 2 weeks. CONCLUSIONS: TMS may advance our understanding of the mechanism and treatment of auditory hallucinations.

The use of pindolol with fluoxetine in the treatment of major depression: final results from a double-blind, placebo-controlled trial.

BACKGROUND: Preliminary reports have suggested that concomitant institution of pindolol and serotonin reuptake inhibitors robustly hastens clinical response; however, contradictory evidence from a randomized double-blind, controlled trial was recently reported by this group in a population of depressed patients who were prescribed fluoxetine and pindolol. Herein, we report final results from an extended sample size. METHODS: Drug-free outpatients with a major depressive episode were randomized in a double-blind manner to one of two treatment conditions: fluoxetine (20 mg daily) with pindolol (7.5 to 10 mg daily) or fluoxetine (20 mg daily) with placebo. After 6 weeks, patients were followed for 3 more weeks in a single-blind manner, on fluoxetine and placebo pindolol. RESULTS: Eighty-six patients completed at least 1 or more weeks on protocol, with 45 and 41 patients randomized to the pindolol and placebo groups respectively. After 2 weeks on protocol, partial remission (i.e., at least 50% decrease in depression rating scores from baseline) rates for pindolol (16%) and placebo (19%) groups were comparable. By the study's end, a partial remission was achieved, at least transiently, for 67% of the pindolol group and 80% of the placebo group. Pindolol treatment was associated with statistically significant reduction in blood pressure and pulse as compared to the control group. The two groups did not have overall differences in rates of attrition, time to response, and side effects. CONCLUSIONS: In accord with our previously published findings, these extended results do not support the efficacy of pindolol in hastening clinical response to fluoxetine in a patient population with predominantly chronic and recurrent depression.

Transient depressive relapse induced by catecholamine depletion: potential phenotypic vulnerability marker?

BACKGROUND: Although state-related alterations in catecholamine function have been well-described in depressed subjects, enduring abnormalities have been less reliably identified. In our study, medication-free subjects with fully remitted major depression underwent a paradigm of catecholamine depletion, via use of the tyrosine hydroxylase inhibitor alpha-methylparatyrosine. METHOD: Subjects underwent 2 sets of testing conditions in a double-blind, random-ordered, crossover design, approximately 1 week apart. They underwent active catecholamine depletion (via oral administration of 5 g alpha-methylparatyrosine) or sedation-controlled, sham catecholamine depletion (via oral administration of 250 mg diphenhydramine hydrochloride), during a 2-day observation. Serial mood ratings and blood samples were obtained. RESULTS: Fourteen subjects completed the active testing condition; 13 completed sham testing. Subjects experienced marked, transient increases in core depressive and anxiety symptoms, as demonstrated by a mean 21-point increase on Hamilton Depression Rating Scale scores. Furthermore, 10 (71%) of 14 subjects fulfilled relapse criteria during active testing, whereas 1 (8%) of 13 subjects did so during sham testing. The severity of the depressive reaction correlated with baseline plasma cortisol levels (r = 0.59; P =.04). CONCLUSIONS: Euthymic, medication-free subjects with a history of major depression demonstrate significant depressive symptoms when undergoing testing with alpha-methylparatyrosine. This depressive reaction may represent a reliable marker for a history of depression. Further work is needed to clarify the significance of this finding.