The impact of neurocognitive impairment on occupational recovery of clinically stable patients with bipolar disorder: a prospective study.

OBJECTIVE: Many patients with bipolar disorder do not regain their premorbid level of occupational functioning even after mood episodes have resolved. The reasons for this are not well understood. We evaluated the relationship between neurocognition and occupational function in bipolar disorder patients, following symptomatic recovery. METHODS: A total of 79 previously employed adults with bipolar I disorder who achieved symptomatic recovery (i.e., at least six weeks clinically euthymic) following a manic episode underwent a neurocognitive evaluation and assessment of occupational functioning. Study participants were evaluated every three months thereafter for up to nine months. Factor analysis was applied to reduce the initial set of neurocognitive variables to five domains: episodic memory, working memory/attention, executive function, visual scanning, and speed of processing. Multiple logistic regression models were used to examine the joint predictive values of these domains for determining occupational recovery. RESULTS: At the time of symptomatic recovery, four of five neurocognitive factors were significant predictors of concomitant occupational recovery and the fifth, executive function, showed a trend in the same direction. For those not occupationally recovered at baseline, longitudinal analyses revealed that changes between baseline and the three-month follow-up timepoint in most cognitive domains were robust and highly significant predictors of occupational recovery at three months. CONCLUSIONS: These findings indicate that better neurocognitive function in multiple domains and improvement in these domains over time are strongly predictive of subsequent occupational recovery. Treatments that target cognitive deficit may therefore have potential for improving long-term vocational functioning in bipolar illness.

Combination loxapine and aripiprazole for refractory hallucinations in schizophrenia.

OBJECTIVE: To document the effects of combining loxapine with aripiprazole for refractory hallucinations in 2 patients with chronic schizophrenia. CASE SUMMARY: Two patients with schizophrenia and auditory hallucinations that were unresponsive to what was considered adequate treatment with multiple typical and atypical antipsychotic medications given over several years were prescribed a combination of aripiprazole 20-30 mg and high-dose loxapine (100-300 mg/day). Both patients had refused clozapine and depot antipsychotics. Aripiprazole/loxapine therapy resolved hallucinations in both patients, and discontinuation of either medication resulted in a return of persecutory voices. Breakthrough hallucinations in both individuals responded to increasing the loxapine dosage. Adverse effects included hypersalivation and tremor, which were treated with benztropine and propranolol. The patients also reported mild sedation, which resolved after several weeks of treatment. Both patients continued to do well during 2 years after starting this combination of medications. DISCUSSION: Recent research has indicated serotonergic and dopaminergic abnormalities in the superior temporal gyrus of patients with a history of chronic auditory hallucinations. Both loxapine and aripiprazole have effects on dopaminergic and postsynaptic serotonergic (5-HT2A) receptor systems, which could account for synergistic effects in treating refractory hallucinations. The combination appears safe, even when loxapine is given in high dosages. Patients should be monitored for the development of parkinsonian tremors. CONCLUSIONS: The combination of aripiprazole and high-dose loxapine should be considered in patients with schizophrenia who develop treatment-refractory hallucinations, particularly those who are unwilling to accept treatment with either depot antipsychotics or clozapine.

Adjunctive aripiprazole for bupropion-resistant major depression.

OBJECTIVE: To examine the effects of adjunctive aripiprazole in patients with major depression refractory to adequate therapy with bupropion. CASE SUMMARY: Four consecutive patients diagnosed with major depression that was not responsive to a minimum of 2 months of therapy with bupropion 150-450 mg/day were given adjunctive aripiprazole 2.5-10 mg/day and followed for at least 4 months. Chart notes were used to record patient responses. All patients reported rapid improvement in depressive symptoms following the addition of low-dose aripiprazole. Antidepressant effects were sustained for at least 4 months in all patients; however, the mood disturbance subsequently returned in 2 patients. Adjunctive aripiprazole was well tolerated, with one patient developing akathisia that responded to lowering the aripiprazole dose and another exhibiting worsening of preexisting insomnia. Weight and metabolic parameters were not monitored during the observation period. DISCUSSION: Transitory improvements in depressive symptoms that occurred in some of the 4 patients may have been due to compensatory mechanisms in dopaminergic systems. Adjunctive use of the atypical antipsychotic aripiprazole has been demonstrated to benefit depressed patients who are resistant to selective serotonin-reuptake inhibitors. The response to aripiprazole in patients refractory to bupropion has not been previously reported. CONCLUSIONS: Adjunctive aripiprazole given in low doses resulted in rapid improvements in depressed patients who were refractory to adequate therapy with bupropion. Additional studies are required to determine whether these results can be generalized to other depressed individuals who are refractory to bupropion treatment.

Adjunctive aripiprazole in bipolar I depression.

BACKGROUND: Aripiprazole has demonstrated efficacy in treatment of bipolar mania, as well as in the maintenance treatment of bipolar disorder. There has been only one report supporting a role for this agent in the depressed phase of the illness. OBJECTIVE: To evaluate the effectiveness of adjunctive aripiprazole in bipolar I depressed patients who are nonresponders to standard therapy. METHODS: Chart records were reviewed for all patients with bipolar I depression, diagnosed by Diagnostic and Statistical Manual of Mental Disorders, 4th revision, criteria between June 2004 and January 2006 from the Long Beach Veterans Affairs Mood Disorders Clinic. Included subjects had experienced moderate to marked depressive symptoms (Clinical Global Impression-Bipolar Depression > or =4) despite at least 2 months of treatment with adequate doses of at least one mood stabilizer. In addition, all subjects had been treated subsequently with aripiprazole 15-30 mg/day added to the existing regimen. Detailed chart notes were used to retrospectively rate symptoms. The presence or absence of each symptom was recorded before and after aripiprazole augmentation. Based on these data, Clinical Global Impression bipolar severity (CGI-BP-S) ratings and CGI-BP improvement scores for bipolar I depression were assigned. RESULTS: Ten subjects met study criteria. Adjunctive aripiprazole given for 21-110 days resulted in significant improvements in CGI-BP-S depression ratings. Seven of 10 patients were assigned CGI-BP improvement ratings of much or very much improved. Adverse events were mild and included akathisia, nausea, and insomnia. Dose adjustments of aripiprazole or the addition of drugs to treat adverse effects excluded subjects from further data collection. No patient stopped aripiprazole due to adverse effects. CONCLUSIONS: This study adds to a previous report indicating beneficial effects of adjunctive aripiprazole in treatment of bipolar I depression. Double-blind, placebo-controlled investigations are needed to confirm these findings.

Quetiapine for insomnia associated with refractory depression exacerbated by phenelzine.

OBJECTIVE: To report the successful treatment of phenelzine-associated insomnia with low-dose quetiapine in a patient with refractory depression. CASE SUMMARY: A 42-year-old white man with severe major depression unresponsive to selective serotonin-reuptake inhibitors, bupropion, and tricyclic antidepressants improved following treatment with the monoamine oxidase inhibitor (MAOI) phenelzine. Insomnia, present to a moderate degree prior to antidepressant therapy, worsened markedly following phenelzine treatment and failed to respond to diphenhydramine, temazepam, triazolam, clonazepam, zolpidem, or trazodone given at high therapeutic doses. Sleep disturbance resolved with low-dose (50 mg) adjunctive quetiapine, with no adverse effects. DISCUSSION: Major depression refractory to standard therapy is a common and serious condition. Some cases respond to MAOIs; however, orthostatic hypotension and insomnia frequently occur. Potentially serious MAOI interactions with psychotropic drugs have raised concerns about combining these agents. In this case, a failure of a number of other medications known to treat MAOI-associated insomnia safely prompted a trial of quetiapine. Despite the possibility that enhanced serotonergic activity might have resulted in serotonin syndrome, no adverse interactions between phenelzine and quetiapine were noted. The use of low-dose, once-daily quetiapine, along with its unique binding properties, may account for its increased safety in combination with phenelzine. CONCLUSIONS: This case illustrates that low-dose quetiapine may be an alternative treatment for phenelzine-associated insomnia. Further case reports are needed to establish the safety and effectiveness of combining these agents.

Selective serotonin reuptake inhibitor-related extrapyramidal symptoms in autistic children: a case series.

Abnormal movements occur rarely with selective serotonin reuptake inhibitors (SSRIs). This report describes four consecutive autistic children who developed extrapyramidal side effects (EPS) following SSRI exposure. Videotapes, physician notes, and parental interviews were used retrospectively to rate symptoms on the Extrapyramidal Symptom Rating Scale. Findings suggest that EPS is a potential complication of SSRI treatment in autistic children.

Once-daily high-dose pindolol for SSRI-refractory depression.

Selective serotonin reuptake inhibitor (SSRI) augmentation with the 5-HT1A antagonist pindolol has met with mixed results. Recent studies using positron emission tomography (PET) suggest that pindolol doses used in these studies were too low to effect 5-HT1A autoreceptor blockade. To test the hypothesis that a single higher dose of pindolol would effectively augment antidepressant responses in SSRI-refractory patients, nine subjects with major depression unresponsive to paroxetine 40 mg/day given for 2 months or more were randomized to AM pindolol 7.5 mg (n=4) or placebo (n=5). Subjects were administered the Hamilton Depression Scale (HAM-D), the Hamilton Anxiety Scale (HAM-A), the Bech-Rafaelsen Melancholia Scale, and the Zung Depression Inventory at baseline and weeks 1, 2, 3, and 4. Subjects receiving pindolol exhibited significant improvements in all ratings beginning at week 2 which continued through week 4. Aside from transient dizziness and a five-point decrease in systolic/diastolic blood pressure associated with pindolol, no adverse effects were reported. Although results must be verified in a larger sample, these findings support previous studies indicating that pindolol can accelerate antidepressant responses during SSRI therapy. In addition, results reported here suggest that a single high dose of pindolol (7.5 mg) is a more effective augmentation strategy in SSRI-refractory patients compared with the same total dose given at 2.5 mg tid.

Exacerbation of mania secondary to right temporal lobe astrocytoma in a bipolar patient previously stabilized on valproate.

OBJECTIVES: To investigate breakthrough mania secondary to a right temporal lobe neoplasm in a bipolar patient previously stabilized on sodium divalproex. BACKGROUND: Right hemispheric brain tumors involving the orbitofrontal or basotemporal cortex are a rare cause of secondary mania. In such cases, early neurologic signs may be difficult to distinguish from bipolar symptoms. Breakthrough mania secondary to brain neoplasm in a bipolar patient stabilized on medication is an extremely rare phenomena which has not been previously reported. METHOD: The clinical course of a bipolar subject stabilized on valproate who developed mania secondary to a right temporal lobe astrocytoma is described. Serial brain magnetic resonance imaging (MRI), baseline electroencephalogram (EEG), and neuropsychiatric evaluations were used to examine the relationship between the patient's brain mass and behavioral disturbances. RESULTS: Symptoms were those that accompanied prior episodes of mania. In addition, signs of temporal lobe dysfunction were evident including periods of detachment, déjà vu experiences, and olfactory hallucinations. In the context of mania, depersonalization was initially attributed to bipolar symptoms. Only several months later, when olfactory hallucinations and alterations in consciousness became evident, was a temporal lobe lesion suspected. Neuropsychiatric abnormalities responded to a combination of surgical intervention, radiation therapy, and topiramate, however the tumor was advanced and invasive at diagnosis resulting in a poor prognosis. CONCLUSIONS: This case suggests that clinicians examining unexplained cases of breakthrough mania should be vigilant for early signs of temporal lobe dysfunction, which could aid in detecting treatable lesions.

Adjunctive quetiapine in bipolar patients partially responsive to lithium or valproate.

Despite therapeutic treatment with lithium or valproate, patients with bipolar I disorder often require adjunctive therapy to treat persistent symptoms. In order to evaluate the effects of quetiapine for bipolar symptoms inadequately responsive to mood stabilizers, a retrospective chart review was undertaken at the Veterans Affairs (VA) Long Beach Mood Disorders Clinic for all bipolar I outpatients who had been prescribed adjunctive quetiapine during an 18-month study period. Among 75 lithium- or valproate-treated patients receiving quetiapine, 16 were identified in whom therapeutic treatment with lithium (> or =0.8 meq/l) or valproate (> or =75 microg/ml) could be verified during the 2-month period prior to quetiapine initiation. Chart notes were utilized by the principal investigator to assign Clinical Global Impression Bipolar ratings (CGI-BP) before and after 30-120 days of quetiapine treatment (mean=173+/-157 mg). Nine of 16 lithium- or valproate-stabilized bipolar patients (56%) were judged much or very much improved in CGI-BP overall ratings following adjunctive quetiapine. In addition, for the entire sample, quetiapine augmentation resulted in significant improvements in clinician-rated bipolar severity scores (CGI-BP) for mania, depression, and overall bipolar illness. The majority of quetiapine-related symptomatic improvement was due to diminished insomnia, agitation, irritability, and mood disturbance. Side effects were mild and transitory including sedation and dizziness. Low-dose quetiapine may be a useful and well-tolerated adjunct for some bipolar patients with incomplete response to lithium or valproate.

Quetiapine for treatment of refractory symptoms of combat-related post-traumatic stress disorder.

To assess the effects of adjunctive quetiapine for treatment of refractory symptoms of combat-related post-traumatic stress disorder (PTSD), charts of Vietnam veterans with war-connected PTSD who had been prescribed quetiapine were reviewed. Only patients with symptoms that had not responded to adequate therapy with two or more psychotropic medications prior to quetiapine treatment were analyzed. Addition of quetiapine to ongoing therapy resulted in further symptomatic improvements in DSM-IV PTSD criterion B (re-experiencing) for 35%, criterion C (avoidance/numbing) for 28%, and criterion D (arousal) for 65% of study subjects. Low doses of quetiapine (mean = 155 +/- 130 mg) were associated with minimal side effects. These results, although retrospective, suggest that augmentative quetiapine may benefit some refractory symptoms of PTSD in combat veterans.

Impulsive aggressive behavior: open-label treatment with citalopram.

BACKGROUND: Results from open-label and placebo-controlled trials suggest that the selective serotonin reuptake inhibitors reduce impulsive aggressive behavior. The objective of this open-label study was to investigate whether citalopram treatment has anti-aggressive effect on impulsive aggressive subjects meeting DSM-IV criteria for a cluster B personality disorder or intermittent explosive disorder. METHOD: In this 8-week trial, subjects were initiated on 20 mg/day of citalopram and titrated up to 60 mg/day by the fourth week, if tolerated. The primary outcome measure was the Overt Aggression Scale-Modified (OAS-M), a scale used to quantify verbal and physical aggression, subjective irritability, and overt irritability. Secondary outcome measures included the Barratt Impulsiveness Scale and Buss-Durkee Hostility Inventory. RESULTS: Of 25 subjects enrolled, 20 completed the study. The mean daily dose was 45.5 mg, and citalopram was generally well tolerated. Statistically significant decreases were found in the OAS-M aggression scores (32.82 +/- 19.76 to 4.73 +/- 7.57, p =.000), subjective irritability scores (3.50 +/- 0.60 to 1.45 +/- 1.18, p =.000), and overt irritability scores (3.23 +/- 0.81 to 0.91 +/- 1.02, p =.000). CONCLUSION: These results suggest that citalopram is an effective treatment for reducing impulsive aggressive behavior.