Linda C. Schaffer

Psychiatric reactions to isotretinoin in patients with bipolar disorder

BACKGROUND Isotretinoin (Accutane(R)) has been available for the treatment of severe cystic acne for about twenty-five years. There have been several reports of adverse psychiatric reactions to isotretinoin, including depressive symptoms and suicide. However, there have been only three case reports of patients with bipolar disorder (BD) who experienced an untoward psychiatric side effect while receiving isotretinoin treatment. In this study, the psychiatric side effects from isotretinoin were assessed in a larger group of BD patients than has previously been reported. METHODS A retrospective chart review of 300 BD outpatients identified ten patients treated with isotretinoin. RESULTS Nine of these ten patients experienced a significant worsening of mood symptoms, and three developed suicidal ideation. Eight experienced a reversal of the relapsed mood symptoms when the isotretinoin was discontinued, whether prematurely or after a full course. LIMITATIONS The limitations of this study include small sample size, retrospective data collection, absence of double-blind controlled design, and inability to control for spontaneous mood episodes in patients with BD. CONCLUSIONS These results indicate that BD patients treated with isotretinoin for acne are at risk for clinically significant exacerbation of mood symptoms, including suicidal ideation, even with concurrent use of psychiatric medicines for BD. The clinical implications of this study are especially relevant to the treatment of patients with BD because acne usually occurs during adolescence, which is often the age of onset of BD and because a common side effect of lithium (a standard treatment for BD) is acne.

Open maintenance treatment of bipolar disorder spectrum patients who responded to gabapentin augmentation in the acute phase of treatment

This report describes the results of maintenance treatment with gabapentin in 18 previously refractory Bipolar Disorder patients who initially responded to augmentation with gabapentin during the acute phase of their therapy. Seven of the original 18 patients (39%) have continued to experience benefit from maintenance gabapentin treatment. Only three patients had to discontinue the gabapentin because of side effects. None of the 18 patients experienced an obvious significant adverse drug-drug interaction. Five of the patients discontinued gabapentin because of diminished clinical efficacy after a significant period of positive therapeutic effect. The results of this small open study suggest that gabapentin may be effective as an augmenting agent in the maintenance phase of treatment of some bipolar spectrum patients.

An open case series on the utility of tiagabine as an augmentation in refractory bipolar outpatients

BACKGROUND Tiagabine (Gabitril) is a GABA uptake inhibitor recently introduced in the United States as an adjunctive treatment for partial complex seizures. Three published studies have addressed the use of tiagabine for bipolar disorder (BPD); two described positive results and one negative results. We assessed the efficacy of add-on tiagabine in a larger sample of adult BPD outpatients. METHODS Twenty-two adult outpatients with DSM-IV diagnosed BPD of some type who were considered unsatisfactory responders to standard medications for BPD were treated in an open fashion with adjunctive tiagabine in a low-dose range. After baseline demographic data and mood state at the time of entry were documented, each patient was monitored clinically for at least 6 months while the dose of tiagabine was adjusted according to the patients clinical status. The subjects were rated using the clinical global impression-bipolar version scale (CGI-BP). RESULTS After 6 months, eight (36%) of the patients were responders to tiagabine by CGI-BP rating. The dose range of tiagabine for responders was 1-8 mg per day. All 14 nonresponders had to discontinue tiagabine because of unacceptable but reversible side effects; one nonresponder experienced breakthrough absence seizures. LIMITATIONS This study was performed in a nonrandom, open naturalistic clinical setting. The sample size was small. CONCLUSIONS Low-dose tiagabine appears to have mood-stabilizing and antimanic properties as an add-on medication for some adult outpatients who have BPD refractory to standard medications. Tiagabine appears to be safe for most adult BPD outpatients. The results of this preliminary open study await confirmation by double-blind controlled studies.

Efficacy and safety of nonbenzodiazepine hypnotics for chronic insomnia in patients with bipolar disorder

BACKGROUND Insomnia in patients with bipolar disorder (BD) can cause distress, daytime dysfunction, cognitive impairment, worsening of hypomanic/manic symptoms and increased suicide risk. Physicians often prescribe hypnotics for BD patients with insomnia although no hypnotic has a specific FDA indication for this use. In this study, the patterns of use, efficacy and safety of five nonbenzodiazepine hypnotics (NBZHs) were assessed in a large group of outpatients with BD. METHOD A chart review was performed for all older adolescents and adult BD outpatients in a private outpatient clinic. Clinical data was collected for any patient who had ever been prescribed a NBZH for insomnia and included successful current use, past unsuccessful treatments, side effects, duration of use, concurrent psychiatric medications, and absence or presence of untoward events often associated with chronic use of hypnotics. RESULTS A significant number of BD patients take NBZHs as needed or on a daily basis. Four NBZHs had adequate success rates; ramelteon was limited in efficacy. Some patients experienced satisfactory results from a NBZH after unsuccessful trials with one or more other NBZHs. About half of the current NBZH users are taking them on a daily long-term basis, and none of these patients have experienced unacceptable untoward events. About three quarters of the chronic NBZH users are taking antimanic medications concurrently, and less than half of the chronic users are taking antidepressants. LIMITATIONS The results may not be generalizable to other BD populations. A control group was not included in the design. Chronic users of NBZHs were not asked to discontinue their NBZH in order to confirm indication for long-term use. CONCLUSIONS Most NBZHs can be effective and safe agents for selected BD outpatients with episodic or chronic insomnia. Failure to respond to one or more NBZH does not preclude a satisfactory response to a different NBZH. Some BD patients who take maintenance antimanic agents also require NBZH treatment. Overactivation from antidepressant treatment does not contribute to chronic NBZH use in most BD patients.

An open trial of pregabalin as an acute and maintenance adjunctive treatment for outpatients with treatment resistant bipolar disorder

BACKGROUND Pregabalin is a structural analog of GABA, similar to gabapentin. It does not have a FDA indication for any psychiatric disorder in the USA. There has been one case report of the successful use of pregabalin as an augmenting agent in a patient with Bipolar Disorder (BD). In the present open label study, not subsidized by the manufacturer, the investigators prospectively evaluated the acute and maintenance efficacy of pregabalin as an adjunctive medication for a group of treatment refractory outpatients with BD. METHODS Older adolescent and adult outpatients with any type of DSM-IV diagnosed BD, who were considered treatment nonresponders to multiple standard medications for BD, were treated with adjunctive pregabalin. The baseline mood state before initiation of pregabalin was compared to the mood state after an acute trial of pregabalin using the Clinical Global Impression-Bipolar Version Scale (CGI-BP). All acute responders were treated for a minimum of two months. Follow-up maintenance treatment data was obtained for the acute pregabalin responders for three years after the 18 month acute phase of the study. RESULTS Fifty-eight total patients were treated adjunctively with pregabalin. Twenty-four (41%) were rated as acute responders. For the acute responders, pregabalin produced either a mood stabilizing effect, antidepressant effect or antimanic effect. Intolerable side-effects were the most common reason (79%) for a failed acute trial of pregabalin. None of the side effects resulted in serious medical complications. No patient abused pregabalin, and there were no adverse drug-drug interactions despite an average of 3.3 concurrent other psychiatric medications. The maintenance data revealed that 10 (42%) of the original 24 acute pregabalin responders were still taking pregabalin as an add-on medicine for an average of 45.2 months (range 42-48, SD: 2.35). LIMITATIONS This study has an open label observation design. CONCLUSIONS The results of this preliminary open study suggest that pregabalin is a safe and effective acute and maintenance adjunctive treatment for a significant number of treatment-resistant outpatients with any type of BPD. It appears to have mood stabilizing and antidepressant properties in addition to antimanic effects. Similar studies using a double-blind, randomly controlled design would be useful to confirm the reliability and validity of the results of this study.

The use of primidone in the treatment of refractory bipolar disorder

Four anticonvulsant medications (carbamazepine, valproate, gabapentin and lamotrigine) have received attention in the psychiatric literature as efficacious treatment for bipolar disorder, either as monotherapy or as adjunctive agents. Although two earlier reports in 1993 suggested that primidone may also be helpful for bipolar disorder, this older anticonvulsant has not been evaluated in any subsequent studies to confirm these earlier findings. In the present prospective open study, 26 patients with refractory bipolar disorder were treated with primidone as an adjunctive therapy. Eight (31%) patients experienced a persistent positive therapeutic effect. Five (19%) patients were considered partial or temporary responders to primidone. The remaining 13 patients (50%) were considered treatment failures. Although a 31% response rate is considered modest in most psychotropic medication studies, the authors believe that this success rate is significant in this refractory patient population and should provide impetus for future more scientific studies to confirm the preliminary findings of this open trial.

An open trial of lurasidone as an acute and maintenance adjunctive treatment for outpatients with treatment-resistant bipolar disorder

To the Editors: L urasidone is an atypical antipsychotic that has received approval from the Food and Drug Administration (FDA) for schizophrenia and for monotherapy and adjunctive treatment for major depressive episodes (MDEs) in bipolar disorder (BD). Patients who completed the acute treatment phase (6 weeks) of both MDE FDA clinical trials participated in an open-label extension study for 6 months. The results of this unpublished study indicated that maintenance treatment with lurasidone was safe and well tolerated and produced sustained improvement in depressive symptoms. The ability of lurasidone to block serotonin-7 (5-HT7) receptors may contribute to its antidepressant effect.

Is DST status associated with depression characteristics

Depressed inpatients have a DST non-suppression rate that is several times greater than that of depressed outpatients. To explore what clinical features of depression might explain this difference, 25 depressed inpatients who were DST non-suppressors were compared with 16 DST suppressors, using 70 clinical variables. Those variables that were different between these two groups of inpatients were then used to compare depressed inpatients and outpatients. Three variables that were significantly associated with DST status in depressed inpatients were also found to differentiate between depressed inpatients and depressed outpatients. DST suppression was associated with a family history of alcoholism, with the symptom hypersomnia, and with a younger age at index interview.

An Open Trial of Lurasidone as an Acute and Maintenance Adjunctive Treatment for Outpatients With Treatment-Resistant Bipolar Disorder: Response to Letter to the Editors.

W e appreciate the interest of the authors of the critique of our study. In the second paragraph, their critique states, “Lurasidone holds Food and Drug Administration (FDA) approval for indications of schizophrenia and bipolar depression as monotherapy or adjunct therapy with divalproic acid or lithium. Due to this, it is important to understand how Schaffer and colleagues concluded that lurasidone is effective for the full range of bipolar disorder mood states.” This comment calls into question what FDA approval means. Food and Drug Administration approval does not necessarily limit efficacy to the specific disorder or diagnosis defined by the study; it only speaks to the studies that have been submitted to it in the approval process. The critique authors further buttress their argument, “no placebo-controlled studies evaluating lurasidone in mixed or manic episode bipolar disorder are available at this time.” We note that one of the important purposes of naturalistic studies is to provide information about the potential efficacy of a pharmaceutical compound for unapproved uses. Furthermore, the critique appears to be based on the standards for a double-blind, controlled study; however, our study is naturalistic in design, and this intent was made clear in the letter. In the following paragraphs, we will address the specific comments made by the authors of the critique. In the first paragraph of their letter, the authors indicate that our study produced conclusions related tomanic episodes of bipolar disorder, and this was not the case. Our conclusions were for episodes of depression and mixed/rapid-cycling symptoms. In fact, we noted in our article that our results were of interest because they were mostly for non–bipolar I disorder patients. The authors of the critique also note that baseline data and data at the conclusion of the acute and maintenance phases of the trial were not presented. We did document mood states at baseline and at the end of the 2-month acute trial using the Change Scale of the Clinical Global Impression– Bipolar Version (CGI-BP). These results were indirectly presented as number of