Insomnia in Tinnitus Patients: A Prospective Study Finding a Significant Relationship.

Tinnitus is a highly prevalent medical disorder occurring in 10-30% of the general population. This disorder often becomes chronic and severe effecting quality of life contributing to significant psychiatric consequences; one that we have written about recently is comorbid insomnia. The latter can predispose effected persons to depressive episodes and a worsening of their total functioning. We have reported in the past that comorbid insomnia occurs in 10-80% of tinnitus patients with most reports finding over a 40% frequency. Unfortunately, these prior studies tended to evaluate only insomnia as a symptom and not as a diagnosis; therefore its seriousness and implications could not be assessed. Furthermore, most studies utilized only open-ended questionnaires with many being sent via the mail. Our study evaluated 72 tinnitus patients who were prospectively evaluated over the telephone for a tinnitus treatment study program at our center focusing on possible co-morbid insomnia symptoms as well as whether the insomnia satisfied a diagnosis with its accompanying dysfunctional state. The interview included questions regard a full range of questions assessing sleep onset, sleep continuity, early morning awakening, sleep duration as well as daytime consequences necessary for a diagnosis of insomnia. We found that not only were insomnia symptoms highly prevalent, but 60% of the tinnitus sample met strict diagnostic criteria (DSM-IV-TR) of insomnia secondary to a general medical condition, i.e., tinnitus. Alarmingly, only 4 % were being treated for their insomnia. In addition, our data suggests that tinnitus patients with co-morbid insomnia have a more severe form of tinnitus and thus, may need further care and treatment.

A review of antidepressant-induced urinary hesitancy: a focus on levomilnacipran ER including two case presentations(5633).

INTRODUCTION: Levomilnacipran ER was recently FDA approved as Fetzima® for the treatment of MDD. Urinary hesitancy can be an adverse event associated with levomilnacipran treatment. AREAS COVERED: This manuscript details the longitudinal course of levomilnacipran-induced urinary hesitancy in 2 cases that were in a pivotal clinical trial, examining possible predisposing factors and treatment issues. This manuscript also reviews the literature comparing urinary hesitancy associated with levomilnacipran versus other antidepressants. Antidepressants that are potent norepinephrine reuptake inhibitors like levomilnacipran, may have increased rates of associated urinary hesitancy. The latter can cause significant discomfort and a compromised quality of life. Occasionally, it can progress to urinary retention necessitating an emergency medical intervention. EXPERT OPINION: All patients being treated with antidepressants should be carefully monitored for this side effect. Discontinuation of treatment or reduction of the dose of antidepressant frequently relieves urinary hesitancy; alternatively, treatment with an alpha1A antagonist, e.g., tamsulosin may relieve antidepressant-induced urinary hesitancy within hours to days; such strategies allow for continued antidepressant treatment without urinary hesitancy recurring. Thus, with appropriate clinical care, the benefits using levomilnacipran outweigh its risks.

Levomilnacipran for the treatment of major depressive disorder: a review.

Levomilnacipran (LVM, Fetzima(®)) was recently approved by the US Food and Drug Administration for the treatment of major depressive disorder. It is a unique dual neurotransmitter reuptake inhibitor. In contrast with other selective serotonin norepinephrine reuptake inhibitors, including duloxetine, venlafaxine, and desvenlafaxine, it has greater selectivity for inhibiting norepinephrine reuptake than serotonin reuptake. Our review focuses on the efficacy, safety, and tolerability data for five double-blind, placebo-controlled, short-term studies and two long-term studies. In the short-term studies, LVM was found to be more effective than placebo in reducing depression (Montgomery-Åsberg Depression Rating Scale) scores as well as improving functional impairment (Sheehan Disability Scale) scores. Long-term studies found LVM to be similarly effective but in the only placebo-controlled long-term study, LVM was not significantly superior to placebo. LVM is fairly well tolerated, with the most common adverse events being nausea, headache, dry mouth, hyperhidrosis, and constipation. Discontinuation rates were mildly increased in those being treated with LVM (9%) versus placebo (3%). Adverse events were not dose-related except for urinary hesitancy and erectile dysfunction. LVM was weight neutral, was not toxic to the liver, and did not cause clinically significant QTc prolongation. Consistent with being a predominant potentiator of norepinephrine, pulse and blood pressure were significantly elevated by LVM but rarely induced tachycardia or hypertension. LVM is a relatively safe alternative antidepressant treatment with minimal drug-drug interactions. It is the only antidepressant that has in its labeling that it is not only effective in improving depression but also effective in improving impaired functioning. Whether this important effect on functioning is unique to LVM must be researched. In addition, whether LVM might be effective in norepinephrine-deficit depression, refractory depression, atypical depression, or seasonal depression is yet to be evaluated. Ultimately, head-to-head studies comparing LVM with other antidepressants will determine the place of LM in antidepressant treatment.

Pharmacotherapy Treatment Options for Insomnia: A Primer for Clinicians.

Insomnia is a prevalent disorder with deleterious effects such as decreased quality of life, and a predisposition to a number of psychiatric disorders. Fortunately, numerous approved hypnotic treatments are available. This report reviews the state of the art of pharmacotherapy with a reference to cognitive behavioral therapy for insomnia (CBT-I) as well. It provides the clinician with a guide to all the Food and Drug Administration (FDA) approved hypnotics (benzodiazepines, nonbenzodiazepines, ramelteon, low dose sinequan, and suvorexant) including potential side effects. Frequently, chronic insomnia lasts longer than 2 years. Cognizant of this and as a result of longer-term studies, the FDA has approved all hypnotics since 2005 without restricting the duration of use. Our manuscript also reviews off-label hypnotics (sedating antidepressants, atypical antipsychotics, anticonvulsants and antihistamines) which in reality, are more often prescribed than approved hypnotics. The choice of which hypnotic to choose is discussed partially being based on which segment of sleep is disturbed and whether co-morbid illnesses exist. Lastly, we discuss recent label changes required by the FDA inserting a warning about "sleep-related complex behaviors", e.g., sleep-driving for all hypnotics. In addition, we discuss FDA mandated dose reductions for most zolpidem preparations in women due to high zolpidem levels in the morning hours potentially causing daytime carry-over effects.

EMSAM (deprenyl patch): how a promising antidepressant was underutilized.

The EMSAM patch is a unique monoamine oxidase inhibitor (MAOI) being the only antidepressant utilizing a transdermal delivery system. This was welcomed by clinicians who hoped that EMSAM would be better tolerated than oral MAOIs and non-MAOI antidepressants, as well as being effective for treatment in a wide spectrum of depressed patients including atypical depression, bipolar depression, and refractory depression. Unfortunately, the clinical use of EMSAM has been underutilized and its potential usefulness overlooked. This article suggests that fear of possible side effects, particularly the "cheese reaction" and serotonin syndrome, are some of the main contributors to underutilization by clinicians. These risks have been significantly exaggerated with the 6 mg/day dose not even requiring a special diet. Other contributing factors leading to underutilization are reviewed such as: the lack of studies addressing many important clinical questions; inadequate data analyses; not evaluating the effect of EMSAM on comorbid psychiatric conditions, particularly anxiety disorders; lack of antidepressant comparators versus EMSAM; no dose-response relationship examined; various depressive subtypes and conditions are unexplored, eg, bipolar depression and refractory depression; poor insurance coverage for an expensive medication; as well as minimal marketing efforts and postmarketing studies. On the other hand, many potential advantages of EMSAM are not highlighted enough in the literature and by pharmaceutical companies which might have increased clinical interest and utilization of the antidepressant. For example, the advantages of EMSAM include: avoidance of swallowing issues, as can be seen with oral antidepressants; minimal side effects, probably due to a favorable pharmacokinetic profile; minimal evidence of suicidal behavior, probably relating to the transdermal route of administration; low rates of inducing hypomanic/manic episodes; as well as significant efficacy in "anxious depression" and atypical depression. Recent efforts in conducting some post hoc analyses and presentations on EMSAM may yet stimulate further clinical interest and use of this antidepressant.

Efficacy and safety of levomilnacipran sustained release 40 mg, 80 mg, or 120 mg in major depressive disorder: a phase 3, randomized, double-blind, placebo-controlled study.

OBJECTIVE: This phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and tolerability of fixed-dose levomilnacipran sustained release (SR) compared with placebo in patients with major depressive disorder (MDD); the study was conducted from September 2009-May 2011. METHOD: Outpatients met DSM-IV-TR criteria for MDD with an ongoing major depressive episode ≥ 8 weeks' duration. After a 1-week placebo lead-in, patients were randomly assigned to receive placebo (n = 179) or levomilnacipran SR 40 mg (n = 181), 80 mg (n = 181), or 120 mg (n = 183) once daily for 8 weeks of double-blind treatment, followed by a 2-week double-blind down-taper. The primary efficacy parameter was change from baseline on the clinician-rated Montgomery-Asberg Depression Rating Scale (MADRS) total score. The prespecified secondary efficacy parameter was change from baseline in Sheehan Disability Scale (SDS) total score. Additional efficacy measures included the 17-item Hamilton Depression Rating Scale (HDRS(17)) and Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I). Safety and tolerability were also evaluated. RESULTS: The least squares mean difference (LSMD) for change from baseline in MADRS total score was significantly superior to placebo for all dose groups: -3.23 (P = .0186), -3.99 (P = .0038), and -4.86 (P = .0005) for levomilnacipran SR 40, 80, and 120 mg, respectively. The LSMD was significantly different for levomilnacipran SR 80 mg and 120 mg versus placebo on the SDS (-2.51 and -2.57, respectively, P < .05 for both doses), HDRS(17) (-2.09 and -2.34, respectively, P < .05 for both doses), CGI-S (-0.43 [P < .01] and -0.35 [P < .05], respectively), and CGI-I (-0.34 and -0.32, respectively, P < .05 for both doses) assessments. The most common treatment-emergent adverse events (≥ 10% of any treatment group) were headache, nausea, constipation, dry mouth, increased heart rate, and hyperhidrosis. CONCLUSIONS: Levomilnacipran SR demonstrated significant improvement in depressive symptoms and functioning relative to placebo. In this study, levomilnacipran SR was generally well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00969709.

Improved insomnia symptoms and sleep-related next-day functioning in patients with comorbid major depressive disorder and insomnia following concomitant zolpidem extended-release 12.5 mg and escitalopram treatment: a randomized controlled trial.

OBJECTIVE: This investigation was performed to assess the efficacy and safety of zolpidem extended-release in patients with insomnia associated with major depressive disorder (MDD). METHOD: Patients (N = 385) received open-label escitalopram 10 mg/d and were randomized to concomitant zolpidem extended-release 12.5 mg/night or placebo for 8 weeks (phase 1) in a randomized, parallel-group, multicenter trial. Responders (≥ 50% in 17-item Hamilton Depression Rating Scale [HDRS(17)] score) continued 16 weeks of double-blind treatment (phase 2); escitalopram only was given during a 2-week run-out period. The study was conducted between February 2006 and June 2007. The primary efficacy measure was change from baseline in subjective total sleep time. Secondary efficacy measures included subjective sleep-onset latency, number of awakenings, wake time after sleep onset, sleep quality, sleep-related next-day functioning, HDRS(17), Sleep Impact Scale score, Patient and Clinical Global Impressions of Insomnia Treatment, the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire, and the Quality of Life Enjoyment and Satisfaction Questionnaire. Adverse events were recorded throughout the study; sleep measures were also evaluated during the run-out period. RESULTS: Throughout phase 1, zolpidem extended-release led to significantly greater improvements in total sleep time (P < .0001), wake time after sleep onset, sleep onset latency, number of awakenings, and sleep quality (P ≤ .0003), and some measures of sleep-related next-day functioning but not in depressive symptoms or quality of life. During phase 2, improvements with the zolpidem extended-release/escitalopram group occurred for total sleep time (significant [P < .05] at weeks 12 and 16), as well as for a few other secondary efficacy measures but not in depressive symptoms or quality of life. The most common adverse events associated with combination treatment included nausea, somnolence, dry mouth, dizziness, fatigue, and amnesia. CONCLUSIONS: Zolpidem extended-release administered concomitantly with escitalopram for up to 24 weeks was well tolerated and improved insomnia and some sleep-related next-day symptoms and next-day functioning in patients with MDD but did not significantly augment the antidepressant response of escitalopram. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00296179.

Zolpidem extended-release improves sleep and next-day symptoms in comorbid insomnia and generalized anxiety disorder.

A multicenter, double-blind, parallel-group study was designed to assess the efficacy and safety of zolpidem extended-release coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder. Patients (N = 383) received open-label escitalopram 10 mg/d and were randomized to either adjunct zolpidem extended-release 12.5 mg or placebo. The primary efficacy measure was change from baseline to week 8 in subjective total sleep time. Secondary efficacy measures included subjective sleep onset latency, number of awakenings, wake time after sleep onset, sleep quality, the Hamilton Rating Scale for Anxiety, the Beck Anxiety Inventory, the Sleep Impact Scale, the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire, and the Sheehan Disability Scale. The last-observation-carried-forward method was used to impute missing values for most efficacy measures. Safety was monitored at each visit. At week 8 and all time points, there was a significant improvement in the zolpidem extended-release/escitalopram group compared with placebo/escitalopram for total sleep time (P < 0.0001). Most of the secondary efficacy measures also significantly favored zolpidem at most visits (P < 0.0001). The most common treatment-emergent adverse events in both groups were nausea, dizziness, headache, fatigue, and dry mouth. Concurrent zolpidem extended-release/escitalopram, compared with placebo/escitalopram, significantly improved insomnia and sleep-related next-day symptoms, but not anxiety symptoms, in patients with comorbid insomnia and generalized anxiety disorder.

Sleep disturbances in patients with post-traumatic stress disorder: epidemiology, impact and approaches to management.

Subjective reports of sleep disturbance indicate that 70-91% of patients with post-traumatic stress disorder (PTSD) have difficulty falling or staying asleep. Nightmares are reported by 19-71% of patients, depending on the severity of their PTSD and their exposure to physical aggression. Objective measures of sleep disturbance are inconsistent, with some studies that used these measures indicating poor sleep and others finding no differences compared with non-PTSD controls. Future research in this area may benefit from examining measures of instability in the microstructure of sleep. Additionally, recent findings suggest that sleep disordered breathing (SDB) and sleep movement disorders are more common in patients with PTSD than in the general population and that these disorders may contribute to the brief awakenings, insomnia and daytime fatigue in patients with PTSD. Overall, sleep problems have an impact on the development and symptom severity of PTSD and on the quality of life and functioning of patients. In terms of treatments, SSRIs are commonly used to treat PTSD, and evidence suggests that they have a small but significant positive effect on sleep disruption. Studies of serotonin-potentiating non-SSRIs suggest that nefazodone and trazodone lead to significant reductions in insomnia and nightmares, whereas cyproheptadine may exacerbate sleep problems in patients with PTSD. Prazosin, a centrally acting alpha1-adrenoceptor antagonist, has led to large reductions in nightmares and insomnia in small studies of patients with PTSD. Augmentation of SSRIs with olanzapine, an atypical antipsychotic, may be effective for treatment-resistant nightmares and insomnia, although adverse effects can be significant. Additional medications, including zolpidem, buspirone, gabapentin and mirtazapine, have been found to improve sleep in patients with PTSD. Large randomised, placebo-controlled trials are needed to confirm the above findings. In contrast, evidence suggests that benzodiazepines, TCAs and MAOIs are not useful for the treatment of PTSD-related sleep disorders, and their adverse effect profiles make further studies unlikely. Cognitive behavioural interventions for sleep disruption in patients with PTSD include strategies targeting insomnia and imagery rehearsal therapy (IRT) for nightmares. One large randomised controlled trial of group IRT demonstrated significant reductions in nightmares and insomnia. Similarly, uncontrolled studies combining IRT and insomnia strategies have demonstrated good outcomes. Uncontrolled studies of continuous positive airway pressure for SDB in patients with PTSD show that this treatment led to significant decreases in nightmares, insomnia and PTSD symptoms. Controlled studies are needed to confirm these promising findings.

Interferon-induced depression in chronic hepatitis C: a review of its prevalence, risk factors, biology, and treatment approaches.

Hepatitis C viral infection is a global health problem that affects approximately 4 million people in the United States. Combination treatment with pegylated interferon (IFN)-alpha plus ribavirin has been shown to be most effective in treating patients with chronic hepatitis C (CHC). Despite its efficacy, one of the most common side effects of this regimen is depression. Whereas IFN-alpha has been found to induce depression in chronic myelogenous leukemia, melanoma, and renal cell carcinoma, CHC patients may be especially prone to develop IFN-induced depression. This review includes a summary of differences between IFN-alpha and IFN-beta and addresses whether pegylation of IFN (versus nonpegylated IFN) gives rise to a treatment with reduced potential to induce depressive symptoms. Consideration is also given to evidence showing that treatment with ribavirin may contribute to IFN-induced depression. Thyroid disorders and anemia (as well as other medical conditions) have also been associated with IFN exposure and may account for some incidences of depression in CHC patients. Evidence is reviewed indicating that prior psychiatric and mood disorders (especially previous episodes of major depressive disorder), just prior to IFN treatment, contribute to the propensity to develop depression during treatment. In addition, a brief description is provided of potential biological mechanisms of IFN-induced depression (ie, monoamines, hypothalamic-pituitary-adrenocortical [HPA] axis, proinflammatory cytokines, peptidases, intercellular adhesion molecule-1, and nitric oxide). Finally, a discussion is provided on the use of antidepressants as a preventative versus restorative treatment, including a commentary on risks of using antidepressants in this patient population.

Increased personality disorders and Axis I comorbidity in atypical depression.

OBJECTIVE: Comparison of patients with and without atypical depression on comorbid Axis I and I disorders to determine whether atypical depression is associated with a higher comorbidity. METHOD: Twenty-nine major depressive disorder patients with and without atypical depression were compared on clinical measures using multiple regression analyses. RESULTS: Atypical depression predicted the presence of comorbid Axis I (100% vs 33%), Axis II (90% vs 35%), and both Axis I and II (65% vs 8.14%) disorders. Personality disorders did not mediate the relationship between atypical depression and Axis I comorbidity. CONCLUSIONS: The high prevalence of Axis I and II comorbidity in major depression may be explained, at least in part, by the presence of atypical depression. Our findings also suggest that the increased Axis I comorbidity observed in atypical depression is independent of the effects of personality disorders and is probably a direct effect of atypical depression subtype. Future research should confirm whether clinical findings associated with atypical depression are independent of their association with personality disorders in a larger sample of depressed patients and also examine treatment implications in atypical depression other than a preferential monoamine oxidase inhibitor responsivity.

Recombinant human interferon-alpha does not alter reward behavior, or neuroimmune and neuroendocrine activation in rats.

Recombinant human interferon-alpha (IFN-alpha) induces depression, and neuroendocrine and neuroimmune activation, in a significant number of patients undergoing treatment for viral illnesses (e.g., hepatitis C), yet these effects have not been consistently reproduced in rodents. As such, we sought to determine the effects of acute or chronic IFN-alpha treatment on basic reward and immobility in the forced swim test (FST), neuroendocrine and neuroimmune activation, and monoamine turnover in brain. In the first experiment, male Wistar rats (N = 7/group) treated with human recombinant IFN-alpha (100,000 IU/kg, i.p.), as compared to saline, did not exhibit alterations to rate of sucrose pellet self-administration or total reinforcers obtained, corticosterone release, plasma IL-6 release, IL-1beta or IL-6 mRNA expression in hippocampus, or monoamine turnover in prefrontal cortex, striatum, nucleus accumbens, or amygdala. However, acute IFN-alpha decreased body weight and produced a trend toward reduced food consumption in the home cage 2 h after injection. In the second experiment, Wistar rats (N=4/group) were subjected to a chronic treatment regimen of saline or IFN-alpha (100,000 IU/kg, i.p.) once daily for 14 consecutive days. The data reveal that animals exposed to chronic IFN-alpha exhibited similar amounts of time immobile and similar latencies to primary immobility in the FST as compared to saline-treated controls. Chronic IFN-alpha did not induce corticosterone release, plasma TNF-alpha, or IL-6 release. Tissue monoamine analysis revealed that chronic IFN-alpha reduced DA levels in prefrontal cortex, and decreased 5-HT levels and increased 5-HT turnover in amygdala. In the third experiment, Wistar rats (N = 4/group) were exposed to either acute or chronic pegylated IFN-alpha (pegIFN-alpha: 3.25, 10 or 75 mg/kg, i.p.) at one of several time points from 1 h to 23 days. The data reveal that neither acute nor chronic pegIFN-alpha induced corticosterone release. Overall, the current report demonstrates that neither acute nor chronic IFN-alpha induced depressive-like behavior and neither IFN-alpha nor peg-IFN-alpha was capable of inducing neuroendocrine or neuroimmune activation. Despite the neurochemical alterations observed in the chronic treatment regimen, the data indicate that recombinant human IFN-alpha does not produce a robust model of depressive-like behavior in rodents.

Interferon-induced depression: strategies in treatment.

Interferon (IFN) is a pro-inflammatory cytokine that is widely used for the treatment of a number of disorders including viral infections, hematological proliferative disorders, and skin malignancies. Unfortunately, IFN frequently induced depression and has led to compromised tolerability with lowering of the dose of IFN and even discontinuation of treatment. Thus, it is imperative to diagnose IFN-induced depression early, evaluate whether this depression is associated with IFN-induced anemia or thyroid dysfunction, which can be corrected, and if necessary treat with antidepressants. IFN-induced depression is highly responsive to antidepressants with benefits occurring frequently at relatively low doses and after only a few weeks. Although SSRIs have mainly been studied, non-SSRIs appear to be effective also. Antidepressants have a number of risks and side effects that must be considered and may enter into the decision as to which antidepressant to choose. If IFN induces a depression in a patient with a bipolar disorder history, antidepressant treatment must include a mood stabilizer. In the case of vulnerable patients (e.g., those who have significant depressive symptoms prior to IFN or who have had an IFN-induced depression in the past) prophylactic antidepressant treatment appears to decrease the likelihood of having an IFN-induced depression. On the basis of known and effective treatment strategies, IFN-induced depression should not be an obstacle for continued treatment in most patient populations.

Acute diclofenac treatment attenuates lipopolysaccharide-induced alterations to basic reward behavior and HPA axis activation in rats.

RATIONALE: Non-steroidal anti-inflammatory drugs (NSAIDs) counteract stress hormone and pro-inflammatory cytokine activation, and are being considered as therapeutics for Alzheimer's and Parkinson's disease, and multiple sclerosis. Previous data from our laboratory revealed that repeated treatment with the NSAID diclofenac attenuated lipopolysaccharide (LPS)-induced alterations to reward behavior, implicating a role for NSAIDs in alleviating depressive-like behavior. OBJECTIVES: To extend these findings, we sought to determine whether acute treatment with diclofenac would attenuate LPS-induced alterations to basic reward behavior, as well as neuroendocrine and neuroimmune function. METHODS: Male, Wistar rats (n=8-9/grp) pressed a lever for sucrose pellet reward and after establishing a steady baseline were exposed to an injection of saline (1 ml/kg, SC) or diclofenac (2.5 mg/kg, SC) 30 min prior to a second injection of saline or LPS (20 microg/kg, IP). RESULTS: In saline pre-treated rats, LPS significantly reduced rate of sucrose pellet self-administration and total reinforcers obtained, suggestive of an anhedonia response. In addition, LPS increased corticosterone release, increased plasma intereleukin (IL)-1beta release, increased IL-1beta and IL-6 mRNA in hippocampus, increased corticotropin releasing hormone (CRH) mRNA in pituitary, and decreased CRH-1 mRNA in pituitary. Importantly, the behavioral and neuroendocrine effects, but not neuroimmune effects, produced by LPS were significantly attenuated in rats pre-treated with diclofenac. CONCLUSIONS: These new data provide a comprehensive assessment of the acute effects of diclofenac on LPS exposure in rats and confirm a role for NSAIDs in attenuating endotoxin-induced anhedonia. Of particular importance, the data reveal that the observed effects are mediated via the hypothalamic pituitary adrenal axis at the level of the pituitary or above.

Effect of lamotrigine on cognitive complaints in patients with bipolar I disorder.

BACKGROUND: This analysis describes the effects of bipolar I disorder on self-reported neurocognitive measures and remediation of these deficits with lamotrigine therapy. METHOD: Data were derived from 2 clinical trials designed to assess the efficacy of lamotrigine as maintenance therapy for recently manic (N = 349) or depressed (N = 966) patients (DSM-IV criteria). During the 8- to 16-week open stabilization phase, patients received lamotrigine as monotherapy or as adjunctive therapy (target dose = 200 mg/day, minimum dose = 100 mg/day) while other psychotropic drugs were discontinued. The Medical Outcomes Study Cognitive Scale (MOS-Cog) and the AB-Neurological Assessment Scale (AB-NAS) were used to measure cognitive functioning at baseline and at the end of the open-label phase. To examine the relationship between depressive and manic symptomatology, initiation of lamotrigine, and cognitive functioning, correlational analyses and analyses of covariance were conducted. RESULTS: Bipolar patients in both trials had significant cognitive impairment; however, it was much greater in index episode depressed bipolar patients compared with index episode manic patients. In both studies, substitution of lamotrigine for other psychotropic medications significantly improved the mean scores from baseline to the end of the open-label phase on the MOS-Cog and the AB-NAS (p < .0001). Among patients who took lamotrigine as monotherapy, the mean MOS-Cog score also improved significantly versus baseline (+32.2, or 81%, for depressed patients, p < .0001; and +19.9, or 35%, for manic patients, p < .0001). Mean AB-NAS scores (-19.7, or -55%, for depressed patients, p < .0001; and -7.2, or -32%, for manic patients, p = .0062) showed similar improvement. Cognitive impairment was significantly correlated with depression symptom severity based on Hamilton Rating Scale for Depression scores (p < .0001). After controlling for change in mood, age, gender, baseline score, duration of illness, and duration of use of other psychotropics, a significant improvement in cognition was observed during the open-label phase when lamotrigine was used as monotherapy/adjunctive therapy. CONCLUSION: Treatment with lamotrigine as monotherapy and as adjunctive therapy was associated with improved cognitive functioning and reduced neurocognitive side effects, regardless of index mood polarity.