Suicidal Ideation and Suicidal Behavior as Rare Adverse Events of Antidepressant Medication: Current Report from the AMSP Multicenter Drug Safety Surveillance Project.

Background: Suicidal ideations, suicide attempts, and fatal suicides are rare adverse drug reactions to antidepressant drugs, but they essentially are clinically relevant. Drawing on a larger dataset of the European drug surveillance program, the present naturalistic study updates a previous contribution (Stübner et al., 2010). Methods: First an analysis of the comprehensive data collected in 81 psychiatric hospitals from 1993 to 2014 by the European drug surveillance program Arzneimittelsicherheit in der Psychiatrie was made. All documented single cases of suicidal ideations or behavior judged as adverse drug reactions to antidepressant drugs were carefully assessed as to their clinical features and drug prescriptions. Results: Among 219,635 adult hospitalized patients taking antidepressant drugs under surveillance, 83 cases of suicidal adverse drug reactions occurred (0.04%): 44 cases of suicidal ideation, 34 attempted suicides, and 5 committed suicides were documented. Restlessness was present in 42 patients, ego-dystonic intrusive suicidal thoughts or urges in 39 patients, impulsiveness in 22 patients, and psychosis in 7 patients. Almost all adverse drug reactions occurred shortly after beginning antidepressant drug medication or increasing the dosage. Selective serotonin reuptake inhibitors caused a higher incidence of suicidal ideation and suicidal behavior as adverse drug reactions than noradrenergic and specific serotonergic antidepressants or tricyclic antidepressants, as did monotherapy consisting of one antidepressant drug, compared to combination treatments. Conclusions: The study supports the view that antidepressant drug-triggered suicidal ideation and suicidal behavior (primarily with selective serotonin reuptake inhibitors) are rare. Special clinical features (restlessness, ego-dystonic thoughts or urges, impulsiveness) may be considered as possible warning signs. A combination therapy might be preferable to antidepressant drug monotherapy when beginning treatment.

Open-label study of duloxetine for the treatment of obsessive-compulsive disorder.

BACKGROUND: This study sought to investigate the efficacy of duloxetine for the treatment of obsessive-compulsive disorder (DSM-IV). METHODS: Twenty individuals were enrolled in a 17-week, open-label trial of duloxetine at Massachusetts General Hospital. Data were collected between March 2007 and September 2012. Study measures assessing obsessive-compulsive disorder symptoms, quality of life, depression, and anxiety were administered at baseline and weeks 1, 5, 9, 13, and 17. The primary outcome measures were the Yale-Brown Obsessive Compulsive Scale and Clinical Global Improvement scale. RESULTS: For the 12 study completers, pre- and posttreatment analyses revealed significant improvements (P<.05) on clinician- and self-rated measures of obsessive-compulsive disorder symptoms and quality of life. Among the 12 completers, more than one-half (n=7) satisfied full medication response criteria. Intention-to-treat analyses (n=20) showed similar improvements (P<.05) on primary and secondary study outcome measures. CONCLUSION: The results of this study suggest that duloxetine may provide a significant reduction in symptoms for patients with obsessive-compulsive disorder. ClinicalTrials.gov NCT00464698; http://clinicaltrials.gov/ct2/show/NCT00464698?term=NCT00464698&rank=1.

Measurement of GABA using J-difference edited 1H-MRS following modulation of synaptic GABA concentration with tiagabine.

Though GABA is the major inhibitory neurotransmitter in the brain, involved in a wide variety of brain functions and many neuropsychiatric disorders, its intracellular and metabolic presence provides uncertainty in the interpretation of the GABA signal measured by (1)H-MRS. Previous studies demonstrating the sensitivity of this technique to pharmacological manipulations of GABA have used nonspecific challenges that make it difficult to infer the exact source of the changes. In this study, the synaptic GABA reuptake inhibitor tiagabine, which selectively blocks GAT1, was used to test the sensitivity of J-difference edited (1)H-MRS to changes in extracellular GABA concentrations. MEGA-PRESS was used to obtain GABA-edited spectra in 10 male individuals, before and after a 15-mg oral dose of tiagabine. In the three voxels measured, no significant changes were found in GABA+ concentration after the challenge compared to baseline. This dose of tiagabine is known to modulate synaptic GABA and neurotransmission through studies using other imaging modalities, and significant increases in self-reported sleepiness scales were observed. Therefore, it is concluded that recompartmentalization of GABA through transport block does not have a significant impact on total GABA concentration. Furthermore, it is likely that the majority of the magnetic resonance spectroscopy (MRS)-derived GABA signal is intracellular. It should be considered, in individual interpretation of GABA MRS studies, whether it is appropriate to attribute observed effects to changes in neurotransmission.

A randomised trial of the effect of the glycine reuptake inhibitor Org 25935 on cognitive performance in healthy male volunteers.

OBJECTIVE: Cognitive impairment is integral to many neurological illnesses. Specific enhancement of glutamatergic transmission may improve memory and learning. Org 25935 increases the synaptic availability of glycine, an obligate co-agonist with glutamate at N-methyl-D-aspartate receptors. We hypothesised that Org 25935 would acutely improve the learning and memory of healthy volunteers. METHODS: A randomised, double-blind, parallel-group, single-dose study of Org 25935 and placebo was carried out. Thirty-two healthy male volunteers took either 12-mg Org 25935 or matching placebo and were later assessed with the manikin task, digit span and verbal memory tests. Systematic assessments of cardiovascular and adverse events were also taken. RESULTS: There was no effect of Org 25935 on reaction time, number of correct responses or learning (greater or slower improvement over successive tasks) compared with placebo. Org 25935 caused significantly more dizziness and drowsiness compared with placebo; these side effects were mainly mild. CONCLUSIONS: A single dose of Org 25935 does not improve learning or memory in healthy male individuals. However, the drug was well tolerated, and it remains to be seen whether it would have a positive effect on cognition in patient groups with pre-existing cognitive deficits.

Neuroendocrine and behavioral consequences of untreated and treated depression in pregnancy and lactation.

Depression during pregnancy and in the post partum period is a significant health issue in modern society. The estimated prevalence of depression in pregnancy ranges from 13-20%. The major dilemma for gynecologists is to treat or not to treat depression during gestation and lactation. Consequences of untreated depression can be so serious that the benefit of antidepressant therapy may overweigh the possible risk for injury of fetal/neonatal development. Currently, selective serotonin re-uptake inhibitors (SSRIs) and serotonin and noradrenaline re-uptake inhibitors (SNRIs) are commonly used for treatment of maternal depression. The review article brings up-to-date knowledge on effects of maternal adversity (depression) and/or antidepressants on the development of the hypothalamus-pituitary-adrenal axis of the offspring in relation to postnatal behavior and reactivity to stressful stimuli. Treated as well as untreated maternal depression presents a risk for the developing fetus and neonate. The authors stress the need to evaluate the relative safety of SNRIs/SNRIs by means of relevant experimental models to assess if these drugs can be assigned to treat pregnant and lactating depressive women.

Efficacy and safety of monoamine reuptake inhibitors in attention deficit hyperactivity disorder: A Bayesian network meta-analysis.

The use of first-line drugs in clinical practice for attention deficit hyperactivity disorder (ADHD) is limited by their adverse effects. Many novel monoamine reuptake inhibitors (MRIs) with better safety profiles and comparable efficacy are also being tried for ADHD. This network meta-analysis (NMA) has evaluated the efficacy and safety of MRIs in ADHD. The data was extracted from 31 relevant clinical trials after a literature search on MEDLINE/PubMed, Embase, Scopus, Cochrane databases, and clinical trial registries. Quality assessment was performed using the risk of bias assessment tool (RoB2) by Cochrane Collaboration, and the random-effects model was used to estimate the effect size. Standardised mean difference (SMD) and 95% credible interval(95%CrI) were reported for the reduction in ADHD rating scale score. Network geometry was visualised, and node splitting was done for the closed triangles. Meta-regression was done for the duration of therapy. PRISMA-NMA guidelines were followed in selecting, analyzing, and reporting findings. The drugs showing significant reduction on the ADHD rating scale as compared to placebo are bupropion (SMD: 0.33; 95%CrI: 0.60,-0.059), dasotraline(SMD: 0.49; 95%CrI: 0.82,-0.16), venlafaxine(SMD: 0.71; 95%CrI: 1.3,-0.15), viloxazine(SMD: 0.45; 95%CrI: 0.77,-0.12). Other drugs (centanafadine, duloxetine, edivoxetine, reboxetine, tipepidine, vortioxetine) were no better than placebo in reducing symptom severity of ADHD. The efficacy of none of the drugs was found to be significantly different as compared to methylphenidate. Among all, duloxetine (OR:15; 95%CrI:1.8130) showed significantly more treatment-emergent adverse events than methylphenidate. In conclusion, venlafaxine, viloxazine, and bupropion are the most efficacious MRIs for ADHD symptom reduction as compared to placebo with high certainty of evidence.

The role of adrenergic neurotransmitter reuptake inhibitors in the ADHD armamentarium.

INTRODUCTION: Adrenergic neurotransmitter reuptake inhibitors are gaining attention in treatment for attention-deficit hyperactivity disorder (ADHD). Due to their effects on norepinephrine, dopamine, and serotonin neurotransmission, they benefit both ADHD and comorbid disorders and have some other advantages including longer duration of action and fewer adverse effects compared to stimulants. There is continued interest in these agents with novel mechanisms of action in treatment of ADHD. AREAS COVERED: The authors conducted a PubMed literature search using the following key words: 'ADHD' AND 'adrenergic reuptake inhibitors' OR 'nonstimulants' OR 'atomoxetine' OR 'Viloxazine' OR 'Dasotraline' OR 'Centanafadine' OR 'PDC-1421' OR 'Reboxetine' OR 'Edivoxetine' OR 'Bupropion' OR 'Venlafaxine' OR 'Duloxetine.' They reviewed FDA fact sheets of available medications for safety/tolerability studies and reviewed published clinical studies of these medications for treatment of ADHD. EXPERT OPINION: Adrenergic neurotransmitter reuptake inhibitors fit the diverse needs of children and adolescents with ADHD with 1) poor tolerability to stimulants (e.g. due to growth suppression, insomnia, rebound irritability, co-morbid depression, anxiety and tic disorders, substance abuse or diversion concerns), 2) cardiac risks, and/or 3) need for extended duration of action. Their differences in receptor affinities and modulating effects support the unique benefits of individual agents.

Attenuation of the disruptive effects of (+/-)3,4-methylenedioxymethamphetamine and cocaine on delayed matching-to-sample performance with D1 versus D2 antagonists.

Evidence suggests that acute exposure to (+/-)3,4-methylenedioxymethamphetamine (MDMA) produces qualitatively similar effects on recognition task performance as other stimulant-type drugs. The current study examined whether there was a similar neurochemical basis to these memory effects by examining the effects of a D1 receptor antagonist (SCH23390) and D2 antagonist (eticlopride) on MDMA- or cocaine-induced impairments in delayed matching-to-sample performance in rats. At low doses it was shown that eticlopride was ineffective in antagonizing either MDMA or cocaine's effects, and at higher doses exacerbated their effects. In contrast, the D1 receptor antagonist SCH23390 was only able to significantly attenuate the disruption caused by MDMA, but not cocaine's effects. Therefore, although present evidence suggests that the effect of acute MDMA on memory-task performance may be related to its effects at D1 receptor sites, there may be differences between MDMA and cocaine in the precise neurochemical pathways involved despite their having similar cognitive effects.

The loudness dependence of auditory evoked potentials and effects of psychopathology and psychopharmacotherapy in psychiatric inpatients.

OBJECTIVE: Many studies have provided evidence for the loudness dependence of auditory evoked potentials (LDAEP) as a marker for central serotonergic activity but remained inconclusive for its suitability in clinical use. METHODS: A cross-sectional sample of 162 psychiatric inpatients (major depression N = 86, bipolar disorder N = 12, schizophrenia N = 50, and schizoaffective disorder N = 14) and 40 healthy subjects was retrospectively examined for LDAEP and effects of psychopathology and psychopharmacology. RESULTS: The LDAEP was weaker in patients with affective disorders than in healthy subjects but did not differentiate between the total patient sample and healthy controls. LDAEP correlated significantly with dimensions of the Brief Symptom Inventory in the total patient sample (depression, paranoid ideation, psychoticism, Global Symptom Index, and Positive Symptom Distress Index), in patients with affective disorders (depression) and with schizophrenia spectrum disorders (depression, psychoticism, Global Symptom Index, and Positive Symptom Distress Index). Similar correlations were found in depressed patients with a single noradrenergic and specific serotonergic antidepressant or serotonin-norepinephrine reuptake inhibitor. There was a negative correlation between dosage of typical antipsychotics and LDAEP. Hypnotics generally led to a lower LDAEP. CONCLUSION: The LDAEP in patients is related to severity of psychopathologic syndromes irrespective of diagnosis. Chronic psychopharmacologic treatment may also differentially modulate the LDAEP, but longitudinal studies are needed.

Randomized placebo- and active-controlled study of desvenlafaxine for menopausal vasomotor symptoms.

OBJECTIVE: To evaluate the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) vs. tibolone and placebo for menopausal vasomotor symptoms and the incidence of uterine bleeding. METHODS: This 12-week, double-blind, randomized, controlled trial was conducted at 35 sites in Europe, two sites in South Africa, and one site in Mexico. Postmenopausal women with ≥50 moderate or severe hot flushes per week (n = 485) were randomized to desvenlafaxine 100 mg/day, tibolone 2.5 mg/day, or placebo. Reduction in the average daily number of moderate and severe hot flushes at weeks 4 and 12 (primary endpoint) was evaluated using analysis of covariance. Safety assessments included incidence of uterine bleeding, adverse events, laboratory values, and vital signs. RESULTS: At week 12, no statistically significant difference was observed in reduction of the average daily number of moderate and severe hot flushes for desvenlafaxine (-5.78) vs. placebo (-5.82; p = 0.921), although time to 50% reduction was significantly less than placebo (13 vs. 26 days, p = 0.006). Hot flush reduction with tibolone (-8.21) was significantly greater than placebo (p < 0.001). Nausea was the most common adverse event with desvenlafaxine, was generally mild to moderate, and resolved within the first 2 weeks. Significantly more subjects experienced bleeding with tibolone (23%) vs. desvenlafaxine (12%; p < 0.024) or placebo (9%; p < 0.001). CONCLUSIONS: Desvenlafaxine did not separate from placebo in reducing the number of moderate to severe hot flushes at week 12, although it did allow women to achieve 50% reduction sooner than placebo. Tibolone did separate from placebo, but with smaller than expected effect. The placebo effect was high (57%). Adverse drug reactions were consistent with the known safety profile of desvenlafaxine, and significantly more women who received tibolone experienced episodes of bleeding compared with women who received desvenlafaxine or placebo.

Why the Maternal Medication List Matters: Neonatal Toxicity From Combined Serotonergic Exposures.

Serotonergic medications are used for the prevention and treatment of depression during pregnancy. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SNRIs) can cause poor neonatal adaptation, which has been attributed to withdrawal versus toxicity. Bupropion, a norepinephrine-dopamine reuptake inhibitor, is often used as an adjunctive agent to selective serotonin reuptake inhibitors or SNRIs for refractory depression. Quetiapine, an atypical antipsychotic, may also be used in more complex cases. When combined with serotonergic drugs, bupropion and quetiapine are associated with increased risk of serotonin syndrome in adults. We describe a neonate exposed to venlafaxine (an SNRI), bupropion, and quetiapine in utero who presented nearly immediately after birth with encephalopathy and abnormal movements. The severity and rapidity of symptoms may be attributable to potentiation of venlafaxine's serotonergic effects by bupropion and quetiapine. Neonatal providers should be aware of maternal medications and prepare for possible adverse effects, particularly from common psychotropic exposures.

Effects of duloxetine in treatment-refractory men with posttraumatic stress disorder.

INTRODUCTION: Although there is evidence that selective serotonin reuptake inhibitors provide some benefit in the treatment of post-traumatic stress disorder (PTSD), most meta-analytical reviews have concluded that effect sizes are small and, moreover, that there may be relatively little benefit for some populations (e. g., combat veterans with co-morbid major depression, MDD). This study aimed to evaluate the effectiveness and tolerability of the dual reuptake inhibitor duloxetine in the treatment of PTSD and co-morbid MDD. METHODS: Twenty-one treatment refractory, male, combat-related patients with PTSD and co-morbid MDD were enrolled in a naturalistic study and twenty completed the trial. Duloxetine was given between 60 and 120 mg daily over 8 weeks. RESULTS: Duloxetine led to a significant improvement of PTSD-characteristic symptoms as well as co-morbid MDD. Duloxetine effectively reduced nightmares, which is important because decreasing nightmares has been associated with improved sleep in PTSD. DISCUSSION: The results of this naturalistic study suggest that duloxetine is an effective and well-tolerated treatment for patients with PTSD and co-morbid MDD. These initial results need to be extended to the study of women with PTSD.

Autonomy of autonomic dysfunction in major depression.

OBJECTIVE: To investigate cardiac autonomic dysfunction in patients with major depressive disorder (MDD). Research in this area has faced several limitations because of the heterogeneity of the disease, the influence of medication, and methodological shortcomings. METHODS: Participants were 75 patients suffering from an acute recurrent episode of MDD and 75 matched controls. All participants were assessed at baseline for linear and nonlinear parameters of heart rate variability, QT variability and baroreflex sensitivity. Participants with MDD were reassessed after 7 to 9 days of treatment with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin and noradrenaline selective reuptake inhibitor (SNRI) antidepressant. RESULTS: In the initial examination, patients showed an overall shift of autonomic balance toward sympathetic predominance as compared with matched controls, with a decrease in parasympathetic parameters and baroreflex sensitivity, and an increase in sympathetically influenced QT variability. Overall, antidepressant treatment exacerbated this imbalance, with differential effects observed for SSRI and SNRI treatment. In contrast to autonomic dysfunction in other disorders, such as schizophrenia, autonomic dysfunction in MDD appeared to be independent of disease severity. CONCLUSIONS: Patients suffering from MDD show profound autonomic dysfunction, which is exacerbated by SNRI and to a lesser degree by SSRI treatment. This information could prove important when selecting antidepressant medication for patients at risk for cardiac arrhythmias.

Desvenlafaxine for the treatment of vasomotor symptoms associated with menopause: a double-blind, randomized, placebo-controlled trial of efficacy and safety.

OBJECTIVE: The objective of the study was to assess the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) for the treatment of vasomotor symptoms. STUDY DESIGN: This was a 26 week, double-blind, placebo-controlled trial of 567 postmenopausal women (mean age, 53.7 years; time since natural menopause, 4.8 years) experiencing 50 or more hot flushes (HFs) per week, randomly assigned to desvenlafaxine (100 or 150 mg) or placebo. Change from baseline in average daily number of moderate to severe HFs and average daily HF severity were compared with placebo at weeks 4, 12, and 26. RESULTS: A significantly greater decrease from baseline in number of HFs occurred at weeks 4 and 12 with 100 and 150 mg desvenlafaxine compared with placebo (week 12 reductions: 60%, 66%, and 47%, respectively; all P < or = .002). Only the 150 mg dose showed significant improvement from baseline at 26 weeks compared with placebo (week 26 reductions: 61%, 69%, and 51%, respectively), although the study was not powered to demonstrate efficacy beyond the initial 12 weeks of therapy. The average daily severity decreased significantly more at weeks 4 and 12 with desvenlafaxine compared with placebo (all P < or = .002). Significantly more desvenlafaxine-treated subjects than placebo-treated subjects discontinued because of adverse events during week 1 only. CONCLUSION: Desvenlafaxine is an effective treatment for menopausal HFs.

Desvenlafaxine: application withdrawal. Desvenlafaxine: withdrawal of marketing application for depression also.

A welcome move! This psychoactive agent has an unfavourable risk-benefit balance in both hot flushes and depression.

Solriamfetol: First Global Approval.

Solriamfetol (Sunosi™) is an orally active, selective dopamine and norepinephrine reuptake inhibitor that was recently approved in the USA as a treatment for excessive daytime sleepiness (hypersomnia) associated with narcolepsy and obstructive sleep apnoea (OSA). Norepinephrine and dopamine influence various physiologic functions, including sleep-wake regulation, and excessive sleepiness has been linked with dysregulation of dopaminergic and norepinephrine systems. This article summarizes the milestones in the development of solriamfetol leading to this first approval as a treatment for excessive daytime sleepiness associated with narcolepsy and OSA.

Single-Dose Pharmacokinetics and Safety of Solriamfetol in Participants With Normal or Impaired Renal Function and With End-Stage Renal Disease Requiring Hemodialysis.

Solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with wake-promoting effects, is renally excreted ∼90% unchanged within 48 hours. Effects of renal impairment and hemodialysis on the pharmacokinetics and safety of 75-mg single-dose solriamfetol were evaluated in adults with normal renal function (n = 6); mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment; and end-stage renal disease (ESRD) with and without hemodialysis (n = 7). Relative to normal renal function, geometric mean area under the plasma concentration-time curve from time zero to infinity increased 53%, 129%, and 339%, and mean half-life was 1.2-, 1.9-, and 3.9-fold higher with mild, moderate, and severe renal impairment, respectively. Renal excretion of unchanged solriamfetol over 48 hours was 85.8%, 80.0%, 66.4%, and 57.1% in normal, mild, moderate, and severe renal impairment groups, respectively; mean maximum concentration and time to maximum concentration did not vary substantially. Decreases in solriamfetol clearance were proportional to decreases in estimated glomerular filtration rate. Geometric mean area under the plasma concentration-time curve from time zero to time of last quantifiable concentration increased 357% and 518% vs normal in ESRD with and without hemodialysis, respectively, with half-life >100 hours in both groups. Over the 4-hour hemodialysis period, ∼21% of solriamfetol dose was removed. Adverse events included headache (n = 1) and nausea (n = 1). Six days after dosing, 1 participant had increased alanine and aspartate aminotransferase, leading to study discontinuation. While these adverse events were deemed study-drug related, they were mild and resolved. Results from this study combined with population pharmacokinetic modeling/simulation suggest that solriamfetol dosage adjustments are necessary in patients with moderate or severe but not with mild renal impairment. Due to significant exposure increase/prolonged half-life, dosing is not recommended in patients with ESRD.

Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a randomized controlled trial.

OBJECTIVE: To compare efficacy and safety of desvenlafaxine succinate (desvenlafaxine) with placebo for the treatment of vasomotor symptoms. METHODS: This randomized, double-blind, placebo-controlled trial enrolled 707 healthy, postmenopausal women experiencing 50 or more moderate-to-severe hot flushes per week. Participants randomly received desvenlafaxine 50, 100, 150, or 200 mg or placebo daily. Trial duration was 52 weeks. Primary outcomes were change from baseline in average daily number of moderate-to-severe hot flushes and in daily hot flush severity score at weeks 4 and 12. RESULTS: Six hundred twenty women with an average of 11 moderate-to-severe hot flushes per day at baseline completed at least one on-therapy evaluation for primary efficacy end points; 519 participants completed 12 weeks of treatment, and 368 completed the study. Desvenlafaxine 100 mg/d achieved a significantly greater reduction compared with placebo in average daily number of hot flushes at weeks 4 (P=.013) and 12 (P=.005), reaching a 64% decrease from baseline at week 12, and the 75% responder rate was significantly higher for desvenlafaxine 100 mg (50%) compared with placebo (29%; P=.003; number needed to treat=4.7) at week 12. Average daily severity of hot flushes was significantly lower in the desvenlafaxine 100-mg group compared with placebo at week 12 (P=.020). Desvenlafaxine-treated women reported significantly more treatment-emergent adverse events than placebo-treated women during the first week of therapy only. CONCLUSION: Desvenlafaxine is an effective nonhormonal treatment for vasomotor symptoms in postmenopausal women. Its tolerability profile is consistent with that of other serotonin-norepinephrine reuptake inhibitors. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00421031 LEVEL OF EVIDENCE: I.

Bupropion and nicotine patch as smoking cessation aids in alcoholics.

This is a double-blind placebo-controlled study of sustained-release bupropion as a smoking cessation aid in alcoholics undergoing treatment for their alcoholism. Participants (N=58) were enrolled within 1 week of entry into alcohol treatment from community and Veterans Affairs Substance Use Disorder programs. All participants received nicotine patch and were invited to attend a smoking cessation lecture and group. Cigarette smoking and alcohol outcomes were measured at 6 months. Bupropion when added to nicotine patch did not improve smoking outcomes. One third of participants on bupropion reported discontinuing the drug during weeks 1-4. Participants reported cigarette outcomes with nicotine patch that are similar to those seen in the general population. All study participants significantly reduced cigarette use. Comorbid affective disorder or antipersonality disorder did not affect outcomes. Alcohol outcomes were improved in those who discontinued cigarettes.