The efficacy of lamotrigine in bipolar disorder: A systematic review and meta-analysis.

OBJECTIVE: To provide up-to-date clinical guidance on the efficacy of lamotrigine in bipolar disorder (BD). METHODS: Eligible studies were identified during a systematic literature search according to PRISMA-guidelines. We included randomized controlled trials (RCTs) and cohort studies that quantitatively assessed lamotrigine's efficacy in BD. We divided the included studies into three groups: 1. acute treatment of depression, 2. acute treatment of mania and hypomania, and 3. maintenance treatment. Analyses were stratified by control group (placebo vs active comparator) and treatment strategy (monotherapy vs add-on treatment). RESULTS: We included 20 RCTs (n = 1166 lamotrigine users) and 20 cohort studies (n = 11,141 lamotrigine users). Twenty-four of these studies were included in meta-analyses. During depressive episodes, greater decreases in depressive symptomatology were associated with initiation of lamotrigine as add-on treatment than with placebo (SMD -0.30 [95% CI = -0.51, -0.10], df = 3, p = 0.004). Decreases in depressive symptomatology did not differ significantly between lamotrigine and the active comparator (SMD -0.28 [95% CI = -1.06, 0.50], df = 3, p = 0.488). As a maintenance treatment, lamotrigine was associated with a significantly lower relapse/recurrence rate than placebo (risk ratio (RR) 0.84 [95% CI = 0.71, 0.99], df = 2, p = 0.037). Relapse/recurrence rates did not differ significantly between lamotrigine and lithium (RR 1.06 [95% CI = 0.89, 1.25], df = 2, p = 0.513). A qualitative assessment of high-quality register-based studies found that lamotrigine was associated with lower hospital admission rates than other commonly used treatment regimes. CONCLUSIONS: There is substantial evidence for the efficacy of lamotrigine in BD, specifically as add-on treatment during acute depressive episodes and as maintenance treatment for preventing relapse and recurrence.

[Reactions on 'The effectiveness of monoamine oxidase inhibitors in treatment-resistant depressive disorders in clinical practice; a retrospective open-label study']. / Reacties op: 'De effectiviteit van monoamineoxidaseremmers bij therapieresistente depressie in de klinische praktijk; een retrospectieve openlabelstudie'.

Reactions on 'The effectiveness of monoamine oxidase inhibitors in treatment-resistant depressive disorders in clinical practice; a retrospective open-label study'.

[The dysregulated brain - Consequences of spatial and temporal brain complexity for bipolar disorder pathophysiology and diagnosis]. / Het ontregelde brein; consequenties van ruimtelijke en temporele complexiteit van het brein voor pathofysiologie en diagnostiek van de bipolaire stoornis.

BACKGROUND: Despite the existence of several pathophysiological theories about bipolar disorder, it has so far been difficult to find diagnostic biomarkers and to develop new pharmacologic treatments based on the more novel theories. AIM: To reflect on the causes and consequences of problems that beset pathophysiological research into psychiatric disorders in general and bipolar disorder in particular. METHOD: In this essay we address the problems facing professionals engaged in research into bipolar disorder and we interpret these problem in the light of brain complexity. RESULTS: The complexity of the brain can be divided into two types: spatial complexity, which reflects the various physiological levels of the central nervous system (genetic, molecular, cellular, neuronal circuits and phenomenological levels), and temporal complexity, i.e. neurodevelopment. We discuss the consequences of these two types of complexity and make suggestions relating to clinical practice and pathophysiological psychiatric research. CONCLUSION: To achieve further progress in the field of brain research, we need to acquire a deeper understanding of the spatial and temporal complexity of the brain and consider the possible consequences of such knowledge for the pathophysiology and treatment of psychiatric illnesses such as bipolar disorder.

Immune dysregulation in offspring of a bipolar parent. Altered serum levels of immune growth factors at adolescent age.

Immune dysregulation plays a role in the vulnerability for mood disorders. Immune growth factors, such as Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein-2 (IGF-BP2), Epidermal Growth Factor (EGF), IL-7 and sCD25 have repeatedly been reported altered in patients with mood disorders. The aim of this study was to investigate levels of these factors in serum of adolescent bipolar offspring, who have a heightened risk for mood disorder development and to also analyze the data combined with previously published data. Growth factors were assessed by CBA/ELISA in adolescent bipolar offspring (n=96, mean age=16years) and in age- and gender-matched healthy controls (n=50). EGF belonged to a mutually correlating cluster of mainly neurotrophic compounds including S100B and BDNF, which were in general decreased in serum. IL-7, SCF, IGF-BP2 and sCD25, belonged to a different mutually correlating cluster of immune growth factors, which were in general increased: IGF-BP2 significantly in serum of offspring without a mood disorder, IL-7 and SCF in serum of offspring who had experienced a mood episode. This pattern of de- and increases was not different between bipolar offspring that developed or did not develop a mood disorder over time, apart from the IGF-BP2 level, which was near significantly higher in offspring later developing a mood disorder. Correlations with the previously published immune-cellular abnormalities were not found. In conclusion non-affected adolescents at familial mood disorder development risk were characterized by a distinct pattern of a series of compounds operating in a network of hematopoiesis, neurogenesis and inflammation.

Baseline dimensional psychopathology and future mood disorder onset: findings from the Dutch Bipolar Offspring Study.

OBJECTIVE: To identify the early signs of mood disorder development, specifically bipolar disorder (BD), in a population at familial risk for BD. METHOD: The sample included 107 Dutch adolescent bipolar offspring (age 12-21) followed into adulthood (age 22-32). Lifetime DSM-IV axis I diagnoses were examined at baseline, 1-, 5-, and 12- year follow-up. Symptoms were assessed at baseline on a 3-point Likert scale at baseline with the K-SADS-PL and were analyzed using symptom and sum scores. As observed in previous studies, BD typically starts with other mood disorders. Therefore, the sample was stratified in offspring with a mood diagnosis (n = 29) and without (n = 78) at baseline. RESULTS: Subthreshold manic experiences proved the strongest predictor of BD conversion (n = 10; HR2.16, CI95% 1.23-3.78). At symptom level, elated mood, decreased need of sleep, racing thoughts, suicidal ideation, and middle insomnia were significantly associated with BD conversion. Depressive symptoms proved the strongest predictor for first mood episode onset (n = 28; HR1.27, CI95% 1.02-1.58). CONCLUSION: This study extends our knowledge of prodromal manifestations of BD in a high-risk population. Although preliminary, findings of this study provide potential targets for early identification and underscore the importance of detailed assessment of manic symptomatology in bipolar offspring.

A dynamic course of T cell defects in individuals at risk for mood disorders.

OBJECTIVES: T cell abnormalities have been repeatedly reported in adult patients with mood disorders, suggesting a role of these cells in the pathogenesis of these disorders. In the present study, we explored the dynamics of circulating T cell subsets over time in a population at high familial risk for developing a mood disorder. METHODS: Children of a parent with bipolar disorder (bipolar offspring, N=140) were assessed at three time-points: adolescence, young adulthood and adulthood. We carried out a detailed fluorescence-activated cell sorting (FACS) analysis to determine various T cell subsets from frozen stored peripheral blood mononuclear cells of bipolar offspring and age- and gender-matched healthy controls at each time-point. RESULTS: Throughout the period of observation reduced levels of CD3+ and CD3+ CD4+ T cells were observed. In bipolar offspring Th1, Th2, Th17 and natural T regulatory cells (Tregs) followed a dynamic course over time with reduced levels of Tregs in adolescence and a reduced relative number of Th1, Th17 cells in young adulthood. In post hoc analysis Tregs were inversely associated with the pro-inflammatory monocyte state determined previously (rs=-0.220, p=0.001). Significant associations between T cell subset abnormalities and psychopathology such as mood disorders were not found. CONCLUSIONS: A subtle partial T cell defect was present in bipolar offspring from adolescence through adulthood. Within this defect the dynamic change of inflammatory and regulatory T cell subsets suggests a high inflammatory state during adolescence, a reduced inflammatory state during young adulthood and a virtually normalized state at adulthood.

[Reasons for including the Inventory of Depressive Symptomatology (IDS) and its shortened version (QIDS) in routine outcome monitoring by the Foundation Benchmark Mental Health (SBG)]. / Inventory of Depressive Symptomatology en verkorte versie in routine outcome monitoring van Stichting Benchmark GGZ.

BACKGROUND: Increasingly, health insurance companies are asking for treatment results in mental health care to be expressed in actual numbers. They base their request on the data supplied by sbg (Stichting Benchmark ggz) and the procedures that sbg has followed. For the purpose of benchmarking, the sbg has accepted a limited number of questionnaires. These tools are not suitable for performing routine outcome monitoring (rom) in clinical practice. There is a urgent need for these questionnaires to be replaced by a widely-used depression questionnaire, namely the ids. AIM: To present arguments supporting the view that the ids is an excellent and useful instrument that the sbg should accept as a measuring tool. METHOD: We discuss the quality of the ids by reviewing the literature. RESULTS: The ids is a high quality instrument well suited for measuring the severity of depressions and also is sufficiently sensitive for measuring mood improvements.
CONCLUSION: The ids is an excellent tool for performing rom measurements and is available free of charge. The authors argue that the sbg should accept this questionnaire as a suitable instrument for benchmarking.

The role of life events and psychological factors in the onset of first and recurrent mood episodes in bipolar offspring: results from the Dutch Bipolar Offspring Study.

BACKGROUND: Life events are an established risk factor for the onset and recurrence of unipolar and bipolar mood episodes, especially in the presence of genetic vulnerability. The dynamic interplay between life events and psychological context, however, is less studied. In this study, we investigated the impact of life events on the onset and recurrence of mood episodes in bipolar offspring, as well as the effects of temperament, coping and parenting style on this association. METHOD: Bipolar offspring (n = 108) were followed longitudinally from adolescence to adulthood. Mood disorders were assessed with: the Kiddie Schedule of Affective Disorders and Schizophrenia - Present and Lifetime Version or the Structured Clinical Interview for DSM-IV Axis I disorders; life events with the Life Events and Difficulties Schedule; and psychological measures using the Utrecht Coping List, Temperament and Character Inventory and short-EMBU (memories of upbringing instrument). Anderson-Gill models (an extension of the Cox proportional hazard model) were utilized. RESULTS: Life events were associated with an increased risk for first and, although less pronounced, subsequent mood episodes. There was a large confounding effect for the number of previous mood episodes; findings suggest a possible kindling effect. Passive coping style increased the risk of mood episode onset and recurrent episodes, but also altered the effect of life events on mood disorders. Harm avoidance temperament was associated with mood episode recurrence. CONCLUSIONS: Life events are especially a risk factor in the onset of mood disorders, though less so in recurrent episodes. Psychological features (passive coping and harm-avoidant temperament) contribute to the risk of an episode occurring, and also have a moderating effect on the association between life events and mood episodes. These findings create potential early intervention strategies for bipolar offspring.

Genetic and environmental influences on cortical surface area and cortical thickness in bipolar disorder.

BACKGROUND: The risk of developing bipolar disorder (BD) has been linked to structural brain abnormalities. The degree to which genes and environment influence the association of BD with cortical surface area remains to be elucidated. In this twin study, genetic and environmental contributions to the association between liability to develop BD and surface area, thickness and volume of the cortex were examined. METHOD: The study cohort included 44 affected monozygotic (nine concordant, 12 discordant) and dizygotic (four concordant, 19 discordant) twin pairs, and seven twins from incomplete discordant monozygotic and dizygotic discordant twin pairs. In addition, 37 monozygotic and 24 dizygotic healthy control twin pairs, and six twins from incomplete monozygotic and dizygotic control pairs were included. RESULTS: Genetic liability to develop BD was associated with a larger cortical surface in limbic and parietal regions, and a thicker cortex in central and parietal regions. Environmental factors related to BD were associated with larger medial frontal, parietal and limbic, and smaller orbitofrontal surfaces. Furthermore, thinner frontal, limbic and occipital cortex, and larger frontal and parietal, and smaller orbitofrontal volumes were also associated with environmental factors related to BD. CONCLUSIONS: Our results suggest that unique environmental factors play a prominent role in driving the associations between liability to develop BD and cortical measures, particularly those involving cortical thickness. Further evaluation of their influence on the surface and thickness of the cortical mantle is recommended. In addition, cortical volume appeared to be primarily dependent on surface and not thickness.

Increased parental history of bipolar disorder in the United States: association with early age of onset.

OBJECTIVE: Early-onset bipolar (BP) disorder and other poor prognosis characteristics are more prevalent in patients from the United States than from the Netherlands and Germany (abbreviated as Europe). We explored the impact of parental loading for affective illness on onset and other characteristics of BP disorder. METHOD: Parental history for unipolar (UP) and bipolar (BP) depression and course of illness characteristics were obtained from self-report in adults (average age 42) with BP disorder. Illness characteristics were examined by χ2 and multinomial logistic regression in relationship to the degree of parental loading: i) both parents negative; ii) one UP disorder; iii) one with BP disorder; and iv) both affected. RESULTS: After controlling for many poor prognosis factors, compared with those from Europe, patients from the United States had more iii) one parent with BP disorder and iv) both parents affected. An early age of onset of BP disorder was independently associated with this increased parental loading for affective disorder. CONCLUSION: Parental history of BP disorder and both parents with a mood disorder were more common in the United States than Europe and were associated with an early onset of bipolar disorder and other poor prognosis characteristics. These findings deserve replication and exploration of the potential mechanisms involved and their therapeutic implications.

Recurrence of major depressive disorder and its predictors in the general population: results from the Netherlands Mental Health Survey and Incidence Study (NEMESIS).

BACKGROUND: Knowledge of the risk of recurrence after recovery from major depressive disorder (MDD) in the general population is scarce. METHOD: Data were derived from 687 subjects in the general population with a lifetime DSM-III-R diagnosis of MDD but without a current major depressive episode (MDE) or dysthymia. Participants had to be at least 6 months in remission, and were recruited from The Netherlands Mental Health Survey and Incidence Study (NEMESIS), using the composite international diagnostic interview (CIDI). Recency and severity of the last MDE were assessed retrospectively at baseline. Recurrence of MDD was measured prospectively during the 3-year follow-up. Kaplan-Meier survival curves were used to measure time to recurrence. Determinants of time to recurrence were analyzed using proportional hazard models. RESULTS: The estimated cumulative recurrence of MDD was 13.2% at 5 years, 23.2% at 10 years and 42.0% at 20 years. In bivariate analysis, the following variables predicted a shorter time to recurrence: younger age, younger age of onset, higher number of previous episodes, a severe last depressive episode, negative youth experiences, ongoing difficulties before recurrence and high neuroticism. Multivariably, younger age, a higher number of previous episodes, a severe last depressive episode, negative youth experiences and ongoing difficulties remained significant. CONCLUSIONS: In this community sample, the long-term risk of recurrence was high, but lower than that found in clinical samples. Subjects who had had an MDE had a long-term vulnerability for recurrence. Factors predicting recurrence included illness- and stress-related factors.

Poor replication of candidate genes for major depressive disorder using genome-wide association data.

Data from the Genetic Association Information Network (GAIN) genome-wide association study (GWAS) in major depressive disorder (MDD) were used to explore previously reported candidate gene and single-nucleotide polymorphism (SNP) associations in MDD. A systematic literature search of candidate genes associated with MDD in case-control studies was performed before the results of the GAIN MDD study became available. Measured and imputed candidate SNPs and genes were tested in the GAIN MDD study encompassing 1738 cases and 1802 controls. Imputation was used to increase the number of SNPs from the GWAS and to improve coverage of SNPs in the candidate genes selected. Tests were carried out for individual SNPs and the entire gene using different statistical approaches, with permutation analysis as the final arbiter. In all, 78 papers reporting on 57 genes were identified, from which 92 SNPs could be mapped. In the GAIN MDD study, two SNPs were associated with MDD: C5orf20 (rs12520799; P=0.038; odds ratio (OR) AT=1.10, 95% CI 0.95-1.29; OR TT=1.21, 95% confidence interval (CI) 1.01-1.47) and NPY (rs16139; P=0.034; OR C allele=0.73, 95% CI 0.55-0.97), constituting a direct replication of previously identified SNPs. At the gene level, TNF (rs76917; OR T=1.35, 95% CI 1.13-1.63; P=0.0034) was identified as the only gene for which the association with MDD remained significant after correction for multiple testing. For SLC6A2 (norepinephrine transporter (NET)) significantly more SNPs (19 out of 100; P=0.039) than expected were associated while accounting for the linkage disequilibrium (LD) structure. Thus, we found support for involvement in MDD for only four genes. However, given the number of candidate SNPs and genes that were tested, even these significant may well be false positives. The poor replication may point to publication bias and false-positive findings in previous candidate gene studies, and may also be related to heterogeneity of the MDD phenotype as well as contextual genetic or environmental factors.

Genetic risk profiles for depression and anxiety in adult and elderly cohorts.

The first generation of genome-wide association studies (GWA studies) for psychiatric disorders has led to new insights regarding the genetic architecture of these disorders. We now start to realize that a larger number of genes, each with a small contribution, are likely to explain the heritability of psychiatric diseases. The contribution of a large number of genes to complex traits can be analyzed with genome-wide profiling. In a discovery sample, a genetic risk profile for depression was defined based on a GWA study of 1738 adult cases and 1802 controls. The genetic risk scores were tested in two population-based samples of elderly participants. The genetic risk profiles were evaluated for depression and anxiety in the Rotterdam Study cohort and the Erasmus Rucphen Family (ERF) study. The genetic risk scores were significantly associated with different measures of depression and explained up to ∼0.7% of the variance in depression in Rotterdam Study and up to ∼1% in ERF study. The genetic score for depression was also significantly associated with anxiety explaining up to 2.1% in Rotterdam study. These findings suggest the presence of many genetic loci of small effect that influence both depression and anxiety. Remarkably, the predictive value of these profiles was as large in the sample of elderly participants as in the middle-aged samples.

Moderators of the synchrony of change between decreasing depression severity and disability.

OBJECTIVE: To identify moderators of synchrony of change between depression severity and disability. METHOD: From a large cohort study with 2 years of follow-up, patients with major depressive disorder at baseline who decreased at least 25% in depression severity after 2 years (n = 245) were selected. We measured overall and domain-specific disability at baseline, and at 1- and 2-year follow-up. Possible moderators, among which several demographic, clinical, personality, and contextual factors, were measured at baseline. We used linear mixed models to analyze the data. RESULTS: Decrease in depression severity correlated strongly with reductions of overall disability (r = 0.54). Synchrony of change for the disability domains ranged from 0.13 for self-care to 0.47 for participation. From the possible moderators, only age and work stress moderated the association between change in depression severity and disability, with stronger synchrony of change among younger patients and patients who experienced moderate work stress. CONCLUSION: Strong synchrony of change exists between depression severity and disability. Perhaps, because of the strength of this synchrony, few contextual characteristics moderated the association. Clinicians should be aware of the risk of slower or incomplete functional recovery in older people and those without a job or those experiencing low work stress.

The 7-year course of depression and anxiety in the general population.

OBJECTIVE: Insight into the long-term course of depression and anxiety. METHOD: Data were derived from Netherlands Mental Health Survey and Incidence Study/Netherlands Study of Depression and Anxiety, epidemiologic surveys in the adult population in the Netherlands. Three hundred and three respondents with depressive and/or anxiety Composite International Diagnostic Interview (CIDI) disorder were interviewed, examining the 7-year course of depression (n = 141), anxiety (n = 102) and the comorbid state (n = 60) and possible prognostic factors. Outcomes were CIDI diagnostic status after 7 years and percentage of time during 7 years with depressive and/or anxiety symptoms, retrospectively assessed by the Life Chart Interview (LCI). RESULTS: After 7 years, 60.7% of the subjects were free from a 12-month CIDI depression or anxiety diagnosis. The odds were higher for subjects with anxiety and comorbidity compared to subjects with depression. Low physical functioning and high neuroticism predicted the presence of a diagnosis after 7 years. During 7-year follow-up, 37.3% of the subjects were free from depressive and anxiety symptoms according to the LCI, 51.8% had symptoms <50% of the time, and 10.9%≥50% of the time. (Comorbid) anxiety resulted in a poorer course. High neuroticism and childhood adversity predicted more follow-up time with symptoms. CONCLUSION: Course trajectories were more favorable than expected, although comorbidity resulted in poorer course. Neuroticism, physical functioning, and childhood adversity predicted an unfavorable course.

[The algorithm for the biological treatment of depression in the Dutch multidisciplinary guideline on depression]. / Het algoritme voor de biologische behandeling van depressie in de Nederlandse multidisciplinaire richtlijn depressie.

BACKGROUND: Although antidepressants are effective in the treatment of depression, nonresponse is unfortunately a recurring problem. Treatment algorithms can help the health care professional to make consecutive step-by-step choices between the different available treatment options. AIM: To update the biological algorithm in the Dutch multidisciplinary guideline on the treatment of depression. METHOD: The literature was reviewed systematically. RESULTS: There are five steps in the algorithm: 1. Treatment starts with an SSRI, a TCA, an SNRI, mirtazapine or buproprion. 2. If there is no response after 4-10 weeks, administer another antidepressant. 3. Augment medication with lithium. 4. Administer a monoamine oxidase inhibitor. 5. Apply electroconvulsive therapy. CONCLUSION: The algorithm is certainly worth using, but its efficacy needs to be fully investigated.s.

Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo.

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 x 10(-7) for rs2715148 and 1.2 x 10(-6) for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 x 10(-8) for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.

An algorithm for the pharmacological treatment of depression.

OBJECTIVE: Non-response to treatment with antidepressants (AD) is a clinical problem. METHOD: The algorithm for pharmacological treatment of the Dutch multidisciplinary guideline for depression is compared with four other algorithms. RESULTS: The Dutch algorithm consists of five subsequent steps. Treatment is started with one out of many optional ADs (step 1); in case of non-response after 4-10 weeks, best evidence is for switching to another AD (step 2); next step is augmentation with lithium as the best option (step 3); the next step is a monoamine oxidase inhibitor (MAOI) (step 4); and finally electroconvulsive therapy (step 5). There are major differences with other algorithms regarding timing of augmentation step, best agents for augmentation and role of MAOI. CONCLUSION: Algorithms for AD treatment vary according to national and local preferences. Although the evidence for most of the treatment strategies is rather meagre, an AD algorithm appears to be an useful instrument in clinical practice.

Prevalence and predictors of recurrence of major depressive disorder in the adult population.

OBJECTIVE: Knowledge of the risk of recurrence after recovery of a major depressive disorder (MDD) is of clinical and scientific importance. The purpose of this paper was to provide a systematic review of the prevalence and predictors of recurrence of MDD. METHOD: Studies were searched in Medline en PsychINFO using the search terms 'recur*', 'relaps*', 'depress*', 'predict*' and course. RESULTS: Recurrence of MDD in specialised mental healthcare settings is high (60% after 5 years, 67% after 10 years and 85% after 15 years) and seems lower in the general population (35% after 15 years). Number of previous episodes and subclinical residual symptoms appear to be the most important predictors. Gender, civil status and socioeconomic status seem not related to the recurrence of MDD. CONCLUSION: Clinical factors seem the most important predictors of recurrence. Data from studies performed in the general population and primary care on the recurrent course of MDD are scarce.

Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine.

OBJECTIVE: In a previous paper, we reported about the efficacy of the addition of lamotrigine to lithium in patients with bipolar depression. In the second phase of this study paroxetine was added to ongoing treatment in non-responders. METHOD: Bipolar depressed patients (n = 124) treated with lithium were randomized to addition of lamotrigine or placebo. In non-responders after 8 weeks, paroxetine 20 mg was added for another 8 weeks to ongoing treatment. RESULTS: After 8 weeks the improvement in patients treated with lamotrigine vs. patients treated with placebo was significant. After addition of paroxetine this difference disappeared as a result of greater further improvement in the non-responders to placebo. CONCLUSION: Addition of lamotrigine to lithium was found effective in bipolar depressed patients. Further addition of paroxetine in non-responders to lithium plus lamotrigine did not appear to provide additional benefit, while it appeared to do so in non-responders to lithium plus placebo.