Bipolar disorder and ADHD: comorbidity and diagnostic distinctions.

Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BD) are neurodevelopmental disorders with onset in childhood and early adolescence, and common persistence in adulthood. Both disorders are often undiagnosed, misdiagnosed, and sometimes over diagnosed, leading to high rates of morbidity and disability. The differentiation of these conditions is based on their clinical features, comorbidity, psychiatric family history course of illness, and response to treatment. We review recent relevant findings and highlight epidemiological, clinical, family history, course, and treatment-response differences that can aid the differential diagnosis of these conditions in an outpatient pediatric setting.

Is Antipsychotic Drug Use During Pregnancy Associated with Increased Malformation Rates and Worsening of Maternal and Infant Outcomes? A Systematic Review.

There is much debate about continuing antipsychotic medication in patients who need it when they become pregnant because benefits must be weighed against potential teratogenic and malformation effects related to antipsychotics themselves. To address this, we conducted a systematic review on the PubMed, PsycINFO and CINHAL databases and the ClinicalTrials.gov register using the following strategy: (toxicity OR teratogenicity OR malformation* OR "birth defect*" OR "congenital abnormality" OR "congenital abnormalities" OR "brain changes" OR "behavioral abnormalities" OR "behavioral abnormalities") AND antipsychotic* AND (pregnancy OR pregnant OR lactation OR delivery OR prenatal OR perinatal OR post-natal OR puerperium) on September 27, 2023. We found 38 studies to be eligible. The oldest was published in 1976, while most articles were recent. Most studies concluded that the antipsychotics, especially the second-generation antipsychotics, were devoid of teratogenic potential, while few studies were inconclusive and recommended replication. Most authoritative articles were from the Boston area, where large databases were implemented to study the malformation potential of psychiatric drugs. Other reliable databases are from Northern European registers. Overall conclusions are that antipsychotics are no more related to malformations than the disorders themselves; most studies recommend that there are no reasons to discontinue antipsychotic medications in pregnancy.

Neurodevelopment in schizophrenia: the role of the wnt pathways.

OBJECTIVES: To review the role of Wnt pathways in the neurodevelopment of schizophrenia. METHODS: SYSTEMATIC PUBMED SEARCH, USING AS KEYWORDS ALL THE TERMS RELATED TO THE WNT PATHWAYS AND CROSSING THEM WITH EACH OF THE FOLLOWING AREAS: normal neurodevelopment and physiology, neurodevelopmental theory of schizophrenia, schizophrenia, and antipsychotic drug action. RESULTS: Neurodevelopmental, behavioural, genetic, and psychopharmacological data point to the possible involvement of Wnt systems, especially the canonical pathway, in the pathophysiology of schizophrenia and in the mechanism of antipsychotic drug action. The molecules most consistently found to be associated with abnormalities or in antipsychotic drug action are Akt1, glycogen synthase kinase3beta, and beta-catenin. However, the extent to which they contribute to the pathophysiology of schizophrenia or to antipsychotic action remains to be established. CONCLUSIONS: The study of the involvement of Wnt pathway abnormalities in schizophrenia may help in understanding this multifaceted clinical entity; the development of Wnt-related pharmacological targets must await the collection of more data.

Life-saving electroconvulsive therapy in a patient with near-lethal catatonia.

A young woman with bipolar I disorder and comorbid catatonia on enteral nutrition from several months, developed a form of near-lethal catatonia with weight loss, pressure sores, muscle atrophy, electrolyte imbalance, and depression of vital signs. A compulsory treatment was necessary, and informed consent was obtained from her mother for electroconvulsive therapy (ECT). After 7 ECT sessions, the patient recovered and resumed feeding. ECT may save the life of a patient with catatonia provided that legal obstacles are overcome. Clinicians should carefully evaluate patients with near-lethal catatonia, taking into account the risk of pulmonary embolism and other fatal events. The medical-legal issues, which vary across state regulations, should be addressed in detail to avoid unnecessary and potentially harmful delay in intervention.

The Impact of the COVID-19 Pandemic on Postpartum Maternal Mental Health.

OBJECTIVES: There are reports of mental health worsening during the COVID-19 pandemic. We aimed to assess whether this occurred in women who were pregnant at baseline (late 2019) and unaware of the pandemic, and who delivered after the implementation of COVID-19 restrictions and threat (March-April 2020). To compare the pandemic period with the pre-pandemic, we capitalized on a retrospective 2014-2015 perinatal sample which had had affective symptoms assessed. METHODS: The COVID sample were administered the Postnatal Depression Scale (EPDS), Zung Self-Rating Anxiety Scale (SAS), Hypomania Checklist-32 (HCL-32), Pittsburgh Sleep Quality Index (PSQI), and Perceived Stress Scale (PSS) at T0 (pregnancy) and T1 (post-delivery). The Non-COVID sample had completed EPDS and HCL-32 at the same timepoints. RESULTS: The COVID sample included 72 women, aged 21-46 years (mean = 33.25 years ± 4.69), and the Non-COVID sample included 68 perinatal women, aged 21-46 years (mean = 34.01 years ± 4.68). Our study showed greater levels of mild depression in T1 among the COVID sample compared to the Non-COVID sample. No significant differences in terms of major depression and suicidal ideation were found. The levels of hypomania were significantly different between the two groups at T1, with the COVID sample scoring higher than the Non-COVID sample. This may be related to the high levels of perceived stress we found during the postpartum evaluation in the COVID sample. LIMITATIONS: There was a relatively small sample size. CONCLUSIONS: New mothers responded to the pandemic with less mental health impairment than expected, differently from the general population. Women delivering amidst the pandemic did not differ in depressive and anxiety symptoms from their pre-pandemic scores and from pre-pandemic women. Because stress responses have high energy costs, it is optimal for maternal animals to minimize such high metabolic costs during motherhood. Evidence suggests that reproductive experience alters the female brain in adaptive ways. This maternal brain plasticity facilitates a higher purpose, the continuation of the species. This may point to the recruitment of motherhood-related resources, for potentially overcoming the effects of the pandemic on mental health.

The Relevance of Insomnia in the Diagnosis of Perinatal Depression: Validation of the Italian Version of the Insomnia Symptom Questionnaire.

BACKGROUND: Sleep disorders are common in perinatal women and may underlie or trigger anxiety and depression. We aimed to translate and validate and evaluate the psychometric properties of the Italian version of the Insomnia Symptom Questionnaire (ISQ), in a sample of women during late pregnancy and 6-months postpartum according to the DSM-5 criteria. METHODS: The ISQ was administered to 292 women prenatally along with other measures of sleep quality, depression, and anxiety, to examine its construct and convergent validity. Women were readministered the ISQ six months postdelivery to assess test-retest reliability. Women were divided into DSM-5 No-Insomnia (N = 253) and Insomnia (N = 39) groups. RESULTS: The insomnia group had received more psychopharmacotherapy, had more psychiatric family history, increased rates of medically assisted reproduction, of past perinatal psychiatric disorders, and scored higher on almost all TEMPS-A dimensions, on the EPDS, HCL-32, PSQI, and on ISQ prenatally and postnatally. ISQ scores correlated with all scales, indicating adequate convergent and discriminant validity; furthermore, it showed antenatal-postnatal test-retest reliability, 97.5% diagnostic accuracy, 79.5% sensitivity, 94.9% specificity, 70.5% positive predictive power, and 92.8% negative predictive power. CONCLUSIONS: The ISQ is useful, valid, and reliable for assessing perinatal insomnia in Italian women. The Italian version showed equivalent properties to the original version.

The Koukopoulos mixed depression rating scale (KMDRS) and the assessment of mixed symptoms during the perinatal period.

BACKGROUND: Mixed symptoms in depression may underlie bipolar diathesis rather than unipolarity. Uncovering mixed depression (MxD) is crucial for appropriate management, especially in the perinatal period, as it may affect treatment planning and impact future child development. We used a scale specific for identifying MxD and tested its validity in pregnant and postpartum women with depression. METHODS: Women developing a major depressive episode (MDE) during their perinatal period extending from pregnancy to one year postpartum from November-2012 through June-2019 were assessed with BPRS-18, EPDS, CGI-S, GAF, HAM-A, HAM-D, Koukopoulos' Mixed Depression Rating Scale (KMDRS), TEMPS, and YMRS. They were classified, based on KMDRS criteria, as with mixed (MxD) or without (nonMxD) mixed symptoms. We conducted ROC analysis and performed factor analysis of the KMDRS. RESULTS: Of 45 included, MxD (N = 19) were biased towards diagnosis of bipolar disorder and nonMxD (N = 26) towards major depressive disorder. Other sociodemographic variables did not differ significantly between MxD and nonMxD. MxD scored higher on total YMRS, BPRS, and KMDRS, and on KMDRS-6 Subjective Feelings of Irritability and KMDRS-12 Suicidal Impulsiveness items. The KMDRS correlated in the entire sample, in MxD and nonMxD, with the YMRS and the BPRS, while correlating with the HAM-D in nonMxD only. The KMDRS showed acceptable AUC distribution, with a 68% sensitivity and 58% specificity. Best-fit was three-factor-structure, explaining 54.66% of cumulative variance. LIMITATIONS: Small sample and cross-sectional design. CONCLUSIONS: The KMDRS is fit for investigating MxD along with the YMRS and the BPRS in perinatal women with a MDE.

Psychometric Properties of the Perinatal Anxiety Screening Scale Administered to Italian Women in the Perinatal Period.

Literature stressed the importance of using valid, reliable measures to assess anxiety in the perinatal period, like the self-rated Perinatal Anxiety Screening Scale (PASS). We aimed to examine the psychometric properties of the Italian PASS version in a sample of Italian women undergoing mental health screening during their third trimester of pregnancy and its diagnostic accuracy in a control perinatal sample of psychiatric outpatients. Sample comprised 289 women aged 33.17 ± 5.08, range 19-46 years, undergoing fetal monitoring during their third trimester of pregnancy, with 49 of them retested 6 months postpartum. Controls were 60 antenatal or postnatal psychiatric outpatients aged 35.71 ± 5.02, range 22-50 years. Groups were assessed through identical self- and clinician-rating scales. Confirmatory Factor Analysis (CFA), Principal Component Analysis (PCA), Pearson's correlations and receiver operating characteristic were conducted for PASS. PCA and CPA confirmed four-factor structure with slight differences from the original version. Construct validity and test-retest reliability were supported. Cut-off was 26. The PASS correlated with principal anxiety scales. Despite small sample size, findings confirm reliability and validity of the Italian PASS version in assessing anxiety symptoms in the perinatal period. Its incorporation in perinatal care will improve future mother and child psychological health.

[Validation of the Italian version of the Koukopoulos Mixed Depression Rating Scale (KMDRS) in an Italian sample of subjects with mood disorders]. / Validazione della versione italiana della Koukopoulos Mixed Depression Rating Scale (KMDRS) in un campione di pazienti italiani affetti da disturbi dell'umore.

BACKGROUND: The construct of mixed depression (MxD), namely the simultaneous presence of excitatory symptoms during a depressive episode, has gained increased interest in the recent years. The Koukopoulos Mixed Depression Rating Scale (KMDRS) has been recently validated for the diagnosis and assessment of MxD. The aim of this study was to validate the Italian version of the KMDRS. METHODS: Patients with a major depressive episode (MDE) (N=396, age, mean=44.73 years, SD=15.93) were recruited at Lucio Bini Center, Rome, Italy. All participants were administered the Italian version of the KMDRS, the Montgomery-Åsberg Depression Rating Scale (MADRS), the Young Mania Rating Scale (YMRS), the Clinical Global Impressions (CGI), and the Global Assessment of Functioning (GAF). We calculated predictive validity, and performed Receiver Operator Curve (ROC) analysis, Cronbach's alpha, and inter-rater reliability. RESULTS: Predictive validity (C-statistic= 0.80; IC 95%: 0.75, 0.85) and capacity [OR=1.25±.03 (SE); 95% CI: 1.18, 1.32; p<.001] were good, matching those of the original version, whereas internal consistency (Cronbach's alpha = .70, IC 95%: 0.65, 0.75) and interrater reliability (Cohen's kappa= 0.74) were adequate. CONCLUSIONS: The agreement of results with those of the original version point to the validity of the Italian version of KMDRS in assessing MxD.

Stabilization Beyond Mood: Stabilizing Patients With Bipolar Disorder in the Various Phases of Life.

BACKGROUND: There are different ways to define stabilization and currently, the main standpoint regards it as no-depression/no-mania. Furthermore, each person is physiologically different from childhood to adulthood, and in old age, thus the meaning of stabilization should take into account both growth and maturity. We aimed to review systematically studies focusing on mood stabilization in all phases of bipolar disorder (BD) and across all life phases, including pregnancy and the perinatal period, which is still a different phase in women's life cycles. METHODS: We carried out a PubMed search focusing on studies of bipolar disorder treated with drugs and aimed at stabilization with the following search strategy stabiliz*[ti] OR stabilis*[ti] OR stable[ti] OR stability[ti]) AND mood[ti] AND bipolar. In conducting our review, we followed the PRISMA statement. Agreement on inclusion was reached by consensus of all authors through a Delphi rounds procedure. RESULTS: The above search strategy produced 509 records on January 25, 2020. Of them, 58 fitted our inclusion criteria and were discussed. The eligible studies spanned from September 1983 to July 6, 2019. CONCLUSIONS: No clear-cut indications could be drawn due to a number of limitations involving sample inconsistency and different methods of assessing mood stabilization. The evidence collected so far does not allow recommended treatments for Adolescents, pregnant or perinatal women, and aged patients. However, adults, not within these groups, better focused upon. For their manic/mixed phases, second generation antipsychotic drugs may be useful in the short-to-medium run, alone or combined with mood stabilizers (MSs). However, MSs, and especially lithium, continue to be pivotal in chronic treatment. Bipolar depression should rely on MSs, but an antidepressant may be added on and can prove to be helpful. However, there are concerns with the tendency of antidepressants to induce the opposite polarity or mood instability, rendering the need for concurrent MS prescription mandatory.

Perinatal Mixed Affective State: Wherefore Art Thou?

Mixed states in patients with a perinatal mood episode is seldom encountered. Lack of appropriate assessment tools could be partly responsible for this observation. The authors conducted a selective review of studies dealing with the reporting of mixed symptoms in women during the perinatal period with the intention to quantify the phenomenon. In many instances of reported postpartum depression, either a first onset or an onset in the context of bipolar disorder, mixed states were identifiable. However, the strict application of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, mixed features specifier to these episodes risks misdiagnosis.

The Ring of Fire: Childhood Trauma, Emotional Reactivity, and Mixed States in Mood Disorders.

Childhood trauma (CT) is strongly associated with bipolar disorder, possibly through emotional hyperreactivity (EH). Mixed symptoms/states (MSs) are associated with increased illness severity. The authors tested through a systematic review the association between CT and MSs. The authors systematically looked for studies exploring associations between MSs and CT, CT and EH, and EH and MSs. Most literature agrees that MSs are associated with CT; the latter was found to be associated to EH, which is in turn associated with MSs. The literature supports an association between CT and later development of MSs, possibly mediated through EH.

Early clinical predictors of long-term morbidity in major depressive disorder.

AIMS: To identify early clinical factors predictive of later morbidity in major depressive disorder (MDD). METHODS: We analysed factors associated with long-term depressive morbidity (%-time ill) between a first-lifetime major depressive episode and last follow-up of 116 adults diagnosed with DSM-IV major depressive disorder. Bivariate comparisons were followed by multivariable linear regression modelling. RESULTS: Three factors were independently associated with an average of 25%-time-depressed over 17 years at risk: (a) agitated-mixed, or psychotic features in initial major depressive episodes, (b) anxiety syndromes prior to a first-lifetime major depressive episode, and (c) anxiety symptoms in childhood. CONCLUSION: Early anxiety symptoms and syndromes and agitated-mixed or psychotic initial depressive episodes predicted more long-term depressive morbidity in MDD.

Placebo Effect in Obsessive-Compulsive Disorder (OCD). Placebo Response and Placebo Responders in OCD: The Trend Over Time.

BACKGROUND: Placebo response appears to be increasing in antidepressant, antipsychotic and various internal medicine trials. A similar trend has been reported for OCD during 1989-1999. Placebo response is generally considered as the extent to which placebo treatment is associated with core symptom improvement. In this analysis, we used Joinpoint regression to assess the time trend of both placebo response and placebo responder rates according to the year of publication with no time restriction in OCD drug trials. METHODS: We included drug and/or psychotherapy trials vs. placebo from PubMed, Embase, CINAHL, and PsycINFO retrieved through the search (placebo OR sham) AND (obsessive* OR OCD). We included studies through investigator consensus. We then performed on data of included studies log-linear joinpoint segmented regression models using a p<0.05 cutoff. RESULTS: We included 113 studies from 112 published papers. Placebo mean annual response rates in OCD studies significantly increased from 1991 to 2017 with an annual percent change (APC) of 0.66%, while placebo mean annual responder rates also significantly increased from 2010 to 2017, with an APC of 5.45%. Drug mean annual response rates in OCD studies significantly increased from 1987 to 2012 with an APC of 0.72%, while the corresponding responder rates did not show statistically significant APC changes between 1984 and 2017. CONCLUSION: We observed a tendency for placebo to increase both measures of response in OCD clinical drug trials through the years that tend to approximate the responses shown by drugs. Changes in the type of study (moving from classical head to head comparisons to add-on studies in treatmentresistant populations) and countries involved in experimentation may partially account for some portion of these results. It appears that placebo effects are becoming more elusive and out of control.

Pediatric Mania: The Controversy between Euphoria and Irritability.

Pediatric Bipolar Disorder (BD) is a highly morbid pediatric psychiatric disease, consistently associated with family psychiatric history of mood disorders and associated with high levels of morbidity and disability and with a great risk of suicide. While there is a general consensus on the symptomatology of depression in childhood, the phenomenology of pediatric mania is still highly debated and the course and long-term outcome of pediatric BD still need to be clarified. We reviewed the available studies on the phenomenology of pediatric mania with the aim of summarizing the prevalence, demographics, clinical correlates and course of these two types of pediatric mania. Eighteen studies reported the number of subjects presenting with either irritable or elated mood during mania. Irritability has been reported to be the most frequent clinical feature of pediatric mania reaching a sensitivity of 95-100% in several samples. Only half the studies reviewed reported on number of episodes or cycling patterns and the described course was mostly chronic and ultra-rapid whereas the classical episodic presentation was less common. Few long-term outcome studies have reported a diagnostic stability of mania from childhood to young adult age. Future research should focus on the heterogeneity of irritability aiming at differentiating distinct subtypes of pediatric psychiatric disorders with distinct phenomenology, course, outcome and biomarkers. Longitudinal studies of samples attending to mood presentation, irritable versus elated, and course, chronic versus episodic, may help clarify whether these are meaningful distinctions in the course, treatment and outcome of pediatric onset bipolar disorder.

Child and Adolescent Clinical Features Preceding Adult Suicide Attempts.

The objective of this study was to identify the predictive value of juvenile factors for adult suicidal behavior. We reviewed clinical records to compare factors identified in childhood and adolescence between adult suicidal versus nonsuicidal major affective disorder subjects. Suicide attempts occurred in 23.1% of subjects. Age-at-first-symptom was 14.2 vs. 20.2 years among suicidal versus nonsuicidal subjects (p < 0.0001). More prevalent in suicidal versus non-suicidal subjects by multivariate analysis were: depressive symptoms, hyper-emotionality, younger-at-first-affective-episode, family suicide history, childhood mood-swings, and adolescence low self-esteem. Presence of one factor yielded a Bayesian sensitivity of 64%, specificity of 50%, and negative predictive power of 86%. Several juvenile factors were associated with adult suicidal behavior; their absence was strongly associated with a lack of adult suicidal behavior.

Neurobiological Evidence for the Primacy of Mania Hypothesis.

BACKGROUND: Athanasios Koukopoulos proposed the primacy of mania hypothesis (PoM) in a 2006 book chapter and later, in two peer-reviewed papers with Nassir Ghaemi and other collaborators. This hypothesis supports that in bipolar disorder, mania leads to depression, while depression does not lead to mania. OBJECTIVE: To identify evidence in literature that supports or falsifies this hypothesis. METHOD: We searched the medical literature (PubMed, Embase, PsycINFO, and the Cochrane Library) for peer-reviewed papers on the primacy of mania, the default mode function of the brain in normal people and in bipolar disorder patients, and on illusion superiority until 6 June, 2016. Papers resulting from searches were considered for appropriateness to our objective. We adopted the PRISMA method for our review. The search for consistency with PoM was filtered through the neurobiological results of superiority illusion studies. RESULTS: Out of a grand total of 139 records, 59 were included in our analysis. Of these, 36 were of uncertain value as to the primacy of mania hypothesis, 22 favoured it, and 1 was contrary, but the latter pooled patients in their manic and depressive phases, so to invalidate possible conclusions about its consistency with regard to PoM. All considered studies were not focused on PoM or superiority illusion, hence most of their results were, as expected, unrelated to the circuitry involved in superiority illusion. A considerable amount of evidence is consistent with the hypothesis, although indirectly so. LIMITATIONS: Only few studies compared manic with depressive phases, with the majority including patients in euthymia. CONCLUSION: It is possible that humans have a natural tendency for elation/optimism and positive self-consideration, that are more akin to mania; the depressive state could be a consequence of frustrated or unsustainable mania. This would be consistent with PoM.

Features preceding diagnosis of bipolar versus major depressive disorders.

BACKGROUND: Better and earlier predictive differentiation of bipolar (BD) vs. unipolar major depressive disorder (UD) diagnoses should improve long-term clinical planning. METHODS: We reviewed randomly selected clinical records of 334 adults diagnosed with DSM-IV-TR BD-I (n=109), BD-II (n=106), and UD (n=119) and compared features preceding major affective episodes or diagnoses, using bivariate, multivariate, and Bayesian methods. RESULTS: We identified antecedents selectively associated with later BD vs. UD in 52.6% vs. 31.1% of subjects in childhood, starting at age 7.4 years, and 60.0% vs. 32.8% in adolescence, with far more features in BD than UD cases (10.3 vs. 4.64/100 person-years; p<0.001). In multivariate modeling, BD-selective factors were: younger at first clinical event > male sex > family BD-history > cyclothymic or hyperthymic temperament > antecedents/person-year. Nonaffective (anxiety, eating, or substance-use) disorders preceded BD vs. UD in 41.4% vs. 28.6% of subjects (p=0.02). By ROC analysis, differential prediction of BD vs. UD was optimal with any ≥ 3 factors/person. LIMITATIONS: The validity and timing of antecedent events and factors identified retrospectively from clinical records could not be verified independently, but information was recorded systematically and consistently by a single mood-disorder expert prior to diagnosis, and extracted by two independent observers. COMMENT: Early clinical features distinguished later BD from UD, often by years. Such prediction should improve treatment-planning and limit risk of mood-switching.

Three-year, naturalistic, mirror-image assessment of adding memantine to the treatment of 30 treatment-resistant patients with bipolar disorder.

BACKGROUND: Developing safe and effective long-term treatments for bipolar disorder remains a major challenge. Given available treatments, patients with bipolar disorder remain unwell in half of long-term follow-up, mostly in depression. As memantine, an N-methyl-D-aspartate (NMDA)-glutamate receptor antagonist used to treat dementia, has been proposed for testing in bipolar disorder, we carried out a 3 + 3-year, mirror-image, chart-review study of the effects of adding memantine to stably continued, but insufficiently effective, ongoing mood-stabilizing treatments. METHOD: Outpatients diagnosed with DSM-IV-TR bipolar disorder (I or II), followed intensively at the Lucio Bini Mood Disorder Center, Rome, Italy, had responded consistently unsatisfactorily to standard treatments (lithium, anticonvulsants, antipsychotics, antidepressants, and electroconvulsive therapy) for ≥ 3 years (2005-2013). Memantine (20-30 mg/d) was added clinically to otherwise stable regimens for another 3 years. On the basis of chart review, we compared morbidity measures and Clinical Global Impressions scale for Bipolar Disorder (CGI-BP) score before versus during memantine treatment. RESULTS: The 30 bipolar I (n = 17) and II (n = 13) subjects showed consistent morbidity for 3 years before memantine, but improved progressively (r = 0.28, P < .01) over 3 years with memantine (23 ± 4.8 mg/d). Markedly decreased (all P values ≤ .01) were (1) percentage of time ill (total, mania, or depression; averaging -75.0%), (2) CGI-BP severity scores (-67.8%), (3) duration of new episodes (-58.6%), and (4) episodes/year (-55.7%). Subjects with previous rapid or continuous cycling were particularly improved (t = 2.61, P = .016). Adverse effects were mild and rare. CONCLUSIONS: Memantine added substantial long-term benefits by preventing or ameliorating depressive as well as mania-like morbidity in previously consistently poorly responsive patients with bipolar disorder. Further testing in randomized, controlled trials is required.