Long-term treatment of bipolar disorder type I: A systematic and critical review of clinical guidelines with derived practice algorithms.

OBJECTIVES: This systematic review aimed at providing a critical, comprehensive synthesis of international guidelines' recommendations on the long-term treatment of bipolar disorder type I (BD-I). METHODS: MEDLINE/PubMed and EMBASE databases were searched from inception to January 15th, 2019 following PRISMA and PICAR rules. International guidelines providing recommendations for the long-term treatment of BD-I were included. A methodological quality assessment was conducted with the Appraisal of Guidelines for Research and Evaluation-AGREE II. RESULTS: The final selection yielded five international guidelines, with overall good quality. The evaluation of applicability was the weakest aspect across the guidelines. Differences in their updating strategies and the rating of the evidence, particularly for meta-analyses, randomized clinical trials (RCTs) and observational studies, could be responsible of some level of heterogeneity among recommendations. Nonetheless, the guidelines recommended lithium as the 'gold standard' in the long-term treatment of BD-I. Quetiapine was another possible first-line option as well as aripiprazole (for the prevention of mania). Long-term treatment should contemplate monotherapy, at least initially. Clinicians should check regularly for efficacy and side effects and if necessary, switch to first-line alternatives (i.e. Valproate), combine first-line compounds with different mechanisms of action or switch to second-line options or combinations. CONCLUSIONS: The possibility to monitor improvements in long-term outcomes, namely relapse prevention and inter-episode subthreshold depressive symptoms, based on the application of their recommendations is an unmet need of clinical guidelines. In terms of evidence of clinical guidelines, there is a need for more efficacious treatment strategies for the prevention of bipolar depression.

Treatment of bipolar disorders in older adults: a review.

BACKGROUND: Old age bipolar disorder has been an orphan of psychiatric research for a long time despite the fact that bipolar disorder (BD)-I and II together may affect 0.5-1.0% of the elderly. It is also unclear whether aetiology, course of illness and treatment should differ in patients with a first manifestation in older age and patients suffering from a recurrence of a BD known for decades. This narrative review will summarize the current state of knowledge about the epidemiology, clinical features, and treatment of BD in the elderly. METHODS: We conducted a Medline literature search from 1970 to 2021 using MeSH terms "Bipolar Disorder" × "Aged" or "Geriatric" or "Elderly". Search results were complemented by additional literature retrieved from examining cross references and by hand search in text books. Varying cut-off ages have been applied to differentiate old age from adult age BD. Within old age BD, there is a reasonable agreement of distinct entities, early and late-onset BD. They differ to some extent in clinical symptoms, course of illness, and some co-morbidities. Point prevalence of BD in older adults appears slightly lower than in working-age adults, with polarity of episodes shifting towards depression. Psychopharmacological treatment needs to take into account the special aspects of somatic gerontology and the age-related change of pharmacokinetic and pharmacodynamic characteristics. The evidence for commonly used treatments such as lithium, mood-stabilizing antiepileptics, antipsychotics, and antidepressants remains sparse. Preliminary results support a role of ECT as well as psychotherapy and psychosocial interventions in old age BD. CONCLUSIONS: There is an obvious need of further research for all treatment modalities of BD in old age. The focus should be pharmacological and psychosocial approaches, as well as their combination, and the role of physical treatment modalities such as ECT.

The Challenges of Children with Bipolar Disorder.

Childhood onset bipolar disorder (CO-BD) presents a panoply of difficulties associated with early recognition and treatment. CO-BD is associated with a variety of precursors and comorbidities that have been inadequately studied, so treatment remains obscure. The earlier the onset, the longer is the delay to first treatment, and both early onset and treatment delay are associated with more depressive episodes and a poor prognosis in adulthood. Ultra-rapid and ultradian cycling, consistent with a diagnosis of BP-NOS, are highly prevalent in the youngest children and take long periods of time and complex treatment regimens to achieve euthymia. Lithium and atypical antipsychotics are effective in mania, but treatment of depression remains obscure, with the exception of lurasidone, for children ages 10-17. Treatment of the common comorbid anxiety disorders, oppositional defiant disorders, pathological habits, and substance abuse are all poorly studied and are off-label. Cognitive dysfunction after a first manic hospitalization improves over the next year only on the condition that no further episodes occur. Yet comprehensive expert treatment after an initial manic hospitalization results in many fewer relapses than traditional treatment as usual, emphasizing the need for combined pharmacological, psychosocial, and psycho-educational approaches to this difficult and highly recurrent illness.

Efficacy of Carbamazepine and Its Derivatives in the Treatment of Bipolar Disorder.

Background and Objectives: This review is dedicated to the use of carbamazepine and its derivatives oxcarbazepine and eslicarbazepine in bipolar disorder and their relative strengths in treating and preventing new depressive or manic episodes. This paper will discuss the evidence of their efficacy relative to the polarity of relapse from controlled acute and maintenance/relapse prevention studies in bipolar patients. Materials and Methods: A Medline search was conducted for controlled acute and maintenance studies with carbamazepine, oxcarbazepine, and eslicarbazepine in bipolar disorder. In addition, abstracts reporting on controlled studies with these medications from key conferences were taken into consideration. Results: Information was extracted from 84 articles on the acute and prophylactic efficacy of the medications under consideration. They all appear to have stronger efficacy in treating acute mania than depression, which also translates to better protection against manic than depressive relapses for carbamazepine. Still, there is a paucity of controlled acute studies on bipolar depression for all and, with the exception of carbamazepine, a lack of long-term monotherapy maintenance data. For eslicarbazepine, the efficacy in bipolar disorder remains largely unknown. Especially with carbamazepine, tolerability issues and drug-drug interactions need to be kept in mind. Conclusions: Two of the medications discussed in this review, carbamazepine and oxcarbazepine, match Class A criteria according to the criteria proposed by Ketter and Calabrese, meaning acute antimanic efficacy, prevention of manic relapses, and not causing or worsening depression.

Electroconvulsive Therapy (ECT) in Bipolar Disorder Patients with Ultra-Rapid Cycling and Unstable Mixed States.

Background and Objectives: Unstable mixed episodes or rapid switching between opposite affective poles within the scope of short cycles was first characterized in 1967 by S. Mentzos as complex polymorphous states with chaotic overlap of manic and depressive symptoms. Well-known examples include antidepressant-induced mania/hypomania and rapid/ultra-rapid/ultradian cycling, when clinicians observe an almost continuous mixed state with a constant change of preponderance of manic or depressive symptoms. Achieving stable remission in these cases is challenging with almost no data on evidence-based treatment. When mood stabilizers are ineffective, electroconvulsive therapy (ECT) has been suggested. Objectives: After reviewing the evidence from available literature, this article presents our own clinical experience of ECT efficacy and tolerability in patients with ultra-rapid cycling bipolar disorder (BD) and unstable mixed states. Materials and Methods: We conducted an open, one-year observational prospective study with a "mirror image" design, including 30 patients with rapid and ultra-rapid cycling BD on long-term mood stabilizer treatment (18 received lithium carbonate, 6 on valproate and 6 on carbamazepine) with limited effectiveness. A bilateral ECT course (5-10 sessions) was prescribed for regaining mood stability. Results: ECT was very effective in 12 patients (40%) with a history of ineffective mood stabilizer treatment who achieved and maintained remission; all of them received lithium except for 1 patient who received carbamazepine and 2 with valproate. Nine patients (30%) showed partial response (one on carbamazepine and two on valproate) and nine patients (30%) had no improvement at all (four on carbamazepine and two on valproate). For the whole sample, the duration of affective episodes was significantly reduced from 36.05 ± 4.32 weeks in the year prior to ECT to 21.74 ± 12.14 weeks in the year post-ECT (p < 0.001). Depressive episodes with mixed and/or catatonic features according to DSM-5 specifiers were associated with a better acute ECT response and/or long-term mood stabilizer treatment outcome after ECT. Conclusions: ECT could be considered as a useful option for getting mood instability under control in rapid and ultra-rapid cycling bipolar patients. Further randomized trials are needed to confirm these results.

Bipolar Disorder and Comorbid Use of Illicit Substances.

Substance use disorders (SUD) are highly prevalent in bipolar disorder (BD) and significantly affect clinical outcomes. Incidence and management of illicit drug use differ from alcohol use disorders, nicotine use of behavioral addictions. It is not yet clear why people with bipolar disorder are at higher risk of addictive disorders, but recent data suggest common neurobiological and genetic underpinnings and epigenetic alterations. In the absence of specific diagnostic instruments, the clinical interview is conducive for the diagnosis. Treating SUD in bipolar disorder requires a comprehensive and multidisciplinary approach. Most treatment trials focus on single drugs, such as cannabis alone or in combination with alcohol, cocaine, or amphetamines. Synopsis of data provides limited evidence that lithium and valproate are effective for the treatment of mood symptoms in cannabis users and may reduce substance use. Furthermore, the neuroprotective agent citicoline may reduce cocaine consumption in BD subjects. However, many of the available studies had an open-label design and were of modest to small sample size. The very few available psychotherapeutic trials indicate no significant differences in outcomes between BD with or without SUD. Although SUD is one of the most important comorbidities in BD with a significant influence on clinical outcome, there is still a lack both of basic research and clinical trials, allowing for evidence-based and specific best practices.

The CINP Guidelines on the Definition and Evidence-Based Interventions for Treatment-Resistant Bipolar Disorder.

BACKGROUND: Resistant bipolar disorder is a major mental health problem related to significant disability and overall cost. The aim of the current study was to perform a systematic review of the literature concerning (1) the definition of treatment resistance in bipolar disorder, (2) its clinical and (3) neurobiological correlates, and (4) the evidence-based treatment options for treatment-resistant bipolar disorder and for eventually developing guidelines for the treatment of this condition. MATERIALS AND METHODS: The PRISMA method was used to identify all published papers relevant to the definition of treatment resistance in bipolar disorder and the associated evidence-based treatment options. The MEDLINE was searched to April 22, 2018. RESULTS: Criteria were developed for the identification of resistance in bipolar disorder concerning all phases. The search of the literature identified all published studies concerning treatment options. The data were classified according to strength, and separate guidelines regarding resistant acute mania, acute bipolar depression, and the maintenance phase were developed. DISCUSSION: The definition of resistance in bipolar disorder is by itself difficult due to the complexity of the clinical picture, course, and treatment options. The current guidelines are the first, to our knowledge, developed specifically for the treatment of resistant bipolar disorder patients, and they also include an operationalized definition of treatment resistance. They were based on a thorough and deep search of the literature and utilize as much as possible an evidence-based approach.

More assortative mating in US compared to European parents and spouses of patients with bipolar disorder: implications for psychiatric illness in the offspring.

The effect of assortative mating on offspring is often not considered. Here, we present data on illness in the spouse and the parents of patients with bipolar disorder as they affect illness in the offspring. A history of psychiatric illness (depression, bipolar disorder, suicide attempt, alcohol abuse, drug abuse, and "other" illness) was elicited for the parents, spouse, and the offspring of 968 patients with bipolar disorder (540 of whom had children) who gave informed consent for participation in a treatment outcome network. Assortative mating for a mood disorder in the spouse and parents in those from the United States (US) was compared to those from the Netherlands and Germany and related to illnesses in the offspring. There was more illness and assortative mating for a mood disorder in both the spouse and patient's parents from the US compared to Europe. In the parents of the US patients, assortative mating for a mood disorder was associated with more depression, bipolar disorder, alcohol, and "other" illness in the offspring. Compared to the Europeans, there was more assortative mating for mood and other disorders in two generations of those from the US. This bilineal positivity for a parental mood disorder was related to more depression a second generation later in the patients' offspring. In clinical assessment of risk of illness in the offspring, the history of psychiatric illness in the spouse and patient's parents might provide additional information.

Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition.

BACKGROUND: Most people with bipolar disorder spend a significant percentage of their lifetime experiencing either subsyndromal depressive symptoms or major depressive episodes, which contribute greatly to the high levels of disability and mortality associated with the disorder. Despite the importance of bipolar depression, there are only a small number of recognised treatment options available. Consecutive treatment failures can quickly exhaust these options leading to treatment-resistant bipolar depression (TRBD). Remarkably few studies have evaluated TRBD and those available lack a comprehensive definition of multi-therapy-resistant bipolar depression (MTRBD).AimsTo reach consensus regarding threshold definitions criteria for TRBD and MTRBD. METHOD: Based on the evidence of standard treatments available in the latest bipolar disorder treatment guidelines, TRBD and MTRBD criteria were agreed by a representative panel of bipolar disorder experts using a modified Delphi method. RESULTS: TRBD criteria in bipolar depression was defined as failure to reach sustained symptomatic remission for 8 consecutive weeks after two different treatment trials, at adequate therapeutic doses, with at least two recommended monotherapy treatments or at least one monotherapy treatment and another combination treatment. MTRBD included the same initial definition as TRBD, with the addition of failure of at least one trial with an antidepressant, a psychological treatment and a course of electroconvulsive therapy. CONCLUSIONS: The proposed TRBD and MTRBD criteria may provide an important signpost to help clinicians, researchers and stakeholders in judging how and when to consider new non-standard treatments. However, some challenging diagnostic and therapeutic issues were identified in the consensus process that need further evaluation and research.Declaration of interestIn the past 3 years, M.B. has received grant/research support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis, Mayne Pharma, Servier, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay and Wyeth and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Eli Lilly, Grunbiotics, Glaxo SmithKline, Janssen Cilag, LivaNova, Lundbeck, Merck, Mylan, Otsuka, Pfizer and Servier. A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. A.J.C. has in the past 3 years received honoraria for speaking from Astra Zeneca and Lundbeck, honoraria for consulting from Allergan, Janssen, Lundbeck and LivaNova and research grant support from Lundbeck. G.M.G. holds shares in P1Vital and has served as consultant, advisor or CME speaker for Allergan, Angelini, Compass pathways, MSD, Lundbeck, Otsuka, Takeda, Medscape, Minervra, P1Vital, Pfizer, Servier, Shire and Sun Pharma. J.G. has received research funding from National Institute for Health Research, Medical Research Council, Stanley Medical Research Institute and Wellcome. H.G. received grants/research support, consulting fees or honoraria from Gedeon Richter, Genericon, Janssen Cilag, Lundbeck, Otsuka, Pfizer and Servier. R.H.M.-W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, Liva Nova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. R.M. has received research support from Big White Wall, Electromedical Products, Johnson and Johnson, Magstim and P1Vital. S.N. received honoraria from Lundbeck, Jensen and Otsuka. J.C.S. has received funds for research from Alkermes, Pfizer, Allergan, J&J, BMS and been a speaker or consultant for Astellas, Abbott, Sunovion, Sanofi. S.W has, within the past 3 years, attended advisory boards for Sunovion and LivaNova and has undertaken paid lectures for Lundbeck. D.J.S. has received honoraria from Lundbeck. T.S. has reported grants from Pathway Genomics, Stanley Medical Research Institute and Palo Alto Health Sciences; consulting fees from Sunovion Pharamaceuticals Inc.; honoraria from Medscape Education, Global Medical Education and CMEology; and royalties from Jones and Bartlett, UpToDate and Hogrefe Publishing. S.P. has served as a consultant or speaker for Janssen, and Sunovion. P.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. E.V. received grants/ research support, consulting fees or honoraria from Abbott, AB-Biotics, Allergan, Angelini, Dainippon Sumitomo, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka and Sunovion. L.N.Y. has received grants/research support, consulting fees or honoraria from Allergan, Alkermes, Dainippon Sumitomo, Janssen, Lundbeck, Otsuka, Sanofi, Servier, Sunovion, Teva and Valeant. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has also previously received funding for investigator-initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth. P.R.A.S. has received research funding support from Corcept Therapeutics Inc. Corcept Therapeutics Inc fully funded attendance at their internal conference in California USA and all related expenses. He has received grant funding from the Medical Research Council UK for a collaborative study with Janssen Research and Development LLC. Janssen Research and Development LLC are providing non-financial contributions to support this study. P.R.A.S. has received a presentation fee from Indivior and an advisory board fee from LivaNova.

Testing a clinical staging model for bipolar disorder using longitudinal life chart data.

OBJECTIVE: Bipolar disorder has a wide range of clinical manifestations which may progress over time. The aim of this study was to test the applicability of a clinical staging model for bipolar disorder and to gain insight into the nature of the variables influencing progression through consecutive stages. METHODS: Using retrospectively reported longitudinal life chart data of 99 subjects from the Stanley Foundation Bipolar Network Naturalistic Follow-up Study, the occurrence, duration and timely sequence of stages 2-4 were determined per month. A multi-state model was used to calculate progression rates and identify determinants of illness progression. Stages 0, 1 and several other variables were added to the multi-state model to determine their influence on the progression rates. RESULTS: Five years after onset of BD (stage 2), 72% reached stage 3 (recurrent episodes) and 21% had reached stage 4 (continuous episodes), of whom 8% recovered back to stage 3. The progression from stage 2 to 3 was increased by a biphasic onset for both the depression-mania and the mania-depression course and by male sex. CONCLUSIONS: Staging is a useful model to determine illness progression in longitudinal life chart data. Variables influencing transition rates were successfully identified.

Efficacy of Continuation/Maintenance Electroconvulsive Therapy in the Treatment of Patients With Mood Disorders: A Retrospective Analysis.

OBJECTIVE: The aim of the study was to contribute evidence for the efficacy of continuation and maintenance electroconvulsive therapy (c/mECT) going beyond the existing literature by examining longer-term outcomes from a single center. METHODS: We conducted a retrospective observational cohort study for a 14-year period, in which a group of 27 individuals with mood disorders, as defined by International Classification of Diseases-10, were examined and received acute ECT, followed by c/mECT. Mirror-image comparison of individual data sets, 5 years before and after c/mECT, was conducted for the number and mean duration of hospitalizations, as well as inpatient days per year. Statistical analysis was performed using general equation estimation modeling. RESULTS: In 27 patients (63% female, mean ± SD age = 54.3 ± 11.7 years) experiencing either from bipolar (41%) or unipolar (59%) mood disorder, with most patients presenting with a depressive episode at hospital admission (93%), c/mECT was initiated after a successful course of acute ECT in addition to treatment as usual. In a 5-year period before and after starting c/mECT, we observed a significant decline in the mean number of hospitalizations per year (0.64 vs 0.32, P = 0.031), the average number of inpatient days per year (23.7 vs 6.1 days, P < 0.001), and the mean duration of hospital stays (41.6 vs 22.1 days, P = 0.031). CONCLUSIONS: The findings provide further support for the efficacy of c/mECT as an augmentation therapy to psychopharmacological treatment in patients experiencing mood disorders, who have responded to acute ECT. Further studies, however, using a controlled study design and larger sample sizes are needed.

Prevalence of axis II comorbidities in bipolar disorder: relationship to mood state.

OBJECTIVES: A high incidence of Axis II personality disorders is described in patients with bipolar disorder; however, their relationship to mood state remains uncertain. METHODS: A total of 966 outpatients with bipolar disorder gave informed consent and filled out the Personality Disorder Questionnaire, 4th edition (PDQ4) and a questionnaire on demographics and course of illness prior to Bipolar Treatment Outcome Network entry at average age 41 years. Patients were rated at each visit for depression on the Inventory of Depressive Symptoms-Clinician version (IDS-C) and for mania on the Young Mania Rating Scale (YMRS). In a subgroup, the PDQ4 was retaken during periods of depression and euthymia. RESULTS: Patients met criteria for most personality disorders at a much higher rate when they took the PDQ4 while depressed compared to while euthymic, and scores were significantly related to the severity of depression (IDS) and of mania (YMRS) assessed within 2 weeks of taking the PDQ. Even when euthymic, more than quarter to half of the patients met criteria for a cluster A, B or C personality disorder. CONCLUSIONS: A wide range of personality disorders occur in bipolar patients, but are highly dependent on filling out the form while depressed compared to while euthymic. How this relates to having a personality disorder assessed using a structured clinical interview remains to be tested. However, higher PDQ4 scores are related to an earlier age of onset of bipolar disorder and other factors portending a more difficult course of bipolar disorder, and the optimal treatment of these patients remains to be illuminated.

Multigenerational transmission of liability to psychiatric illness in offspring of parents with bipolar disorder.

INTRODUCTION: Instead of the typical assessment of risk of illness in the offspring based on a parent with bipolar disorder, we explored the potential multigenerational conveyance across several disorders of the vulnerability to illness in the offspring of a patient with bipolar disorder. METHODS: A total of 968 outpatients (average age 41 years) with bipolar illness gave informed consent and filled out a detailed questionnaire about a family history in their parents, grandparents, and offspring of: depression; bipolar disorder; alcohol abuse; substance abuse; suicide attempt; or "other" illness. Of those with children, 346 were from the USA and 132 were from Europe. Amount and type of illness in progenitors in two and three previous generations were related to offspring illness. RESULTS: The type of illness seen in both prior generations was associated with the same type of illness in the offspring of a bipolar patient, including depression, bipolar disorder, alcohol and substance abuse and "other" illness, but not suicide attempts. There was an impact of multiple generations, such that depression in grandparents and/or great-grandparents increased the risk of depression in the offspring from 12.6% to 41.4%. CONCLUSIONS: A family history of illness burden in prior generations was previously related to an earlier age of onset of bipolar illness in our adult patients with bipolar disorder and is now also found to be related to the incidence of multiple psychiatric illnesses in their offspring. Genetic and epigenetic mechanisms deserve consideration for this multigenerational conveyance of illness vulnerability, and clinical and public health attempts to prevent or slow this transmission are indicated.

Axis II Personality Disorders Are Linked to an Adverse Course of Bipolar Disorder.

The relationship of personality disorder (PD) psychopathology to the course of bipolar disorder remains inadequately described. After giving informed consent, more than 782 outpatients with bipolar disorder rated themselves on the 99-item Personality Disorder Questionnaire, Version 4 (PDQ4) when depressed or euthymic. They also rated six poor prognosis factors (PPFs). The relationships of the PPFs to the total PDQ4 score were examined by a linear regression. Even after correcting for the higher PDQ4 scores observed when patients were suffering depression, the PDQ4 was significantly related to a history of child abuse, early age of onset, an anxiety disorder comorbidity, rapid cycling, and 20 or more previous episodes, but not substance abuse. The data suggest close relationships between the total burden of PD psychopathology and correlates of an adverse outcome of bipolar disorder. The nature of this of association and approaches to treatment of comorbid PD remain to be further explored.

Revising Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for the bipolar disorders: Phase I of the AREDOC project.

OBJECTIVE: To derive new criteria sets for defining manic and hypomanic episodes (and thus for defining the bipolar I and II disorders), an international Task Force was assembled and termed AREDOC reflecting its role of Assessment, Revision and Evaluation of DSM and other Operational Criteria. This paper reports on the first phase of its deliberations and interim criteria recommendations. METHOD: The first stage of the process consisted of reviewing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and recent International Classification of Diseases criteria, identifying their limitations and generating modified criteria sets for further in-depth consideration. Task Force members responded to recommendations for modifying criteria and from these the most problematic issues were identified. RESULTS: Principal issues focussed on by Task Force members were how best to differentiate mania and hypomania, how to judge 'impairment' (both in and of itself and allowing that functioning may sometimes improve during hypomanic episodes) and concern that rejecting some criteria (e.g. an imposed duration period) might risk false-positive diagnoses of the bipolar disorders. CONCLUSION: This first-stage report summarises the clinical opinions of international experts in the diagnosis and management of the bipolar disorders, allowing readers to contemplate diagnostic parameters that may influence their clinical decisions. The findings meaningfully inform subsequent Task Force stages (involving a further commentary stage followed by an empirical study) that are expected to generate improved symptom criteria for diagnosing the bipolar I and II disorders with greater precision and to clarify whether they differ dimensionally or categorically.

The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 3: The Clinical Guidelines.

Background: The current paper introduces the actual International College of Neuro-Psychopharmacology clinical guidelines for the treatment of bipolar disorder. Concept and structure of the guidelines: The current clinical guidelines are based on evidence-based data, but they also intend to be clinically useful, while a rigid algorithm was developed on the basis of firm evidence alone. Monotherapy was prioritized over combination therapy. There are separate recommendations for each of the major phases of bipolar disorder expressed as a 5-step algorithm. Discussion: The current International College of Neuro-Psychopharmacology clinical guidelines for the treatment of bipolar disorder are the most up-to-date guidance and are as evidence based as possible. They also include recommendations concerning the use of psychotherapeutic interventions, again on the basis of available evidence. This adherence of the workgroup to the evidence in a clinically oriented way helped to clarify the role of specific antidepressants and traditional agents like lithium, valproate, or carbamazepine. The additional focus on specific clinical characteristics, including predominant polarity, mixed features, and rapid cycling, is also a novel approach. Many issues need further studies, data are sparse and insufficient, and many questions remain unanswered. The most important and still unmet need is to merge all the guidelines that concern different phases of the illness into a single one and in this way consider BD as a single unified disorder, which is the real world fact. However, to date the research data do not permit such a unified approach.

The International College of Neuropsychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 4: Unmet Needs in the Treatment of Bipolar Disorder and Recommendations for Future Research.

Background: The current fourth paper on the International College of Neuropsychopharmacology guidelines for the treatment of bipolar disorder reports on the unmet needs that became apparent after an extensive review of the literature and also serves as a conclusion to the project of the International College of Neuropsychopharmacology workgroup. Materials and Methods: The systematic review of the literature that was performed to develop the International College of Neuropsychopharmacology guidelines for bipolar disorder identified and classified a number of potential shortcomings. Results: Problems identified concerned the reliability and validity of the diagnosis of bipolar disorder and especially of bipolar depression. This, in turn, has profound consequences for early detection and correct treatment of the disorder. Another area that needs improvement is the unsatisfactory efficacy and effectiveness of therapeutic options, especially in special populations such as those with mixed features and rapid cycling course. Gender issues and adherence problems constitute an additional challenge. The literature suggests that while treatment providers are concerned more with treatment-related issues, patients and their caregivers worry more about issues pertaining to the availability of services and care, quality of life, and various types of burden. The workgroup identified additional unmet needs related to the current standard of research in bipolar disorder. These include the fragmentation of bipolar disorder into phases that are handled as being almost absolutely independent from each other, and thus the development of an overall therapeutic strategy on the basis of the existing evidence is very difficult. Trials are not always designed in a way that outcomes cover the most important aspects of bipolar disorder, and often the reporting of the results is biased and unsatisfactory. The data on combination treatments and high dosages are sparse, whereas they are common in real world practice. Conclusions: The workgroup endorses the full release of raw study data to the scientific community, and the development of uniform clinical trial standards (also including more realistic outcomes) and the reporting of results. The 2 large appendices summarize the results of this systematic review with regard to the areas of lack of knowledge where further focused research is necessary.

The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 2: Review, Grading of the Evidence, and a Precise Algorithm.

Background: The current paper includes a systematic search of the literature, a detailed presentation of the results, and a grading of treatment options in terms of efficacy and tolerability/safety. Material and Methods: The PRISMA method was used in the literature search with the combination of the words 'bipolar,' 'manic,' 'mania,' 'manic depression,' and 'manic depressive' with 'randomized,' and 'algorithms' with 'mania,' 'manic,' 'bipolar,' 'manic-depressive,' or 'manic depression.' Relevant web pages and review articles were also reviewed. Results: The current report is based on the analysis of 57 guideline papers and 531 published papers related to RCTs, reviews, posthoc, or meta-analysis papers to March 25, 2016. The specific treatment options for acute mania, mixed episodes, acute bipolar depression, maintenance phase, psychotic and mixed features, anxiety, and rapid cycling were evaluated with regards to efficacy. Existing treatment guidelines were also reviewed. Finally, Tables reflecting efficacy and recommendation levels were created that led to the development of a precise algorithm that still has to prove its feasibility in everyday clinical practice. Conclusions: A systematic literature search was conducted on the pharmacological treatment of bipolar disorder to identify all relevant random controlled trials pertaining to all aspects of bipolar disorder and graded the data according to a predetermined method to develop a precise treatment algorithm for management of various phases of bipolar disorder. It is important to note that the some of the recommendations in the treatment algorithm were based on the secondary outcome data from posthoc analyses.

The International College of Neuropsychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 1: Background and Methods of the Development of Guidelines.

Background: This paper includes a short description of the important clinical aspects of Bipolar Disorder with emphasis on issues that are important for the therapeutic considerations, including mixed and psychotic features, predominant polarity, and rapid cycling as well as comorbidity. Methods: The workgroup performed a review and critical analysis of the literature concerning grading methods and methods for the development of guidelines. Results: The workgroup arrived at a consensus to base the development of the guideline on randomized controlled trials and related meta-analyses alone in order to follow a strict evidence-based approach. A critical analysis of the existing methods for the grading of treatment options was followed by the development of a new grading method to arrive at efficacy and recommendation levels after the analysis of 32 distinct scenarios of available data for a given treatment option. Conclusion: The current paper reports details on the design, method, and process for the development of CINP guidelines for the treatment of Bipolar Disorder. The rationale and the method with which all data and opinions are combined in order to produce an evidence-based operationalized but also user-friendly guideline and a specific algorithm are described in detail in this paper.

Meta-Analysis of the Risk of Subsequent Mood Episodes in Bipolar Disorder.

BACKGROUND: Reported relapse and recurrence rates in bipolar disorder (BD) differ significantly between studies. Most data originate from highly selective patients participating in sponsored randomized controlled trials with narrow inclusion criteria. To estimate the true risk of a subsequent mood episode (SME) under real-world conditions, we conducted a meta-analysis of rates of SME as reported in naturalistic BD studies. METHODS: PubMed, ScienceDirect, Scopus, and Web of Knowledge were searched until July 2015. Studies reporting the time until the emergence of an SME, from which individual data or Kaplan-Meier plots with censors marked could be retrieved, were included. RESULTS: Twelve studies comprising 5,837 patients met the inclusion criteria. The median time to an SME in adults after an index episode was 1.44 years. The risk of an SME was 44% during the first year. Not having a SME during this first year lowered this risk to 19% in the second year. The risk was higher in bipolar II disorder (BD-II) than in bipolar I disorder (BD-I; HR = 1.5). In BD-I, the risk of a subsequent manic, mixed, or depressive mood episode was higher after an index episode of the same polarity (HR = 1.89-5.14). The overall risk of an SME was higher in patients with persisting subsyndromal symptoms (HR = 2.17). CONCLUSIONS: The data from this study provide a more reliable estimate of the risk of an SME in BD in real-world settings. Further research into the longitudinal course of BD-II is warranted to confirm its role as a risk factor for SME.