Long-term outcome predictors after functional remediation in patients with bipolar disorder.

BACKGROUND: Improving functioning in patients with bipolar disorder (BD) is one of the main objectives in clinical practice. Of the few psychosocial interventions that have been specifically developed to enhance the psychosocial outcome in BD, functional remediation (FR) is one which has demonstrated efficacy. The aim of this study was to examine which variables could predict improved functional outcome following the FR intervention in a sample of euthymic or subsyndromal patients with BD. METHODS: A total of 92 euthymic outpatients were included in this longitudinal study, with 62 completers. Partial correlations controlling for the functional outcome at baseline were calculated between demographic, clinical and neurocognitive variables, and functional outcome at endpoint was assessed by means of the Functioning Assessment Short Test scale. Next, a multiple regression analysis was run in order to identify potential predictors of functional outcome at 2-year follow-up, using the variables found to be statistically significant in the correlation analysis and other variables related to functioning as identified in the previous scientific literature. RESULTS: The regression model revealed that only two independent variables significantly contributed to the model (F(6,53): 4.003; p = 0.002), namely verbal memory and inhibitory control. The model accounted for 31.2% of the variance. No other demographic or clinical variable contributed to the model. CONCLUSIONS: Results suggest that patients with better cognitive performance at baseline, especially in terms of verbal memory and executive functions, may present better functional outcomes at long term follow-up after receiving functional remediation.

[French Expert advice on the management of valproate in childbearing and pregnant women with bipolar disorder]. / Avis d'experts français sur la prise en charge des femmes en âge de procréer et enceintes souffrant d'un trouble bipolaire traitées par valproate.

INTRODUCTION: The perinatal period is associated with high risk of relapses in women with untreated bipolar disorder (BD) and can have significant consequences on foetal and child development. Valproate is an effective mood stabilizer in BD but it is also the anticonvulsant associated to the highest risks of neurodevelopmental disorders and congenital malformations. The National Agency for the Safety of Medicines and Health Products (ANSM) changed the conditions of use and prescription of valproate in France in 2015. Its prescription is now contraindicated (i.e., not to be prescribed) in women able to have children unless alternative treatments are ineffective or not tolerated. Moreover, valproate could only be prescribed if the protocol of a specific pregnancy prevention program is followed. METHODS: A panel of experts from the French Association for Biological Psychiatry and Neuropsychopharmacology (AFPBN) provided consensus-based recommendations for switching and discontinuation of valproate in women with BD. The development of these recommendations consisted of an adaptation to French clinical practice based on a European expert opinion published in 2019. The experts discussed five real-world clinical situations in light of the scientific evidence and their clinical experience (a. Stable BD patient with valproate monotherapy who is planning pregnancy, b. Stable BD patient with valproate polytherapy who is planning pregnancy, c. Unstable BD patient with frequent relapses and valproate polytherapy who is planning pregnancy, d. Stable BD patient treated with valproate and unexpected pregnancy, e. Unstable BD patient treated with valproate and unexpected pregnancy) and developed, through several rounds of exchange drafts, a French version of clinical recommendations. RESULTS: First of all, some factors need to be considered for establishing personalized practical recommendations for a safe and effective switching or discontinuation of valproate in any clinical situations: planned pregnancy or unplanned pregnancy or current pregnancy, the existence or not of a pregnancy risk minimization program and a complete treatment history. Other factors that should be considered are the predominant polarity, the severity, the stability, the comorbidities associated with BD, the beliefs toward treatments, the family situation and the preference of the patient. The modalities for switching or discontinuation of valproate in women with BD were related to the clinical situation. First-line therapeutic alternatives such as lithium, lamotrigine, quetiapine, olanzapine or aripiprazole were preferred for patients suffering from a clinically stable BD considering pregnancy or pregnant. In patients suffering from clinically unstable BD, to reach stability was considered first. A shared decision-making should be systematically implemented and the patient must be fully informed of the risks related to an in-utero exposure to valproate, and the risks of the discontinuation/switch that is considered. CONCLUSION: Although the adaptation to French practice of the recommendations from the European expert opinion highlighted some differences in the criteria taken into consideration to guide the therapeutic decision, this expert advice will guide the clinician for switching and discontinuation of valproate in BD women able to have children or pregnant.

How to treat mania.

OBJECTIVE: In this paper, we aimed at reviewing evidence-based treatment options for bipolar mania and proposed tentative evidence-based clinical suggestions regarding the management of a manic episode, especially regarding the choice of the proper mood stabilizer and antipsychotic medication. METHOD: A narrative review was undertaken addressing 'treatment of bipolar mania'. Findings have been synthesized and incorporated with clinical experience into a model to support different treatment choices. RESULTS: To date, there is solid evidence supporting the use of several medications, such as lithium, divalproex, and carbamazepine, and antipsychotics, such as chlorpromazine, haloperidol, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, inhaled loxapine, asenapine, and cariprazine in acute mania, and some evidence supporting the use of clozapine or electroconvulsive therapy in treatment-refractory cases. However, in clinical practice, when making decisions about treatment, personalized treatment is needed, according to the different clinical presentations and more complex clinical situations within the manic episode and considering a long-term view and with the objective of not only a symptomatic but also functional recovery. After remission from acute mania, psychoeducation strategies are useful to ensure adherence. DISCUSSION: Despite the evidence forefficacy of many currently available treatments for mania, the majority of RCTs provide little direction for the clinician as to what steps might be optimal in different presentations of mania as well as in the presence of specific patient characteristics. Manic episodes should be managed on a personalized basis considering the clinical course and patient criteria and with the expectation of maintaining that treatment in the long-term.

Mixed states in bipolar and major depressive disorders: systematic review and quality appraisal of guidelines.

OBJECTIVE: This systematic review provided a critical synthesis and a comprehensive overview of guidelines on the treatment of mixed states. METHOD: The MEDLINE/PubMed and EMBASE databases were systematically searched from inception to March 21st, 2018. International guidelines covering the treatment of mixed episodes, manic/hypomanic, or depressive episodes with mixed features were considered for inclusion. A methodological quality assessment was conducted with the Appraisal of Guidelines for Research and Evaluation-AGREE II. RESULTS: The final selection yielded six articles. Despite their heterogeneity, all guidelines agreed in interrupting an antidepressant monotherapy or adding mood-stabilizing medications. Olanzapine seemed to have the best evidence for acute mixed hypo/manic/depressive states and maintenance treatment. Aripiprazole and paliperidone were possible alternatives for acute hypo/manic mixed states. Lurasidone and ziprasidone were useful in acute mixed depression. Valproate was recommended for the prevention of new mixed episodes while lithium and quetiapine in preventing affective episodes of all polarities. Clozapine and electroconvulsive therapy were effective in refractory mixed episodes. The AGREE II overall assessment rate ranged between 42% and 92%, indicating different quality level of included guidelines. CONCLUSION: The unmet needs for the mixed symptoms treatment were associated with diagnostic issues and limitations of previous research, particularly for maintenance treatment.

Aggressiveness in depression: a neglected symptom possibly associated with bipolarity and mixed features.

OBJECTIVE: To evaluate aggressiveness during a major depressive episode (MDE) and its relationship with bipolar disorder (BD) in a post hoc analysis of the BRIDGE-II-MIX study. METHOD: A total of 2811 individuals were enrolled in this multicenter cross-sectional study. MDE patients with (MDE-A, n = 399) and without aggressiveness (MDE-N, n = 2412) were compared through chi-square test or Student's t-test. A stepwise backward logistic regression model was performed. RESULTS: MDE-A group was more frequently associated with BD (P < 0.001), while aggressiveness was negatively correlated with unipolar depression (P < 0.001). At the logistic regression, aggressiveness was associated with the age at first depressive episode (P < 0.001); the severity of mania (P = 0.03); the diagnosis of BD (P = 0.001); comorbid borderline personality disorder (BPD) (P < 0.001) but not substance abuse (P = 0.63); no current psychiatric treatment (P < 0.001); psychotic symptoms (P = 0.007); the marked social/occupational impairment (P = 0.002). The variable most significantly associated with aggressiveness was the presence of DSM-5 mixed features (P < 0.001, OR = 3.815). After the exclusion of BPD, the variable of lifetime suicide attempts became significant (P = 0.013, OR = 1.405). CONCLUSION: Aggressiveness seems to be significantly associated with bipolar spectrum disorders, independently from BPD and substance abuse. Aggressiveness should be considered as a diagnostic criterion for the mixed features specifier and a target of tailored treatment strategy.

Course of residual symptoms according to the duration of euthymia in remitted bipolar patients.

OBJECTIVE: Although many studies showed the negative impact of residual symptoms on the course of bipolar disorder (BD), there is a need to examine potential differences in residual symptoms according to the duration of euthymia in remitted BD patients. METHOD: This was a large cross-sectional study of 525 euthymic BD out-patients. A multivariate analysis of covariance was conducted to compare depressive and manic residual symptoms, sleep disturbances and cognitive complaints among three patient groups on the basis of duration of euthymia (A. 6 months to <1 year; B. 1 year to <3 years; C. 3 years to ≤5 years). RESULTS: A significant difference between the three groups was found in residual symptoms [Pillai's Trace: F(8942) = 4.659, P < 0.001]. Tukey post hoc analysis indicated that patients from Group C presented lower residual depressive symptoms, higher sleep quality and better perceived cognitive performance compared with Group A. Group B also presented better sleep and cognitive outcomes than Group A. In addition, Group C showed the lowest incidence of functional impairment. CONCLUSION: This study suggests that the intensity of residual symptoms and functional impairment in remitted BD patients is negatively related to the duration of euthymia.

Comparison of psychotic bipolar disorder, schizoaffective disorder, and schizophrenia: an international, multisite study.

OBJECTIVE: Nosological distinctions among schizoaffective disorder (SA), bipolar I disorder with psychotic features (BDp), and schizophrenia (SZ) remain unresolved. METHOD: We compared 2269 subjects with psychotic features in DSM-IV-TR diagnoses (1435 BDp, 463 SZ, 371 SA) from 8 collaborating international sites, by 12 sociodemographic and clinical measures, all between diagnostic pairs. RESULTS: In bivariate comparisons, SA was consistently intermediate between BDp and SZ for 11/12 features (except onset stressors), and SZ vs. BDp differed in all 12 factors. SA differed from both BDp and SZ in 9/12 factors: SA and BDp were similar in education and suicidal ideation or acts; SA and SZ were similar in education, onset stressors, and substance abuse. Meta-analytic comparisons of diagnostic pairs for 10 categorical factors indicated similar differences of SA from both SZ and BDp. Multivariate modeling indicated significantly independent differences between BDp and SZ (8 factors), SA vs. SZ (5), and BDp vs. SA (3). Measurement variance was similar for all diagnoses. CONCLUSION: SA was consistently intermediate between BDp and SZ. The three diagnostic groups ranked: BDp > SA > SZ related to lesser morbidity or disability. The findings are not consistent with a dyadic Kraepelinian categorization, although the considerable overlap among the three DSM-IV diagnostic groups indicates uncertain boundaries if they represent distinct disorders.

Bipolar disorder in the elderly: a cohort study comparing older and younger patients.

OBJECTIVE: The purpose of this study was to analyze differences in clinical and socio-demographic characteristics between older and younger bipolar outpatients paying special attention to depressive symptoms in a large, naturalistic cohort. METHOD: Five hundred and ninety-three DSM-IV-TR bipolar outpatients were enrolled. Clinical characteristics were assessed according to DSM-IV-TR (SCID-I). Subjects were categorized into two groups according to current age (older OBD: age > 65 years; younger-YBD: age < 65 years). RESULTS: About 80% of patients were younger (N = 470), and a fifth were older (N = 123), with a mean age of 77.30 years in OBD. Older patients were more likely to be married, not qualified, bipolar II, with depressive polarity of first episode, higher age at illness onset, higher age at first hospitalization. They were more likely to present with depressive predominant polarity, with lifetime history of catatonic, psychotic and melancholic features, age at illness onset >40 years, as well as suffering from more medical comorbidities when compared to younger bipolars. CONCLUSION: The clinical presentation of bipolar disorder in late life would be defined more frequently by melancholic depressive features and a predominantly depressive polarity. These results suggest that treatment strategies for elderly bipolar patients should focus in the prevention of depressive episodes.

Rates and clinical correlates of treatment non-adherence in schizoaffective bipolar patients.

OBJECTIVE: To analyze demographical, clinical, and therapeutic variables that may be associated with pharmacological non-adherence in a sample of schizoaffective patients, bipolar type. METHOD: Adherence to treatment and its clinical correlates were assessed at the end of a 10-year follow-up in 76 patients meeting DSM-IV-TR diagnosis of schizoaffective disorder, bipolar type. Adherent and poorly adherent patients were compared regarding clinical and therapeutic variables. RESULTS: The rate of poorly adherent patients was 32/76 (41.2%) of the sample. Adherent patients were more likely to have presented an affective episode at illness onset and to have fewer purely - non-affective - psychotic episodes. Demographic or other clinical variables were not found to be associated to treatment adherence. Family history for psychiatric disorders or suicide did not correlate either, and neither did any specific pharmacological agent. CONCLUSION: Rates of non-adherence in schizoaffective disorder are high. Adherence seems to be associated to a more affective course of illness (affective first episode and fewer purely psychotic episodes). Patients with more prominent schizophrenia-like characteristics could be at higher risk for poor adherence and need to be closely followed and monitored. Even when properly treated, schizoaffective disorder is a disabling and severe disorder with high risk for recurrences.

[Bipolar disorder, cognitive functioning and hypothalamic-pituitary-thyroid axis]. / Trastorno bipolar, funciones cognitivas y eje hipotalámico-pituitario-tiroideo.

In psychoneuroendocrinology there's a scarcity of knowledge of hypothalamic-pituitary-thyroid axis (HPT) in relation to bipolar disorder (BD) and neuropsychological functions. The aim of this study is to review the current state of the following issues: (1) neuropsychological dysfunctions in BD, as well as their hypothetic aetiology; (2) response of HPT in each phase of BD, and, finally, (3) connection between alterations in HPT and neuropsychological deficits.

Unravelling potential severe psychiatric repercussions on healthcare professionals during the COVID-19 crisis.

The coronavirus disease 2019 (COVID-19) outbreak is putting healthcare professionals, especially those in the frontline, under extreme pressures, with a high risk of experiencing physical exhaustion, psychological disturbances, stigmatization, insomnia, depression and anxiety. We report the case of a general practitioner, without relevant somatic or psychiatric history that experienced a "brief reactive psychosis (298.8)" under stressful circumstances derived from COVID-19. She presented with delusional ideas of catastrophe regarding the current pandemic situation, delusions of self-reference, surveillance and persecution, with high affective and behavioural involvement. Physical examination and all further additional investigations did not reveal any secondary causes. She was administered olanzapine 10 mg with significant psychopathological improvement being later discharged with indications to maintain the treatment. To our knowledge this is the first reported case of severe mental illness in a healthcare professional without previous psychiatric history due to COVID-19 outbreak. Around 85% of patients presenting a brief psychotic disorder will develop a potentially disabling serious psychotic illness in the long-term. This case represents the potentially serious mental health consequences on healthcare professionals throughout the COVID-19 crisis and emphasizes the need to implement urgent measures to maintain staff mental health during the current pandemic.

Lithium and suicide prevention in mood disorders and in the general population: A systematic review.

Suicide contributes to 1-4 % of deaths worldwide every year. We conducted a systematic review aimed at summarizing evidence on the use of lithium for the prevention of suicide risk both in mood disorders and in the general population. We followed the PRISMA methodology (keywords: "lithium", "suicide" AND "suicidal" on Pubmed, Cochrane CENTRAL, Clinicaltrial.gov, other databases). Inclusion criteria: lithium therapy in mood disorder or found in drinking water or scalp in the general population. Exclusion criteria: no lithium administration. From 918 screened references, 18 prospective (number of participants: 153786), 10 retrospective (number of participants: 61088) and 16 ecological studies (total sample: 2062) were included. Most of the observational studies reported a reduction in suicide in patients with mood disorders. All studies about lithium treatment's duration reported that long-term lithium give more benefits than short-term lithium in suicide risk The evidence seems to attribute an intrinsic anti-suicidal property of lithium, independent of its proven efficacy as a mood stabilizer.

Treatment-resistant bipolar depression: towards a new definition.

OBJECTIVE: To summarize the conceptual and operational definitions of treatment-resistant bipolar depression and to review the evidence-based therapeutic options. METHOD: Structured searches of PubMed, Index Medicus, Excerpta Medica and Psyclit conducted in December 2008. RESULTS: Criteria for treatment resistance in bipolar depression are commonly based on concepts stemming from treatment resistance as defined for unipolar depression, an approach that proved to be inadequate. In fact, the addition of an ad hoc criterion based on lithium and other mood stabilizer unresponsiveness after reaching adequate plasma levels appears to be a patch that attempts to take into account the uniqueness of bipolar depression but fails to become operational. Recent data from randomized clinical trials of new anticonvulsants and second-generation antipsychotics should lead to the development of a modern definition of treatment-resistant bipolar depression, and specific therapeutic algorithms. CONCLUSION: We suggest a redefinition of resistant bipolar I and II depression. We propose different degrees of severity within bipolar depression in a stepwise manner.

A systematic review on sleep alterations anticipating the onset of bipolar disorder.

BACKGROUND: Sleep alterations are frequent occurrence in Bipolar Disorder (BD), both in acute and interepisodic phases. Sleep alterations have been also described both long before BD onset, as aspecific risk syndromes, or as immediate prodromes of BD onset. The aim of the present study is to systematically review the relationship between sleep alterations anticipating for the full-blown onset of BD, both in general and according to specific polarities of onset. METHODS: A systematic literature research according to PRISMA statement and considering: 1. prospective studies about BD patients' offspring with sleep alterations who later developed BD. 2. prospective studies assessing patients with sleep disorders who later developed BD. 3. retrospective studies on BD patients where sleep alterations before BD onset of the disease were reported. RESULTS: A total of 16 studies were included in this review. Sleep disturbances may frequently appear 1 year before the onset of BD or more, often during childhood or adolescence. A decreased need for sleep may precede the onset of the illness, specially a manic episode, while insomnia appears to anticipate either a manic or a depressive episode. Hypersomnia seems to precede bipolar depressive episodes. CONCLUSIONS: Sleep alterations frequently appear long before the onset of BD, and appear to be related specifically to the polarity of the index episode. The detection and treatment of sleep alterations in special high risk populations may help achieving an earlier detection of the illness.

The implications of hypersomnia in the context of major depression: Results from a large, international, observational study.

According to the DSM-5, "reduction in the need for sleep" is the only sleep-related criteria for mixed features in depressive episodes. We aimed at studying the prevalence, clinical correlates and the role of hypersomnia in a sample of acutely depressed patients. Secondarily, we factors significantly increasing the odds of hypersomnia were studied. We conducted a post-hoc analysis of the BRIDGE-II-Mix study. Variables were compared between patients with hypersomnia (SLEEP+) and with insomnia (SLEEP-) with standard bivariate tests. A stepwise backward logistic regression model was performed with SLEEP+ as dependent variable. A total of 2514 subjects were dichotomized into SLEEP+ (n = 423, 16.8%) and SLEEP- (n = 2091, 83.2%). SLEEP+ had significant higher rates of obese BMI (p < 0.001), BD diagnosis (p = 0.027), severe BD (p < 0.001), lifetime suicide attempts (p < 0.001), lower age at first depression (p = 0.004) than SLEEP-. Also, SLEEP+ had significantly poorer response to antidepressants (AD) such as (hypo)manic switches, AD resistance, affective lability, or irritability (all 0<0.005). Moreover, SLEEP+ had significantly higher rates of mixed-state specifiers than SLEEP- (all 0 < 0.006). A significant contribution to hypersomnia in our regression model was driven by metabolic-related features, such as "current bulimia" (OR = 4.21) and "overweight/obese BMI (OR = 1.42)". Globally, hypersomnia is associated with poor outcome in acute depression. Hypersomnia is strongly associated with mixed features and bipolarity. Metabolic aspects could influence the expression of hypersomnia, worsening the overall clinical outcome. Along with commonly used screening tools, detection of hypersomnia has potential, costless discriminative validity in the differential diagnosis unipolar and bipolar depression.

Ethical questions in human clinical psychopharmacology: should the focus be on placebo administration?

Of all ethical issues in clinical trial designs, only placebo use is dealt with acrimony and unwarranted, rhetoric emphasis. Many misconceptions are biased and may hamper research in the mechanisms of healing and recovery if placebo is banned from clinical trials, as some influential ethicists propose. Current treatments in psychiatry are by no means optimal and may vary in their effect across studies, rendering difficult to find the best available therapeutic method with which to compare new drugs. Because drugs possess specific mechanisms, it is not possible to compare drugs with different mechanisms as to their relevance in the pathophysiology of a given disorder. Placebo acts through non-specific mechanisms and is the ideal control for any disorder whose pathophysiology is relatively unknown and its treatment is still suboptimal. Sticking to short-term patient benefit in a trial reflects an individualistically oriented thinking in contemporary ethics and is likely to limit further research and efforts to better understand the mechanisms of disease and drug action, but also those related to general body reactance and self-healing, which are enhanced by placebo administration. Because in history ethics are swinging between two opposed views, it is possible that in the near future, the balance will move towards communitarianism, which is more likely to better serve long-term patient needs. Ethicists should also consider some other aspects of human experimentation, such as the consistency of research lines and the trend to substitute older drugs with their metabolites or enantiomers.

A study on the bioequivalence of lithium and valproate salivary and blood levels in the treatment of bipolar disorder.

Lithium (Li) and valproate (VPA) are used in the treatment of bipolar disorder (BD), with narrow therapeutic window requiring periodic control of serum levels. This prevents intoxication, lack of efficacy due to low serum concentrations, and allows monitoring adherence. We aimed at evaluating the bioequivalence of salivary and blood levels of LI or VPA in a sample of adult BD patients. Secondarily, lithium bioequivalence was evaluated across different patients' lifespans. BD patients treated with either Li or VPA underwent contemporary standard serum and salivary measurements. Blood levels of both drugs were taken according to standard procedures. Li salivary levels were performed by an adapted potentiometric method on the AVL9180 electrolyte analyzer. VPA salivary levels were taken with an immune-assay method with turbidimetric inhibition. A total of 50 patients (38 on Li, 12 on VPA) were enrolled. Blood-saliva bioequivalence for VPA was not found due to a high variability in salivary measures. Li measures resulted in a high correlation (r=0.767, p<0.001), showing no partial correlation with age (r=0.147, p=0.380). Li salivary test is a reliable method of measuring Li availability and is equivalent to serum levels. Potential advantages of Li salivary testing are its non-invasive nature and the possibility of doing the test during the usual appointment with the psychiatrist.