Barriers to evidence-based practice implementation in physiotherapy: a systematic review and meta-analysis.

BACKGROUND: To review and meta-analyse the evidence about the prevalence of barriers to evidence-based practice (EBP) reported in physiotherapy. METHODS: Two independent investigators conducted an extensive electronic search in EMBASE, PubMed, Scopus, Web of Science and CINAHL databases from their inception to July 2020 and included the retrieved articles if they investigated barriers to EBP among physiotherapy professionals. Subsequently, they extracted data and assessed the methodological quality using a scale described in a similar previous study. The outcome for meta-analysis was frequency of each reported barrier. Sub-analyses were performed grouping studies based on countries where surveys were performed, classified as either developed or developing countries. RESULTS: Twenty-nine articles were included in the systematic reviews and meta-analysis. Risk of bias assessment of included studies showed a median score: 4 points (interquartile range: 3-4). The findings of meta-analysis revealed that lack of time was the most frequently reported barrier (53.0% [95% confidence interval, 95%CI, 44.0-62.0]), followed by language (36.0% [95%CI 16.0-62.0]), lack of access (34.0% [95%CI 23.0.27]) and lack of statistical skills (31.0% [95%CI 20.0-44.0]). Lack of skills and lack of generalizability were declared as barriers by 27.0% [95%CI 18.0-38.0] and 23.0% [95%CI 15.0-33.0] of responders, respectively. Lack of support and lack of interest are less frequent, with 16.0% [95%CI 11.0-24.0] and 9.0% [95%CI 6.0-15.0] of responses, respectively. Barriers reported in investigations performed in developed countries were less frequent when compared to those performed in developing countries. CONCLUSION: Organizational issues and methodological skills seem key issues to allow the implementation of EBP, suggesting the need to adopt or enhance organizational and training strategies to facilitate the implementation of the EBP. Quantitative synthesis showed high heterogeneity for all analyses, and therefore, pooled data should be interpreted with caution.

An International Society of Bipolar Disorders task force report: Precursors and prodromes of bipolar disorder.

OBJECTIVES: To clarify the clinical features preceding the onset of bipolar disorder (BD) has become a public health priority for the prevention of high morbidity and mortality. BD remains frequently under- or misdiagnosed, and under- or mistreated, often for years. METHODS: We assessed the predictive value of precursors and prodromes of BD. We assessed precursors of first-lifetime manic or hypomanic episodes with/without mixed features in retrospective and prospective studies. The task force evaluated and summarized separately assessments of familial risk, premorbid personality traits, retrospective, and prospective studies. RESULTS: Cyclothymic features, a family history of BD, retrospectively reported attenuated manic symptoms, prospectively identified subthreshold symptoms of hypomania, recurrence of depression, panic anxiety and psychotic features, have been identified as clinical precursors of BD. The prodromal symptoms like [hypo]mania often appears to be long enough to encourage early identification and timely intervention. CONCLUSIONS: The predictive value of any risk factor identified remains largely unknown. Prospective controlled studies are urgently needed for prevention and effective treatment.

What is the role of conventional antidepressants in the treatment of major depressive episodes with Mixed Features Specifier?

The newly introduced Mixed Features Specifier of Major Depressive Episode and Disorder (MDE/MDD) is especially challenging in terms of pharmacological management. Prior to the publication of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, the symptoms of the mixed features specifier were intradepressive hypomanic symptoms, always and only associated with bipolar disorder (BD). Intradepressive hypomanic symptoms, mostly referred to as depressive mixed states (DMX), have been poorly characterized, and their treatment offers significant challenges. To understand the diagnostic context of DMX, we trace the nosological changes and collocation of intradepressive hypomanic symptoms, and examine diagnostic and prognostic implications of such mixed features. One of the reasons so little is known about the treatment of DMX is that depressed patients with rapid cycling, substance abuse disorder, and suicidal ideation/attempts are routinely excluded from clinical trials of antidepressants. The exclusion of DMX patients from clinical trials has prevented an assessment of the safety and tolerability of short- and long-term use of antidepressants. Therefore, the generalization of data obtained in clinical trials for unipolar depression to patients with intradepressive hypomanic features is inappropriate and methodologically flawed. A selective review of the literature shows that antidepressants alone have limited efficacy in DMX, but they have the potential to induce, maintain, or worsen mixed features during depressive episodes in BD. On the other hand, preliminary evidence supports the effective use of some atypical antipsychotics in the treatment of DMX.

Guidelines for the recognition and management of mixed depression.

A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM-5 codified a new nosological entity, the "mixed features specifier," referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM-IV definition of "mixed states" wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.

Actigraph measures discriminate pediatric bipolar disorder from attention-deficit/hyperactivity disorder and typically developing controls.

BACKGROUND: Distinguishing pediatric bipolar disorder (BD) from attention-deficit hyperactivity disorder (ADHD) can be challenging. Hyperactivity is a core feature of both disorders, but severely disturbed sleep and circadian dysregulation are more characteristic of BD, at least in adults. We tested the hypothesis that objective measures of activity, sleep, and circadian rhythms would help differentiate pediatric subjects with BD from ADHD and typically developing controls. METHODS: Unmedicated youths (N = 155, 97 males, age 5-18) were diagnosed using DSM-IV criteria with Kiddie-SADS PL/E. BD youths (n = 48) were compared to typically developing controls (n = 42) and children with ADHD (n = 44) or ADHD plus comorbid depressive disorders (n = 21). Three-to-five days of minute-to-minute belt-worn actigraph data (Ambulatory Monitoring Inc.), collected during the school week, were processed to yield 28 metrics per subject, and assessed for group differences with analysis of covariance. Cross-validated machine learning algorithms were used to determine the predictive accuracy of a four-parameter model, with measures reflecting sleep, hyperactivity, and circadian dysregulation, plus Indic's bipolar vulnerability index (VI). RESULTS: There were prominent group differences in several activity measures, notably mean 5 lowest hours of activity, skewness of diurnal activity, relative circadian amplitude, and VI. A predictive support vector machine model discriminated bipolar from non-bipolar with mean accuracy of 83.1 ± 5.4%, ROC area of 0.781 ± 0.071, kappa of 0.587 ± 0.136, specificity of 91.7 ± 5.3%, and sensitivity of 64.4 ± 13.6%. CONCLUSIONS: Objective measures of sleep, circadian rhythmicity, and hyperactivity were abnormal in BD. Wearable sensor technology may provide bio-behavioral markers that can help differentiate children with BD from ADHD and healthy controls.

Catatonia in an adolescent with velo-cardio-facial syndrome.

Velo-cardio-facial syndrome (VCFS) is the most common microdeletion syndrome in humans and is probably the most frequent genetic cause of psychosis currently known. Many psychiatric disorders have been reported to occur in people with VCFS including, but not limited to schizophrenia, unipolar and bipolar mood disorders (with or without psychotic features), schizoaffective disorder, psychosis NOS, social phobia, generalized and separation anxiety, obsessive-compulsive disorder, autism spectrum disorder, cognitive impairment, and ADHD. This report describes the psychiatric onset and development of catatonia in an adolescent female with VCFS that was undiagnosed until 15 years of age. Catatonia may be a relatively common presentation in people with VCFS with treatment-refractory psychiatric manifestations.

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.

Clinical and Environmental Risk Factors for Bipolar Disorder: Review of Prospective Studies.

LEARNING OBJECTIVES: After participating in this activity, learners should be better able to:• Evaluate factors that have been identified in prospective studies as predicting the onset of bipolar disorder ABSTRACT: The prodromal phase of bipolar disorder (BD) remains incompletely characterized, limiting early detection of BD and delaying interventions that might limit future morbidity and disability. Retrospective and family-risk studies have consistently found evidence of prodromal psychopathology in subjects later diagnosed with BD. Here, we review prospective studies of clinical risk factors and exposures identified before diagnosis of BD: our findings are consistent with those from retrospective and family-risk studies. Affective psychopathology often precedes diagnosis to suggest a homotypic trajectory in developing BD. Early non-affective (heterotypic) psychopathological disturbances, including anxiety and disruptive behavior disorders, as well as environmental factors and exposures, have been found in prospective studies to increase the risk of BD, but tend to lack specificity in predicting BD. Findings from prospective studies are encouragingly similar to those of retrospective and family-risk studies.

Parental Reports of Prodromal Psychopathology in Pediatric Bipolar Disorder.

OBJECTIVES: Early psychopathology in children diagnosed with Bipolar Disorder (BD) remains poorly characterized. Parental retrospective reports provide helpful details on the earliest manifestations and their evolution over time. These symptoms occur early in the course of BD, often before a formal diagnosis is made and/or treatment is implemented, and are of great importance to early recognition and prevention. METHODS: Parents of pre-pubertal children and adolescents with DSM-IV diagnoses of BD attending an outpatient mood disorders clinic provided retrospective ratings of 37 symptoms of child psychopathology. Stability and comorbidity of diagnoses were evaluated, and severity of symptoms for each subject was assessed by identifying the earliest occurrence of the reported symptoms causing impairment. RESULTS: Severe mood instability, temper tantrums, anxiety symptoms, sleep disturbances and aggression were among the most common signs of psychopathology reported in children diagnosed with BD before puberty. Symptoms were already apparent in the first three years in 28%, and formal diagnoses were made before the age of 8 y in the majority of cases. CONCLUSIONS: Retrospective parental reports of early symptoms of psychopathology in pre-pubertal children with BD revealed a very early occurrence of affective precursors (irritability and mood dysregulation) and clinical risk factors like impulsive aggression and anxiety that can precede the syndromal onset of mania by several years. These findings support previous reports suggesting a progression of symptoms from abnormal, non-specific presentations to sub-threshold and finally syndromal BD. The importance of early identification and intervention is discussed.

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.

The role of environmental exposures as risk factors for bipolar disorder: A systematic review of longitudinal studies.

BACKGROUND: The role of environmental risk factors in the development of bipolar disorder (BD) is not well characterized. We evaluate the prevalence, duration, and predictive value of environmental exposures for BD in longitudinal studies. METHODS: We conducted a systematic search of PubMed, Scopus and PsychINFO databases until April 01, 2015, using the following words in combination: prenatal exposure; maternal exposure; trauma; childhood abuse; alcoholism; cannabis; smoking; cocaine; central stimulants; opioids; uv light; pollution; global warming; vitamin d AND bipolar disorder. Additional references were obtained through cross-referencing. We included (1) longitudinal cohort studies or case-control studies nested within longitudinal designs; (2) studies of subjects without lifetime BD diagnoses at initial assessment and a diagnosis of BD at follow-up by clinical or structured assessment. Familial-risk studies were excluded. We tabulated details of study-design, exposure, diagnostic criteria, risk of bipolar disorder expressed as odd ratio (OR), relative risk (RR) or hazard ratio (HR). RESULTS: Of 2119 studies found, 22 met inclusion criteria. Risk factors identified can be grouped in 3 clusters: neurodevelopment (maternal influenza during pregnancy; indicators of fetal development), substances (cannabis, cocaine, other drugs - opioids, tranquilizers, stimulants, sedatives), physical/psychological stress (parental loss, adversities, abuses, brain injury). LIMITATIONS: Heterogeneity of designs and methodology prevented the use of meta-analysis of the findings; studies did not provide sensitivity, specificity and predictive value of the risk factors identified; case-control studies classify cases based on diagnostic membership, but do not control for familial or genetic liability; methods for determining the exposures varied among studies. CONCLUSION: Only preliminary evidence exists that exposure to viral infection, substances or trauma increase the likelihood of BD. Given the limited data available, the specificity, sensitivity and predictive value could not be computed. As exposures are sometimes amenable to prevention, further research is needed.

The Bipolar Prodrome: Meta-Analysis of Symptom Prevalence Prior to Initial or Recurrent Mood Episodes.

OBJECTIVE: The aim of this study was to meta-analyze the prevalence of symptoms before an initial mood episode of bipolar disorder (BD) and the prevalence of subthreshold symptoms before a BD mood episode recurrence, to facilitate early identification and prevention. METHOD: Systematic literature reviews were conducted in PsycINFO and PubMed for prospective or retrospective studies reporting on the prevalence and longest duration of symptoms before an initial or recurrent mood episode of BD. Random effects meta-regression explored whether geographic location, age, percentage of female individuals, and study quality moderated the overall prevalence. RESULTS: In 11 studies (n = 1,078), the prodrome preceding an initial mood episode lasted 27.1 ± 23.1 months (range, 4.6-130 months). In 10 studies (n = 1,000), the subthreshold symptoms preceding a recurrent mood episode lasted 1.0 ± 0.9 months (range, 0.5-1.3 months). The most common symptoms were largely consistent with diagnostic criteria symptoms associated with the subsequent mood polarity for both the initial prodrome and the period prior to a recurrent mood episode. Few moderators of symptom prevalences emerged, and significant heterogeneity remained. CONCLUSION: The initial prodromal period is sufficiently long and characterized by symptoms of the subsequent mood episode to make early identification and intervention programs feasible. Conversely, the period of subthreshold symptoms before a recurrent mood episode is short, mandating adequate psychoeducation of patients and families, monitoring of changes in sleep and activity, plus sufficiently frequent follow-up visits to identify patients before a mood episode recurrence. Future prospective investigations, designed to address the identified shortcomings in the extant literature, are needed to identify more clinically applicable information.

Objective measures of activity and attention in the differential diagnosis of psychiatric disorders of childhood.

Objective measures of attention, concentration, and motor activity can be used effectively in the assessment and differential diagnosis of bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD) in children. Children with BD were evaluated using actigraphy and the McLean Motion Analysis Test (M-MAT), and the results were compared with age- and gender-matched ADHD and normative data. Actigraphy indicated decreased sleep efficiency and duration with BD, with a longer latency and increased nocturnal activity. Using M-MAT clinicians were able to detect cognitive impairment and activation in children with mania, and worse-than-normal scores on measures of attention and increased levels of activity and impulsiveness in children with BD. Thus, objective measures of attention and activity can be of assistance in the differential diagnosis of ADHD and BD.

Depressive mixed states: A reappraisal of Koukopoulos' criteria.

BACKGROUND: Mixed states have been a fundamental part of Kraepelin׳s conceptualization of the manic-depressive illness. However, after Kraepelin, the study of mixed states was not of great interest, until the publication of the RDC criteria (1978) and then the DSM-III edition (1980), where criteria for mixed manic states were operationalized. The most notable victims of DSM nosology were depressive mixed states, in particular depression with flight of ideas and excited (agitated) depression. METHODS: We briefly review the clinical work of Athanasios Koukopoulos on depressive mixed states (in particular agitated depression) pointing out the diagnostic and therapeutic contributions, especially in the lights of Koukopoulos׳ first description of depressive mixed syndrome in 1992. RESULTS: The mixed depressive syndrome is not a transitory state but a state of long duration, which may last weeks or several months. The clinical picture is characterized by dysphoric mood, emotional lability, psychic and/or motor agitation, talkativeness, crowded and/or racing thoughts, rumination, initial or middle insomnia. Impulsive suicidal attempts may be frequent. The family observes incessant complaints, irritability, occasional verbal outbursts, occasional physical aggression, and occasional hypersexuality. Treatment with antipsychotics and ECT is very effective; antidepressants can worsen the clinical picture. LIMITATIONS: Selective but not systematic review of the literature on depressive mixed states. Relatively little research data is currently available for validation of the criteria proposed by Koukopoulos. CONCLUSIONS: Koukopoulos׳ proposal of mixed depression, besides its diagnostic implications, clearly identifying it as manifestations of bipolar disorder, allows for better clinical characterization of cases and improves treatment decisions.

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.

Precursors of bipolar disorders: a systematic literature review of prospective studies.

OBJECTIVE: To evaluate the presence of affective signs and symptoms as precursors of bipolar disorder in prospective studies, including assessment of their prevalence, duration, and predictive value. DATA SOURCES: We followed PRISMA guidelines to search PubMed, CINAHL, PsycINFO, EMBASE, SCOPUS, and ISI Web of Science databases to May 31, 2013, using the terms bipolar disorder AND (antecedent* OR predict* OR prodrom* OR prospect*) AND (diagnosis OR development). Hand searching of identified reports led to additional relevant references. STUDY SELECTION: We included only English-language articles containing (1) prospective, longitudinal studies with at least 2 structured clinical assessments (intake and follow-up); (2) no previous DSM-III or DSM-IV diagnoses of bipolar I or bipolar II; and (3) diagnostic outcome of bipolar I or bipolar II. Studies of subjects at familial risk of bipolar disorder were excluded, as these have been reviewed elsewhere. DATA EXTRACTION: We tabulated details of study design, outcomes, precursors, and predictive value. Only studies reporting a positive predictive association were included. RESULTS: In 26 published reports meeting selection criteria, methods varied widely in terms of design, duration of follow-up, ages, and populations investigated. Despite such heterogeneity in methods, findings were notably consistent. Precursors of bipolar disorder include mood lability, subsyndromal and major depression, subsyndromal hypomanic symptoms with or without major depression, cyclothymia and bipolar not otherwise specified, major depression with psychotic features, and other psychotic disorders. Bipolar disorder was also predicted by juvenile onset of major depression as well as frequency and loading of hypomanic or depressive symptoms. CONCLUSIONS: Despite the limitations of published reports, prospectively identified precursors of bipolar disorder typically arose years prior to syndromal onset, often with significant early morbidity and disability. Prospectively identified precursors of bipolar disorder are generally consistent with findings in retrospective and family-risk studies. Combining precursors and other risk factors may increase predictive value, support earlier diagnosis, improve treatment, and limit disability in bipolar disorder.

Treatment-emergent mania in pediatric bipolar disorder: a retrospective case review.

BACKGROUND: Pediatric bipolar disorder (BPD) can be misdiagnosed as a depressive, attention, conduct, or anxiety disorder and treatment with antidepressants and stimulants is common. Risk of adverse outcomes related to such treatment remains poorly defined. METHODS: We analyzed clinical records of 82 children (mean age 10.6 years) meeting modified DSM-IV diagnostic criteria for BPD to evaluate risk and timing of operationally-defined treatment-emergent mania (TEM) or increased mood-cycling following pharmacological treatment. RESULTS: Of 82 juvenile BPD patients, 57 (69%) had been given a mood-elevating agent at least once; 33/57 (58%) so-exposed met criteria for TEM, with median latency of 14 days; TEM was observed twice as often with antidepressants as stimulants (44% vs. 18%). TEM led to first-recognition of BPD in 14 cases (17%), and some drug-exposed children (4-9%) had prominent suicidal, homicidal or psychotic behavior. In addition to recent exposure to a mood-elevating agent, TEM was associated with early-onset anxiety and female gender. LIMITATIONS: Findings are retrospective in clinically diagnosed and treated outpatients, but involved otherwise unselected cases of juvenile BPD. CONCLUSIONS: TEM was reported in 58% of children with probable juvenile BPD within several weeks of new exposure to a mood-elevating agent.

Clinical risk factors for bipolar disorders: a systematic review of prospective studies.

BACKGROUND: Early phases and suspected precursor states of bipolar disorder are not well characterized. We evaluate the prevalence, duration, clinical features and predictive value of non-affective psychopathology as clinical risk factors for bipolar disorder in prospective studies. METHODS: We screened PubMed, CINAHL, PsycINFO, Embase, SCOPUS, and ISI-Web of Science databases from inception up to January 31, 2014, following PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and searched: bipolar disorder AND [antecedent⁎ OR predict⁎ OR prodrom⁎ OR prospect⁎ OR risk⁎] AND [diagnosis OR development]. We included only English language reports on prospective, longitudinal studies with two structured clinical assessments (intake and follow-up); no DSM intake diagnosis of bipolar-I or -II; diagnostic outcome was bipolar-I or -II. Details of study design, risk factors, and predictive value were tabulated. RESULTS: We found 16 published reports meeting selection criteria, with varying study design. Despite heterogeneity in methods, findings across studies were consistent. Clinical risk factors of bipolar disorder were early-onset panic attacks and disorder, separation anxiety and generalized anxiety disorders, conduct symptoms and disorder, ADHD, impulsivity and criminal behavior. LIMITATIONS: Since risk factors identified in some prospective studies are predictive of other conditions besides bipolar disorder, these preliminary findings require replication, and their sensitivity, specificity and predictive value need to be assessed. CONCLUSIONS: Clinical risk factors for bipolar disorder typically arise years prior to syndromal onset, include anxiety and behavioral disorders with unclear sensitivity and specificity. Prospectively identified clinical risk factors for bipolar disorder are consistent with retrospective and family-risk studies. Combining clinical risk factors with precursors and family-risk may improve early identification and timely and appropriate treatment of bipolar disorder.

Clinical experience using intranasal ketamine in the treatment of pediatric bipolar disorder/fear of harm phenotype.

OBJECTIVES: Intravenous ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to exert a rapid antidepressant effect in adults with treatment resistant depression. Children with bipolar disorder (BD) often respond poorly to pharmacotherapy, including polypharmacy. A pediatric-onset Fear of Harm (FOH) phenotype has been described, and is characterized by severe clinical features and resistance to accepted treatments for BD. The potential efficacy and safety of intranasal ketamine in children with BD with FOH-phenotype were assessed by a systematic retrospective chart review of a case series from the private practice of one of the authors, including cases with clear refractoriness to mood stabilizers, antipsychotics and benzodiazepines. METHODS: A comparison was made between routinely collected symptom measures 1-2 weeks prior to and after the administration of ketamine, in 12 treatment-refractory youth, 10 males 2 females ages 6-19years. RESULTS: Ketamine administration was associated with a substantial reduction in measures of mania, fear of harm and aggression. Significant improvement was observed in mood, anxiety and behavioral symptoms, attention/executive functions, insomnia, parasomnias and sleep inertia. Treatment was generally well-tolerated. CONCLUSIONS: Intranasal ketamine administration in treatment-resistant youth with BD-FOH produced marked improvement in all symptomatic dimensions. A rapid, substantial therapeutic response, with only minimal side effects was observed. Formal clinical trials to assess safety and efficacy are warranted.

Antidepressant-associated mood-switching and transition from unipolar major depression to bipolar disorder: a review.

OBJECTIVES: Compare reported rates of mood-shifts from major depression to mania/hypomania/mixed-states during antidepressant (AD)-treatment and rates of diagnostic change from major depressive disorder (MDD) to bipolar disorder (BPD). METHODS: Searching computerized literature databases, followed by summary analyses. RESULTS: In 51 reports of patients diagnosed with MDD and treated with an AD, the overall risk of mood-switching was 8.18% (7837/95,786) within 2.39 ± 2.99 years of treatment, or 3.42 (95% CI: 3.34-3.50) %/year. Risk was 2.6 (CI: 2.5-2.8) times greater with/without AD-treatment by meta-analysis of 10 controlled trials. Risk increased with time up to 24 months of treatment, with no secular change (1968-2012). Incidence rates were 4.5 (CI: 4.1-4.8)-times greater among juveniles than adults (5.62/1.26 %/year; p<0.0001). In 12 studies the overall rate of new BPD-diagnoses was 3.29% (1928/56,754) within 5.38 years (0.61 [0.58-0.64] %/year), or 5.6-times lower (3.42/0.61) than annualized rates of mood-switching. CONCLUSIONS: AD-treatment was associated with new mania-like responses in 8.18% of patients diagnosed with unipolar MDD. Contributions to mood-switching due to unrecognized BPD versus mood-elevating pharmacological effects, as well as quantitative associations between switching and later diagnosis of BPD not associated with AD-treatment remain uncertain. LIMITATIONS: Rates and definitions of mood-switching with ADs varied greatly, exposure-times rarely were precisely defined, and there was little information on predictive associations between mood-switches and BPD-diagnosis.