Use of Stimulants in Bipolar Disorder.

Several international guidelines indicate stimulants, including methylphenidate (MPH), amphetamines and derivatives, modafinil, and armodafinil among the second-third-line choices for bipolar depression. Efficacy of stimulants has been also reported for the management of residual depressive symptoms such as fatigue and sleepiness and for the management of affective, cognitive, and behavioral symptoms in children and adult bipolar patients with comorbid ADHD. Few case reports show positive results with MPH in the treatment of resistant mania. Finally, MPH might be an option in some bipolar forms observed in psychiatric presentations of frontotemporal dementia and traumatic brain injury. In spite of these preliminary observations, the use of stimulants in bipolar patients is still controversial. Potential of misuse and abuse and mood destabilization with induction of (hypo)manic switches, mixed states, and rapid cycling are the concerns most frequently reported. Our aims are to summarize available literature on this topic and discuss practical management implications.

Clinical features, developmental course, and psychiatric comorbidity of adult autism spectrum disorders.

Autism spectrum disorders (ASDs) include a heterogeneous group of neurodevelopmental disorders with early onset in childhood. ASDs should be considered lifelong clinical entities, although there is a certain variability in developmental trajectories, and therefore should be considered of great interest also for adulthood psychiatrists. A few studies have been carried out to explore the clinical picture and course development of these disorders during adulthood, or their relationship with other mental disorders. Indeed, ASDs often share overlapping features with other disorders, such as schizophrenia and obsessive-compulsive, mood, and personality disorders, and as a result misdiagnoses often occur. The aim of this review is to summarize the available literature on ASDs in adulthood with a specific focus on the clinical picture, course, and psychiatric comorbidity. It is proposed that a careful diagnostic screening for ASDs in adults would contribute to clarifying the relationship with comorbid psychiatric disorders, while improving the possibility of treatment and outcome of such conditions.

[Adult ADHD: clinical aspects and therapeutic implications]. / ADHD nell'adulto: aspetti clinici e implicazioni terapeutiche.

Attention Deficit Hyperactivity Disorder (ADHD) has been originally described as a disorder of childhood and adolescence. In the last years, a huge amount of evidence supports a syndromal continuity form childhood to adulthood. the identification of ADHD in adults raises several problems of differential diagnosis and the disorder is frequently associated with other mental disorders, at least in patients referred to psychiatric settings. It is not clear if adult ADHD is characterized by a specific pattern of symptoms that include attentive deficits and consequent behavioral manifestations, instead of hyperactivity. Comorbidity with other mental disorders influences clinical picture, severity, course and treatment outcome. In particular comorbid ADHD, bipolar disorder and alcohol/substance abuse disorders coexist in a relevant proportion of cases and it might represent a specific phenoptype, associated with treatment resistance. Substances use, often poly-drug abuse, such as alcohol, cocaine, stimulants and heroin, inevitably complicates course and therapeutic choice. The recognition of ADHD in adults has important implications at therapeutic level, even when present as incomplete and residual forms. Psychostimulants and other compounds with specific efficacy on ADHD symptomatology has been shown to be useful also in adults both in monotherapy and in association with other drugs, such as mood stabilizers. However their use should be cautious when a mood disorder coexists, for the possible induction of manic-switches or rapid cycling. Further research is necessary in order to better characterize the clinical picture of ADHD in adults and to elaborate widely shared treatment guidelines.

Adjunctive valproate in panic disorder patients with comorbid bipolar disorder or otherwise resistant to standard antidepressants: a 3-year "open" follow-up study.

The aim of the study was to report on the clinical utility of naturalistic adjunctive treatment with valproate (VPA) in a group of panic disorder (PD) patients with comorbid bipolar disorder (BD) or otherwise resistant to antidepressants. The hypothesis was that these patients might not respond because of coexisting low-grade mood instability and adjunctive VPA treatment might ameliorate PD symptoms. A group of 47 patients with lifetime comorbid BD (n = 35, 74.5%) or otherwise resistant to antidepressants (n = 12, 25.6%), from a population of 326 consecutive outpatients with PD-Agoraphobia evaluated and treated at the Psychiatric Institute of the University of Pisa from 1991 to 1995, and followed for a period of 3 years. All patients were evaluated at baseline and at least every 2 months by means of an intensive interview including semi-structured and structured instruments (SCID, Life-Up, and Panic Disorder/Agoraphobia Interview). Mean dosage was 687 (SD = 234) mg/day (min 400, max 1,500 mg/day). Adjunctive treatment with VPA was well tolerated by all subjects, and there was no treatment interruption because of side effects or adverse events. All antidepressants-resistant subjects and 31 of 35 (88.6%) patients with bipolar comorbidity achieved symptomatological remission. During the observation period, 7 (58.3%) among resistant subjects and 17 (48.6%) of bipolar patients had a relapse of panic disorder after remission. Survival analysis of remission durations and onset relapses for PD and Agoraphobia did not show significant differences between the two groups. Relapses of Agoraphobia were less frequent and more delayed than those for panic. According to the results, VPA seems to be an effective and a well-tolerated adjunctive treatment in PD patients who were resistant to antidepressant therapy or had BD in comorbidity. The results of the study support the hypothesis of resistance to antidepressant treatment being related to mood instability.

Predictors of Depressive Switch in Patients With Bipolar I Disorder Who Initiated or Changed Pharmacologic Treatment for Mania or Mixed-Mania: A Prospective Observational Study.

OBJECTIVE: To evaluate the prevalence and the predictors of depressive switch in patients with bipolar I disorder (BD-I) requiring the initiation or change (but not a dose change) of treatment with oral antipsychotics or mood stabilizers for mania or mixed-mania. METHODS: This was a 3-month, prospective, noninterventional study conducted in 34 Italian psychiatric centers from April 2012 to April 2013. The study sample comprised 234 patients aged 18 years or older presenting with a manic episode according to DSM-IV-TR criteria. Patients were assessed at baseline and at follow-up visits by a variety of measures, including the Clinical Global Impressions scale for use in bipolar illness (CGI-BP). The primary outcome measure was depressive switch, which was defined a posteriori on the basis of a Montgomery-Åsberg Depression Rating Scale total score ≥ 15 and a Young Mania Rating Scale total score < 10 at week 12. A stepwise backward logistic regression model was used to explore the effect of clinical variables on the occurrence of depressive switch. RESULTS: According to the definition used in this study, 26 (11.1%) of 234 patients switched to depression. The variables associated with a depressive switch were prescription of both first- and second-generation antipsychotics (P = .017), depressive-predominant polarity (P = .012), CGI-BP total score at baseline evaluation (P = .024), depressive temperament (P = .063), and age at evaluation (P = .020). CONCLUSIONS: Depressive switch was observed in about 1 of 10 of the BD-I patients. Our results suggest an association between the depressive switch and treatment with both first- and second-generation antipsychotics, depressive-predominant polarity, greater severity of the symptomatology, and older age at evaluation. Further randomized controlled studies are needed to confirm possible predictors of a depressive switch during mania.

Obsessive-compulsive Disorder with Comorbid Bipolar Disorders: Clinical Features and Treatment Implications.

BACKGROUND: Obsessive-compulsive disorder (OCD) symptoms within the context of a bipolar disorder (BD) have been described since the 19th century. Interestingly, the existence of a relevant overlap between the aforementioned psychiatric syndromes has been confirmed by a number of recent epidemiological and family studies. AIMS: The aim of the present paper is to review the clinical features and the therapeutic implications of the OCD-BD comorbidity. DISCUSSION: In the last two decades, the frequent association between OCD and BD has been earning a growing interest given its relevant nosological and therapeutic implications. Usually patients suffering from OCD-BD comorbidity show a peculiar clinical course, characterized by a larger number of concomitant depressive episodes and episodic course. In these cases, the treatment with antidepressants is more likely to elicit hypomanic or manic switches, while mood stabilizers significantly improve the overall clinical picture. Moreover, OCD-BD patients are frequently comorbid with a number of other psychiatric disorders, in particular anxiety disorders, social phobia, and different substance abuses, such as alcohol, nicotine, caffeine and sedatives. CONCLUSIONS: BD-OCD comorbidity needs further investigations in order to provide more solid evidences to give patients a more precise clinical diagnosis and a more targeted therapeutic approach.

Outcome and predictors of remission in bipolar-I patients experiencing manic episode and treated with oral antipsychotics and/or mood stabilizers: a prospective observational study in Italy.

This observational study aimed to identify internal (clinical-demographic, temperamental characteristics) and external (childhood trauma, psychosocial characteristics) factors potentially predicting remission at 12 weeks in bipolar-I patients experiencing manic episode and requiring to start or switch treatment with oral antipsychotics and/or mood stabilizers. The following scales were administered: the Young Mania Rating Scale (YMRS), the Montgomery-Asberg Depression Rating Scale (MADRS), the Functioning Assessment Short Test (FAST), and the Clinical Global Impression for Bipolar Disorders (CGI-BP). A logistic regression analysis was carried out to test the effect of the explored factors on remission rate (YMRS score ≤12), functionality, and clinical outcomes at week 12. Overall, 243 patients were enrolled and 197 (81.1%) completed the follow-up. Remission at week 12 was achieved in 200 (82.3%) patients. Marked improvements from baseline were observed in MADRS, FAST, CGI-BP mania, and bipolar illness scores. None of the factors was associated with remission, or showed strong correlations with the improvements in clinical health state. In our sample, after 12 weeks of initiation or change of oral therapy for mania in bipolar-I patients, treatment was associated with rapid improvements in symptoms and functioning in most patients. Factors predictive of remission and clinical improvements in manic symptoms were not identified.

Electroconvulsive therapy and age: Age-related clinical features and effectiveness in treatment resistant major depressive episode.

OBJECTIVE: This study was aimed to compare clinical features, treatments outcomes and tolerability between young (18-45 years), middle age (46-64 years) and old (≥ 65 years) patients treated with bilateral ECT for treatment resistant major depressive episode. METHOD: 402 patients were evaluated 1 day prior to ECT and a week after the treatment termination using the Clinical Global Impression Scale (CGI), the Hamilton Rating Scale for Depression-17 items (HAM-D-17), the Brief Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale (YMRS) and the Mini Mental State Examination (MMSE). Response was defined as a reduction of at least 50% from baseline on the HAM-D-17 score. Remission was defined as a score ≤ 7 on the HAM-D-17 at the final evaluation. RESULTS: Rates of response were not statistically different in the three groups (69.6% in old versus 63.5% in young and 55.5% in middle age groups). No significant differences were also observed in the proportions of remitters between the age groups (31.4% in young group, 27.7% in middle age group and 29.3% in old group). One week after the end of the ECT course the middle and old age groups showed a statistically significant increase in the MMSE score compared to baseline. We did not find significant differences between the three age groups in rates of premature drops-out due to ECT-related side effects. CONCLUSION: Our data support the use of ECT in elderly patients with treatment-resistant major depressive episode, with rates of response around 70% and effectiveness being independent from age. In the old age group the baseline cognitive impairment improved after ECT and no life-threatening adverse event was detected.

Diagnosis and Treatment of Cyclothymia: The "Primacy" of Temperament.

BACKGROUND: Contrary to DSM-5 definition based on recurrence of low grade hypomanic and depressive symptoms, cyclothymia is better defined in a neurodevelopmental perspective as an exaggeration of cyclothymic temperament. Emotional dysregulation with extreme mood instability and reactivity is the core features of the complex symptomatology. METHOD: In the present article, we critically reviewed the literature on the diagnosis and treatment of cyclothymia, focusing on the temperamental and neurodevelopmental perspectives. RESULTS: Current epidemiological and clinical research showed the high prevalence and the validity of cyclothymia as a distinct form of bipolarity, frequently associated with multiple comorbidities with anxiety, impulse control, substance use, and so called "personality" disorders. Many patients receive correct diagnosis and treatments after many years of illness, when the superposition of complications reduces the possibility of complete remission. A therapeutic model combining the focus on symptomatic presentations with a temperamental perspective seems to represent an effective approach for cyclothymic patients with complex clinical presentations. CONCLUSION: Cyclothymic mood instability is an understudied issue despite the evidence of its clinical relevance. Unresolved issues concern its diagnostic delimitation and the possible relationships with emotional dysregulation observed in other neurodevelopmental disorders. We need to confirm the specificity of the disorder and to improve its recognition in early phase of the life, especially in youth. Early recognition means avoiding unnecessary complications and establishing specific treatments and clinical management since the beginning.

The use of stimulants and atomoxetine in adults with comorbid ADHD and bipolar disorder.

INTRODUCTION: Attention deficit/hyperactivity disorder (ADHD) persists into adulthood in about 50% of the affected children, with high rates of comorbidity with bipolar disorder (BD). Stimulants and atomoxetine (ATX) are effective treatments for ADHD, but their use in adults with comorbid BD (ADHD-BD) has not been extensively studied and may be problematic. AREAS COVERED: The aim of the paper is to summarize the available literature regarding the use of these medications in ADHD-BD adult patients. Results of randomized-controlled and open-label trials, case reports, and case series are reviewed. We also reviewed data relative to some specific issues of this comorbidity in adults, especially substance use disorder, malingering, and stimulants misuse. EXPERT OPINION: ADHD-BD may be associated with more severe symptoms, course, and worst outcome of both conditions. The frequent coexistence with alcohol and substance abuse may further complicate treatment management. Stimulants are the most effective medications for ADHD, but their use may be contraindicated in the presence of a comorbid drug abuse or in patients that simulate or exaggerate ADHD symptoms in order to obtain stimulants for diversion or abuse. ATX may be effective in the treatment of ADHD symptoms in BD patients, with a modestly increased risk of (hypo)manic switches and destabilization of the mood disorder when utilized in association with mood stabilizers. In the majority of the cases, a hierarchical approach is desirable, with mood stabilization preceding the treatment of ADHD symptoms. Although systematic trials on the use of stimulants and ATX in ADHD-BD comorbidity in adulthood are necessary, both treatments should be considered possible options to be carefully evaluated once the patient has been stabilized.

Cyclothymia reloaded: A reappraisal of the most misconceived affective disorder.

Data emerging from both academic centers and from public and private outpatient facilities indicate that from 20% to 50% of all subjects that seek help for mood, anxiety, impulsive and addictive disorders turn out, after careful screening, to be affected by cyclothymia. The proportion of patients who can be classified as cyclothymic rises significantly if the diagnostic rules proposed by the DSM-5 are reconsidered and a broader approach is adopted. Unlike the DSM-5 definition based on the recurrence of low-grade hypomanic and depressive symptoms, cyclothymia is best identified as an exaggeration of cyclothymic temperament (basic mood and emotional instability) with early onset and extreme mood reactivity linked with interpersonal and separation sensitivity, frequent mixed features during depressive states, the dark side of hypomanic symptoms, multiple comorbidities, and a high risk of impulsive and suicidal behavior. Epidemiological and clinical research have shown the high prevalence of cyclothymia and the validity of the concept that it should be seen as a distinct form of bipolarity, not simply as a softer form. Misdiagnosis and consequent mistreatment are associated with a high risk of transforming cyclothymia into severe complex borderline-like bipolarity, especially with chronic and repetitive exposure to antidepressants and sedatives. The early detection and treatment of cyclothymia can guarantee a significant change in the long-term prognosis, when appropriate mood-stabilizing pharmacotherapy and specific psychological approaches and psychoeducation are adopted. The authors present and discuss clinical research in the field and their own expertise in the understanding and medical management of cyclothymia and its complex comorbidities.

Does obesity predict bipolarity in major depressive patients?

BACKGROUND: Differential association of obesity in bipolar and unipolar Major Depressive Episode (MDE) has not been systematically studied. We explore the relationships between obesity and history of manic and hypomanic symptoms in a large national clinical sample of MDE patients. METHOD: The sample comprised 571 consecutive patients with a DSM-IV diagnosis of MDE enrolled in a 7 months period. The study involved 30 psychiatric facilities for outpatients, distributed throughout Italy. Diagnosis was formulated by psychiatrists with extensive clinical experience in the diagnosis and treatment of mood disorders. In all patients height (meters) and weight (kilograms) were systematically measured at the moment of the clinical evaluation. The severity of depressive and anxious symptomatology was self-evaluated by the means of Zung's questionnaires for depression and anxiety. For the evaluation of lifetime manic or hypomanic features, Hypomania Check List-32 was also administered. Obese and Non-Obese subgroups were identified on the basis of a >30 BMI cut off point. RESULTS: BMI ≤30 was observed in 86 (15.1%) of our MDE patients. The Obese and Non-Obese subgroups did not report differences as regards to age and gender distribution. Obese patients reported a lower number of years of education in comparison with Non-Obese patients. As regards to marital status, Obese patients were more frequently married in comparison with the Non-Obese patients. Obese patients were more frequently belonging to the bipolar group than Non-Obese patients. Obese subjects also reported more frequently than Non-Obese an HCL total score >14. The effect of educational level, marital status and bipolar-unipolar distinction on the probability of Obese group membership was analyzed by stepwise logistic regression. Bipolar subtype resulted to be the strongest predictor of Obesity. LIMITATIONS: Pharmacological treatments and co-morbidity with other psychiatric disorders are not explored and accounted for in our analyses. CONCLUSIONS: Obesity in our national sample of patients with MDE is associated with bipolar subtype and (hypo)manic symptoms. These findings suggest the possibility that the presence of obesity in patients with MDE might be related to bipolarity. A common impulsive-addictive diathesis is proposed as mediating mechanism. Further longitudinal studies in clinical and non-clinical populations are necessary to better define the burden and the role of the association between obesity and bipolarity.

Lifetime autism spectrum features in a patient with a psychotic mixed episode who attempted suicide.

We present a case report of a young man who attempted suicide during a mixed episode with psychotic symptoms. The patient's history revealed the lifetime presence of signs and features belonging to the autism spectrum realm that had been completely overlooked. We believe that this case is representative of an important and barely researched topic: what happens to children with nondiagnosed and nontreated subthreshold forms of autism when they grow old. The issue of early recognition of autism spectrum signs and symptoms is discussed, raising questions on the diagnostic boundaries between autism and childhood onset psychotic spectrums among patients who subsequently develop a full-blown psychotic disorder.

Bipolar disorder in adults with Asperger׳s Syndrome: a systematic review.

BACKGROUND: Asperger׳s Syndrome (AS) is a neurodevelopmental disorder included in the Autism Spectrum (ASD). The current literature shows growing evidence of a high rate of comorbidity between AS and other psychiatric disorders, particularly Bipolar Disorder (BD). We reviewed available epidemiological and clinical data on BD-AS comorbidity and its diagnostic and therapeutic implications METHODS: A systematic review of the literature was conducted through PubMed, Scopus and Psych-Info using combinations of the following search terms: Asperger׳s Syndrome, Bipolar Disorder, depression, mood disorder, psychiatric comorbidity, treatment, mood stabilizers, anticonvulsants, antipsychotics, and antidepressants. RESULTS: BD prevalence in adults with AS ranges from 6% to 21.4% of the cases. Relatives of patients with AS showed a doubled risk of being affected by BD and a BD prevalence near to 10%. When comorbid with AS, BD assumes peculiar features which might shape its under-recognition or misdiagnosis (especially schizophrenia when psychotic symptoms are prominent). Although controlled data on pharmacological treatments in BD-AS comorbidity are substantially lacking, information is derived by open observations, case series and chart reviews. Mood stabilizers should be considered the first choice, and antipsychotics, especially second generation drugs (SGA) with 5-HT2a antagonism, have been shown useful in controlling psychotic and behavioral symptoms and improving social withdrawal. Some evidence of efficacy for the treatment of anxiety, obsessive-compulsive symptoms and depression is reported for SSRI antidepressants. The use of these drugs should be carefully monitored, because activation with hypomanic or manic switches is reported up to 54% of the treated subjects. CONCLUSION: BD in AS patients is frequent, usually it onsets during adolescence and is often characterized by atypical presentation, making its correct identification particularly difficult. A correct diagnosis of BD in AS individuals has relevant implications on the choice of adequate psychopharmacological, psycho-social and rehabilitative treatments.