Andrea Fagiolini

Medication effects in neuroimaging studies of bipolar disorder

OBJECTIVE Neuroimaging studies are promising components for a new diagnostic framework for bipolar disorder, but a major issue is the potential confound of psychotropic medication upon experimental measures. Withdrawing all individuals from medication and examining only unmedicated individuals may be clinically unfeasible, and examining only unmedicated individuals may render findings less generalizable. METHOD The authors review structural and functional neuroimaging studies of medicated and unmedicated patients with bipolar disorder to discern the possible confounding effect of medication. RESULTS Findings from studies identified on MEDLINE that included medicated individuals with bipolar disorder indicated either no significant effect or ameliorative effects of psychotropic medications on abnormal structural and functional neuroimaging measures relevant to pathophysiologic mechanisms of the disorder. Different strategies for assessing medication effects are compared. CONCLUSIONS Neuroimaging studies of bipolar disorder ideally should recruit both unmedicated and medicated individuals. Individuals who are unable to tolerate medication withdrawal likely have more severe illness and are especially informative for research examining biomarkers of illness and treatment response.

Cardiovascular disease and hypertension among adults with bipolar I disorder in the United States

OBJECTIVE Despite ample evidence of excess cardiovascular mortality in bipolar disorder (BD), few studies have demonstrated increased prevalence of cardiovascular disease (CVD) and/or hypertension (HTN) in BD. We therefore examined this topic in a representative epidemiologic sample. METHOD The 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions was used to determine whether prevalence of physician-diagnosed CVD and HTN is elevated among subjects with lifetime bipolar I disorder (BD-I), and whether CVD and HTN are prevalent at earlier ages among subjects with BD-I. RESULTS The age-, race-, and sex-adjusted prevalence of CVD was significantly greater among subjects with BD-I versus controls [odds ratio (OR) = 4.95, 95% confidence interval (CI): 4.27-5.75] and versus subjects with major depressive disorder [(MDD); OR =1.80, 95% CI: 1.52-2.14], as was the prevalence of HTN (OR = 2.38, 95% CI: 2.16-2.62 versus controls, OR = 1.44, 95% CI: 1.30-1.61 versus MDD; p < 0.0001 for all). Controlling additionally for marital status, education, income, obesity, smoking, anxiety disorders, and substance use disorders did not substantially alter these findings. The mean age of BD-I subjects with CVD and HTN was 14 and 13 years younger, respectively, than controls with CVD and HTN. CONCLUSIONS Adults with BD-I are at increased risk of CVD and HTN, prevalent over a decade earlier than non-BD adults. Strategies are needed to prevent excessive and premature cardiovascular burden in BD-I.

Schizoaffective disorder: diagnostic issues and future recommendations

OBJECTIVE Difficulties surrounding the classification of mixed psychotic and affective syndromes continue to plague psychiatric nosology. This paper addresses the controversy regarding the diagnostic validity of schizoaffective disorder (SAD), a diagnosis that is used in both DSM-IV and ICD-10 and one that encroaches on both schizophrenia (SCZ) and bipolar disorder (BD). METHODS A systematic synthesis of clinical and empirical literature, including evidence from cognitive, neurobiological, genetic, and epidemiological research, was undertaken with the aim of evaluating the utility of the SAD classification. RESULTS Distinctions between the diagnostic categories of SCZ, SAD and BD are not clearly demarcated by findings from neuropsychological, neuroimaging, molecular neurobiology, or genetic epidemiology studies. On the contrary, convergent evidence purports overlap across current diagnostic boundaries in the heritability and pathophysiology of psychotic and affective disorders. However, there are some disorder-specific findings. CONCLUSIONS Schizoaffective disorder is a prototypic boundary condition that epitomizes the pitfalls of the current categorical classification system. Future revisions to the DSM should consider the implementation of one of two alternative models to account for individuals presenting with mixed psychotic and affective symptoms. These include the views that (i) SAD is a comorbid set of symptoms that occur as a by-product of two separate disorders (SCZ and BD) or, that (ii) SAD exists as the mid-point on a continuum between SCZ and BD, such that the incorporation of these two disorders onto one dimension may be a suitable alternative. Hence the category SAD should be omitted in future revisions of DSM, allowing the development of meaningful nomenclature that rests upon further rigorous investigation of differences and similarities between disorders.

The Effects of Undertreated Chronic Medical Illnesses in Patients With Severe Mental Disorders

Severe mental disorders such as bipolar disorder and schizophrenia often co-occur with chronic medical illnesses, especially cardiovascular disease and diabetes. These comorbidities are associated with a more severe course of mental illness, reduced quality of life, and premature mortality. Although the association between mental disorders and physical health complications has long been recognized, medical conditions remain undertreated in clinical psychiatric practice, and the life expectancy for individuals with serious psychiatric disorders is approximately 30% shorter than that of the general US population. Factors that are related to the mental illness (eg, cognitive impairment, reduced ability to function, and a lack of communication skills) as well as factors such as the high cost of medical care may make accessing general health care a difficult task for patients. Even when medical care is received by patients, the quality is often poor, and dangerous illnesses may be undiagnosed and untreated. In addition, harmful side effects of medications used to treat psychiatric disorders, unhealthy habits and lifestyles, and a possible genetic susceptibility to medical conditions increase the likelihood of comorbid physical conditions in patients with severe mental illness. Implementing behavioral interventions into clinical practice may help patients improve their overall health and prevent chronic medical conditions.

The Role of Interpersonal and Social Rhythm Therapy in Improving Occupational Functioning in Patients With Bipolar I Disorder

OBJECTIVE Recent studies demonstrate the poor psychosocial outcomes associated with bipolar disorder. Occupational functioning, a key indicator of psychosocial disability, is often severely affected by the disorder. The authors describe the effect of acute treatment with interpersonal and social rhythm therapy on occupational functioning over a period of approximately 2.5 years. METHOD Patients with bipolar I disorder were randomly assigned to receive either acute and maintenance interpersonal and social rhythm therapy, acute and maintenance intensive clinical management, acute interpersonal and social rhythm therapy and maintenance intensive clinical management, or acute intensive clinical management and maintenance interpersonal and social rhythm therapy, all with appropriate pharmacotherapy. Occupational functioning was measured with the UCLA Social Attainment Scale at baseline, at the end of acute treatment, and after 1 and 2 years of maintenance treatment. RESULTS The main effect of treatment did not reach conventional levels of statistical significance; however, the authors observed a significant time by initial treatment interaction. Participants initially assigned to interpersonal and social rhythm therapy showed more rapid improvement in occupational functioning than those initially assigned to intensive clinical management, primarily accounted for by greater improvement in occupational functioning during the acute treatment phase. At the end of 2 years of maintenance treatment, there were no differences between the treatment groups. A gender effect was also observed, with women who initially received interpersonal and social rhythm therapy showing more marked and rapid improvement. There was no effect of maintenance treatment assignment on occupational functioning outcomes. CONCLUSIONS In this study, interpersonal and social rhythm therapy, with its emphasis on amelioration of interpersonal and role functioning, improved occupational functioning significantly more rapidly than did a psychoeducational and supportive approach with no such emphasis on functional capacities.

The influence of illness-related variables, personal resources and context-related factors on real-life functioning of people with schizophrenia.

In people suffering from schizophrenia, major areas of everyday life are impaired, including independent living, productive activities and social relationships. Enhanced understanding of factors that hinder real‐life functioning is vital for treatments to translate into more positive outcomes. The goal of the present study was to identify predictors of real‐life functioning in people with schizophrenia, and to assess their relative contribution. Based on previous literature and clinical experience, several factors were selected and grouped into three categories: illness‐related variables, personal resources and context‐related factors. Some of these variables were never investigated before in relationship with real‐life functioning. In 921 patients with schizophrenia living in the community, we found that variables relevant to the disease, personal resources and social context explain 53.8% of real‐life functioning variance in a structural equation model. Neurocognition exhibited the strongest, though indirect, association with real‐life functioning. Positive symptoms and disorganization, as well as avolition, proved to have significant direct and indirect effects, while depression had no significant association and poor emotional expression was only indirectly and weakly related to real‐life functioning. Availability of a disability pension and access to social and family incentives also showed a significant direct association with functioning. Social cognition, functional capacity, resilience, internalized stigma and engagement with mental health services served as mediators. The observed complex associations among investigated predictors, mediators and real‐life functioning strongly suggest that integrated and personalized programs should be provided as standard treatment to people with schizophrenia.

Bipolar disorder and the metabolic syndrome: causal factors, psychiatric outcomes and economic burden.

Overweight and obesity are highly prevalent in patients with bipolar disorder, and metabolic disorders also affect a significant portion of this population. Obesity and metabolic disorders cause significant economic burden and impair quality of life in both the general population and patients with bipolar disorder. This review examines the relationship between bipolar disorder and the metabolic syndrome, and the associated economic impact.The metabolic syndrome and bipolar disorder appear to share common risk factors, including endocrine disturbances, dysregulation of the sympathetic nervous system, and behaviour patterns, such as physical inactivity and overeating. In addition, many of the commonly used pharmacological treatments for bipolar disorder may intensify the medical burden in bipolar patients by causing weight gain and metabolic disturbances, including alterations in lipid and glucose metabolism, which can result in an increased risk for diabetes mellitus, hypertension, dyslipidaemia, cardiovascular disease and the metabolic syndrome. These medical co-morbidities and obesity have been associated with a worse disease course and likely contribute to the premature mortality observed in bipolar patients. Weight gain is also a major cause of treatment noncompliance, increased use of outpatient and inpatient services and, consequently, higher healthcare costs. Prevention of weight gain and metabolic disturbances or early intervention when these are present in bipolar disorder could result in significant health and economic benefits.

Is treatment-resistant depression a unique subtype of depression?

Treatment-resistant depression (TRD) continues to represent a major challenge for treating clinicians. This report reviews the relevant literature to evaluate whether TRD can be considered a specific subtype of depression based on 1) clinical characteristics and course (behavioral phenotype), 2) neurobiological profile, and 3) context and environment in which TRD develops. Although patients with TRD share a number of clinical, neurobiological, and context and environment characteristics, the lack of available data and the clinical heterogeneity of this condition do not currently permit the classification of TRD as a unique subtype of depression; however, this topic is worthy of further evaluation and research. Performing genetics and neuroimaging studies on patients enrolled in large, prospective and controlled studies may provide enough data for classifying TRD (or at least a part of what is currently described as TRD) as a specific subtype of depression. This in turn may facilitate the identification of more effective treatment strategies.

Predictors and moderators of time to remission of major depression with interpersonal psychotherapy and SSRI pharmacotherapy.

BACKGROUND Although many studies suggest that, on average, depression-specific psychotherapy and antidepressant pharmacotherapy are efficacious, we know relatively little about which patients are more likely to respond to one versus the other. We sought to determine whether measures of spectrum psychopathology are useful in deciding which patients with unipolar depression should receive pharmacotherapy versus depression-specific psychotherapy. METHOD A total of 318 adult out-patients with major depression were randomly assigned to escitalopram pharmacotherapy or interpersonal psychotherapy (IPT) at academic medical centers at Pittsburgh, Pennsylvania and Pisa, Italy. Our main focus was on predictors and moderators of time to remission on monotherapy at 12 weeks. RESULTS Participants with higher scores on the need for medical reassurance factor of the Panic-Agoraphobic Spectrum Self-Report (PAS-SR) had more rapid remission with IPT and those with lower scores on the psychomotor activation factor of the Mood Spectrum Self-Report (MOODS-SR) experienced more rapid remission with selective serotonin reuptake inhibitor (SSRI) pharmacotherapy. Non-specific predictors of longer time to remission with monotherapy included several panic spectrum and mood spectrum factors and the Social Phobia Spectrum (SHY) total score. Higher baseline scores on the 17- and 25-item Hamilton Depression Rating Scales (HAMD-17 and HAMD-25) and the Work and Social Adjustment Scale (WSAS) also predicted a longer time to remission, whereas being married predicted a shorter time to remission. CONCLUSIONS This exploratory study identified several non-specific predictors but few moderators of psychotherapy versus pharmacotherapy outcome. It offers useful indicators of the characteristics of patients that are generally difficult to treat, but only limited guidance as to who benefits from IPT versus SSRI pharmacotherapy.

Prevalence, chronicity, burden and borders of bipolar disorder

Bipolar disorder (BD) has traditionally been thought of as an episodic condition, characterized by periods of hypomania/mania and depression. However, evidence is accumulating to suggest that this condition is associated with significant chronicity. For a large proportion of patients with BD, residual, sub-syndromal symptoms persist between major syndromal episodes, and studies have shown that many patients with bipolar disorder are symptomatic for approximately 50% of the time over follow-up periods of greater than 10 years. Moreover, while the prevalence of BD has been estimated to be around 1-2%, there is growing evidence that this may be a substantial underestimation. There are a number of reasons for this potential underestimation, including difficulties in diagnosis. Adding to the burden of BD is the issue of comorbidity, with an increased prevalence of many chronic conditions in those with a primary diagnosis of BD. Conversely, for many patients with chronic conditions, both medical and psychiatric, BD frequently exists as a comorbid secondary diagnosis. This issue of comorbidity complicates estimates of use of pharmaceutical agents for BD, such as mood stabilizers, which are known to be used off-label in conditions such as borderline personality or substance use disorder. We speculate that such off-label prescribing may not be truly off-label but may be instead fully justified by an overlooked secondary diagnosis of BD. Finally, we discuss the association of bipolar disorder with a significant economic burden, to the individual and to society, both due to the direct costs of medical expenditure and indirect costs such as loss of productivity and increased mortality.