Current Psychiatry Reviews - Volume 9, Issue 1, 2013

The threshold chosen by categorical mental health classifications like DSM-IV-TR or ICD-10 for the diagnosis of bipolar disorders (BP) is too high, elevating the risk of misdiagnosing cases that closely resemble BP under several clinical variables like “major depressive disorder”. Acknowledging and providing the necessary weight to the BP subthreshold forms may improve the clinical practice and reduce the number of patients with misdiagnosis, creating opportunities for better treatment. Increasing evidence support the bipolar spectrum disorder (BPS) concept and factors such us earlier onset age of the first major depressive episode (MDE), brief duration of MDEs, rapid onset of MDEs, more than five previous MDEs, family history of BP, treatment-resistant depression, suicidal behavior, postpartum depression, atypical features, psychotic traits, irritability, overactivity, comorbidity with anxiety disorders, substance abuse, borderline personality disorder, migraine, and irritable temperament are well validated differentiators between unipolar and bipolar depressive disorders. Identifying those factors could increase the lifetime prevalence of BPS to at least 4.8%. New studies on the diagnosis and management of BP should focus on the development of diagnostics dimensional models with categorical benchmarks to recognize BP sub-threshold forms, on the selection of biomarkers for early identification of patients with BPS, especially those with BP family history, and on the promotion of joint efforts between academia, industry, government, and community to search new interventions in BPS management.

Temperaments are permanent variations of personality, traits and ways of reacting that characterize individuals and remain constant throughout several diverse situations. Temperaments play a crucial role in determining emotional reactions, therefore several temperamental models attempted to establish relationship between temperaments and affective disorders. According to the model of Akiskal, affective temperaments are subclinical and subaffective trait-like manifestations of affective disorders. Unlike several models of temperament which were developed theoretically in order to describe healthy human functioning, and were later extrapolated to also capture the pathological domains of mental and behavioral features, the model of affective temperaments was developed on Kraepelinian and Kretschmerian traditions and based on the observation of patients with mood disorders and their healthy first degree relatives and from that point broadened to encompass also the subclinical and nonclinical domains of affective reactivity. There is accumulating evidence concerning the development of affective temperaments based on their adaptive evolutionary characteristics and genetic background, and normative data from large national studies on general and healthy samples indicate their universal characteristics. Studies in affective patient populations indicate that the relationship between affective temperaments and affective illness is more complex than a simple extrapolation from psychopathology and mental health, and affective temperaments may play a patoplastic role in mood disorders determining their evolution, clinical features, main characteristics and outcome. A large body of data on affective temperaments has been published during the last decade, deserving a critical analysis presented in this review.

At present, the classification of mental disorders is tightly rooted in categories despite the fact that a dimensional approach may present some clear advantages. In this review, we compare two dimensional approaches that have been put forward in bipolar disorder. On one hand, the “soft” bipolar spectrum focused on the presentation of affective symptomatology and on the other, the staging model based on the progression of the disorders and impairment in functioning in more severe cases. At a first glance, these concepts may sound as difficult to integrate. However, we hypothesize that a common underlying foundation based on the concept of allostatic load may help to integrate the crossectional phenomenology of the soft spectrum and the progressive neuropsychological and functioning impairment which is experienced by many bipolar patients.

Although No-Type I Bipolar spectrum disorders (NBP-I) are common, recurrent, and disabling, they are underdiagnosed and misdiagnosed in clinical practice. Several data show that NBP-I (especially BP type II) are a significant public health problem, and there is a dearth of studies of effective treatment modalities for the control of acute symptoms and the prevention of mood recurrences (mainly major depressive episodes). Considering the growing need to find effective therapies for patients with NBP-I, this review is based on a systematic search of evidence about the efficacy of treatments for each phase of the NBP-I. Fifty-seven studies were identified and reviewed. Most studies investigating the pharmacotherapy of NBP-I were methodologically limited, having observational or retrospective designs and small samples. Regarding short-term treatment, there is some limited support for the use of risperidone, valproate, and quetiapine in hypomania, and for valproate, quetiapine, fluoxetine, and venlafaxine in treating depression. For long-term treatment, the only preventive therapy for both depression and hypomania that is supported by several controlled studies is quetiapine. Lithium and fluoxetine have shown efficacy in delaying depressive recurrences. Although the adequate treatment for these patients remains to be determined, mood stabilizers and some forms of psychotherapy may be useful for these patients. We conclude that there is a paucity of sound evidence to guide clinicians in treating NBP-I patients. Although progress has been made, more quality research is needed to delineate effective treatment strategies.

Fragile X Syndrome (FXS), the most common inherited cause of intellectual disabilities, is an X-linked dominant disorder caused by the amplification of a CGG repeat in the 5' untranslated region of the fragile X mental retardation gene 1 (FMR1). Prevalence estimates of the disorder are approximately 1/3600. Psychiatric manifestations of the disorder include anxiety, attention deficit hyperactivity disorder, autism, mood instability and aggression. In this article we review the above psychiatric manifestations and challenges to accurate assessment. We also discuss how the neurobiological underpinnings of these symptoms are beginning to be understood and can help guide treatment.

Carriers of the FMR1 premutation (with 55-200 CGG repeats) may present with multiple medical and psychiatric disorders. Middle-aged carriers (males more often than females) may suffer from fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is a newly discovered neurodegenerative disease characterized by intention tremor and ataxia, along with several other neurological features. Psychiatric manifestations are common in premutation carriers of both genders and include attention deficits, anxiety, depression, irritability, impulse dyscontrol, and substance abuse or dependence. Major depressive disorder, panic disorder with or without agoraphobia, generalized anxiety disorder, social phobia, and specific phobia are among the psychiatric diagnoses often encountered in premutation carriers, including those with FXTAS. Later in the course of the illness, cognitive deficits (including dementia) may occur. In this paper, we discuss common psychiatric phenotypes in FXTAS, based on a thorough review of the literature, as well as our own research experience. Symptomatic pharmacologic treatments are available, although disease modifying agents have not yet been developed.

Objective: FMR1 premutation carriers of both genders have a high lifetime prevalence of anxiety and depressive disorders, however little is known regarding the onset ages of these conditions. This study compared onset ages of mood and anxiety disorders in premutation carriers with typical onset ages of the same disorders in the general population. Methods: Eighty-one premutation carriers (42% men; average age 62, SD 10) with and without FXTAS completed the Structured Clinical Interview for DSM-IV-TR. Onset ages of mood and anxiety disorders were compared to the corresponding typical population onset ages using the signed rank test. Results: Overall median onset ages of MDD (46 years old, p < 0.0001), panic disorder (40 years old, p = 0.0067), and specific phobia (11.5 years old, p = 0.0003) were significantly higher in premutation carriers compared to the general population. Median MDD onset ages in male carriers (52 years old) and those with FXTAS (49.5 years old) were significantly higher relative to the general population (median 32, both p < 0.0001). Tremor and ataxia emerged significantly later than MDD and the anxiety disorders studied. Conclusion: Depressive and anxiety disorders in premutation carriers have a later onset compared to the general population, but precede the onset of motor symptoms. This may be due to progressive mRNA toxicity in the limbic system, white matter changes leading to neuronal dysconnectivity, and interaction with environmental factors. Psychosocial factors may be protective. Further research is needed to understand the full spectrum of psychiatric phenotypes in FMR1 premutation carriers.

Background: Psychiatric disorders in women with the FMR1 premutation are common and include attention deficit hyperactivity disorder, anxiety, depression, and eating disorders. This pilot study explored the risk factors for postpartum depression (PPD) in women with the premutation. Methods: We conducted a chart review of 50 women premutation carriers with major depressive disorder who had children. Of these, 7 women had a history of major depressive episodes in the postpartum period. The PPD and non-PPD groups were characterized descriptively based on women’s age at the time of the psychiatric evaluation, race, ethnicity, education level, IQ, CGG repeat size, comorbid psychiatric conditions, parity, and number of children with fragile X syndrome (FXS). Exact logistic regression was used to analyze the relationship between the number of children with FXS and the risk of PPD. Results: The PPD and non-PPD groups were similar on all variables examined, with the exception of the number of affected children. Each of the 7 women with PPD had at least one child with FXS, whereas a third of the women without PPD had no affected children. For each additional affected child, the risk of PPD increased by 158% (exact odds ratio 2.58, 95% CI 0.99-7.59). Further studies are needed to replicate these findings and to better characterize PPD in female premutation carriers.

Premutation carriers of the fragile X mental retardation gene (especially men) older than 50 may develop a neurodegenerative disease, the fragile X-associated tremor/ataxia syndrome (FXTAS). Carriers may present with varied cognitive impairments. Attention, working memory, declarative and procedural learning, information processing speed, and recall are among the cognitive domains affected. Executive dysfunction is a prominent deficit, which has been demonstrated mostly in men with FXTAS. In more advanced stages of FXTAS, both men and women may develop a mixed cortical-subcortical dementia, manifested by psychomotor slowing and deficits in attention, retrieval, recall, visuospatial skills, occasional apraxia, as well as overt personality changes. Studies have shown dementia rates as high as 37-42% in older men with FXTAS, although more research is needed to understand the prevalence and risk factors of dementia in women with FXTAS. Neuropsychiatric symptoms are common and reflect the dysfunction of underlying frontal-subcortical neural circuits, along with components of the cerebellar cognitive affective syndrome. These include labile or depressed mood, anxiety, disinhibition, impulsivity, and (rarely) psychotic symptoms. In this paper we review the information available to date regarding the prevalence and clinical picture of FXTAS dementia. Differential diagnosis may be difficult, given overlapping motor and non-motor signs with several other neurodegenerative diseases. Anecdotal response to cholinesterase inhibitors and memantine has been reported, while symptomatic treatments can address the neuropsychiatric manifestations of FXTAS dementia.

Complex caregiving issues occur in multigenerational families carrying the fragile X mutation and premutation. The same family members may care for children or siblings with fragile X syndrome (FXS) and for elderly parents with fragile X-associated tremor/ataxia syndrome (FXTAS). Family caregivers experience anxiety, depression, neglect of personal health care needs, employment difficulties, and loss of social support, leading to isolation and further psychiatric consequences. There is growing awareness of caregiver burden with regard to parents of children with FXS, but much less is known about the needs of informal caregivers of patients with FXTAS. In this paper, we review the available literature to date and provide suggestions for further exploration of caregivers' needs. Evidence-based strategies to address these needs are included. Many more research studies exploring caregiver burden in multigenerational fragile X families are needed, as well as studies aimed at investigating interventions and their impact on burden reduction.