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Mood disorders in intellectual disability.

PURPOSE OF REVIEW: This article examines reviews and research on the diagnosis and treatment of mood disorders in people with intellectual disability published from September 2004 to December 2005. RECENT FINDINGS: Patients with intellectual disability have limitations in verbal ability, and with increasing levels of disability may have an atypical clinical presentation. Thus, methods to diagnose mood disorders were a major research focus. Informant-rating scales and two self-report instruments provided data on thought patterns, aberrant behavior, appetite, and suicidality. Behavioral symptoms such as aggression were frequently associated with mood disorders. Pharmacotherapy and electroconvulsive therapy were found to be effective treatments. Mood disorders were frequently identified in people with intellectual disability, although suicide was still quite rare. SUMMARY: Patients with milder levels of disability can use self-report measures and can be diagnosed using standard criteria with little modification. For those with more severe disability, diagnosis is challenging and often requires the use of residual categories. Atypical clinical presentation, including maladaptive behaviors, lent support for 'behavioral equivalent' substitutes of standard criteria. Typical pharmacological agents were effective for depression and electroconvulsive therapy for treatment-resistant bipolar disorder.

Aggression↗

Decreased levels of whole blood glial cell line-derived neurotrophic factor (GDNF) in remitted patients with mood disorders.

Recent post-mortem and imaging studies provide evidence for a glial reduction in different brain areas in mood disorders. This study was aimed to test whether glial cell line-derived neurotrophic factor (GDNF), a member of transforming growth factor (TGF)-beta superfamily, in blood levels was associated with mood disorders. We measured GDNF and TGF-beta levels in whole blood in remitted patients with mood disorders [n=56; major depressive disorders (MDD) 39, bipolar disorders (BD) 17] and control subjects (n=56). GDNF and TGF-beta were assayed with the sandwich ELISA method. Total GDNF levels were significantly lower in MDD and in BD than in control subjects (MDD, p=0.0003; BD, p=0.018), while no significant difference in total TGF-beta1 or total TGF-beta2 levels was found in these groups. Our study suggests that lower GDNF levels might be involved in the pathophysiology of mood disorders, although this preliminary study has several limitations.

Adult↗

Organic mood disorder: a valid psychiatry consultation diagnosis?

To determine the validity of the DSM-IIIR category organic mood disorder, we compared 50 psychiatric consultations with this diagnosis to 50 psychiatric consultations diagnosed with major depression in the medically ill. Organic mood disorder patients were more likely to be in the index affective disorder episode and have a negative family history of depression. Despite similar pharmacologic treatment between groups, the organic mood disorder group was less likely to be completely recovered at 4 years follow-up. This study suggests organic mood disorder is a valid diagnosis in the psychiatry consultation service.

Adult↗

Mood disorders: diagnosis, treatment, and support from a patient perspective.

The National Depressive and Manic-Depressive Association (National DMDA) is the largest patient-directed, illness-specific organization in the United States, representing the millions of people living with mood disorders. Recent National DMDA surveys have shown that people with mood disorders often have incorrect information about their illnesses, that misdiagnoses are frequent, that a significant physician/patient communication gap exists, and that noncompliance is widespread. For optimal recovery to occur, it is important that individuals receive correct information about their symptoms and treatments, that physicians and other healthcare providers understand mood disorders from a patient perspective, and that doctors and patients communicate fully throughout the course of treatment about symptoms, side effects, and other concerns. National DMDA plays an important role in the management of mood disorders by urging those who are undiagnosed or untreated to seek treatment; by providing accurate, easy-to-understand information; and by facilitating support groups in which patients and their families can discuss treatment and management of their illnesses. The organization encourages patients to play active roles in their treatment plans and to attend support groups, which have been shown to increase patient compliance and decrease the incidence of psychiatric hospitalization. According to the US Surgeon General, stigma is the number one barrier to mental health care, and National DMDA's evidence supports this. National DMDA works to combat stigma with education, advocacy, and patient self-help. Increased awareness and openness about mood disorders can lead to increased acceptance, which, in turn, can lead to more timely diagnosis and treatment.

Humans↗

Rapid cycling mood disorder in the elderly.

Rapid cycling mood disorder is an unusual and difficult syndrome to recognize in the elderly. A case of this disorder is presented in a patient with subtle central nervous system dysfunction who was treated for depression with tricyclic antidepressants. CNS dysfunction and antidepressants have both been identified as risk factors for rapid cycling. Successful treatment with carbamazepine lends credence to the concept of limbic system dysregulation being an underlying, important factor in cyclical affective disorder.

Aged↗

Mood Disorders in Neurologic Illness.

Patients with neurologic illness frequently develop secondary mood disorders that are broadly categorized as unipolar or bipolar. Accurate diagnosis is essential because the treatment of unipolar disorders is markedly different from that of bipolar disorders. Aggressive treatment of mood disorders improves quality of life, reduces morbidity and mortality, and may prevent worsening of both psychiatric and neurologic disease. Antidepressants and psychotherapy are both effective for patients suffering from depressive disorders. Choice of antidepressant depends on the patient's particular symptom complex; medication side effects, which may exacerbate the underlying neurologic condition; potential interactions with other drugs; and costs. Bipolar disorder associated with neurologic illness typically requires treatment with mood stabilizers such as lithium, divalproex sodium, carbamazepine, or verapamil. Although psychotherapy in combination with pharmacologic therapy improves the outcome in bipolar illness, psychotherapy alone is not effective for this condition. Electroconvulsive therapy is an effective treatment for both depression and mania. It may have particular usefulness in Parkinson's disease, for which it has been shown to improve the movement disorder itself. Treatment of bipolar disorder, psychotic depression, or refractory depression is complicated and should be referred to a psychiatrist.

Journal Article↗

Beyond monoamines: glutamatergic function in mood disorders.

The monoamine theory has implicated abnormalities in serotonin and norepinephrine in the pathophysiology of major depression and bipolar illness and contributed greatly to our understanding of mood disorders and their treatment. Nevertheless, some limitations of this model still exist that require researchers and clinicians to seek further explanation and develop novel interventions that reach beyond the confines of the monoaminergic systems. Recent studies have provided strong evidence that glutamate and other amino acid neurotransmitters are involved in the pathophysiology and treatment of mood disorders. Studies employing in vivo magnetic resonance spectroscopy have revealed altered cortical glutamate levels in depressed subjects. Consistent with a model of excessive glutamate-induced excitation in mood disorders, several antiglutamatergic agents, such as riluzole and lamotrigine, have demonstrated potential antidepressant efficacy. Glial cell abnormalities commonly associated with mood disorders may at least partly account for the impairment in glutamate action since glial cells play a primary role in synaptic glutamate removal. A hypothetical model of altered glutamatergic function in mood disorders is proposed in conjunction with potential antidepressant mechanisms of antiglutamatergic agents. Further studies elucidating the role of the glutamatergic system in the pathophysiology of mood and anxiety disorders and studies exploring the efficacy and mechanism of action of antiglutamatergic agents in these disorders, are likely to provide new targets for the development of novel antidepressant agents.

Bipolar Disorder↗

GABA and mood disorders: a brief review and hypothesis.

Considerable evidence implicates the neurotransmitter gamma-aminobutyric acid (GABA) in the biochemical pathophysiology of mood disorders. Animal models of depression show regional brain GABA deficits and GABA agonists have antidepressant activity in these models. Somatic treatments for depression and mania upregulate the GABAB receptor, similar to the effect of GABA agonists. Clinical data indicate that decreased GABA function accompanies depressed or manic mood states. GABA agonists are effective antidepressant and antimanic agents. Low GABA levels are found in brain, cerebrospinal fluid and plasma of patients with depression and in plasma of patients with mania. Plasma GABA levels, which reflect brain GABA, are not normalized with treatment and clinical remission in depression, suggesting low GABA is not a marker for mood state. Some somatic treatments, including valproic acid and electroconvulsive shock, reduced plasma GABA and response to these correlates with higher levels of baseline plasma GABA. From these data, a GABA hypothesis for mood disorders is formulated. Low GABA function is proposed to be an inherited biological marker of vulnerability for development of mood disorders. Environmental factors, including stress and excessive alcohol use, may increase GABA, causing symptoms of depression or mania. Treatment, or the passage of time, then returns GABA to its presymptomatic baseline as the symptoms remit. This hypothesis, applicable to a subset of mood disordered persons, is testable.

Biomarkers↗

Clozapine in severe mood disorders.

BACKGROUND: A growing literature suggests that the atypical antipsychotic agent clozapine may be effective in schizoaffective and psychotic mood disorders. METHOD: To evaluate the efficacy and tolerability of clozapine in severe mood disorders, we reviewed published studies on clozapine in schizophrenia, bipolar disorder, schizoaffective disorder, major depression, and organic disorders with psychotic or major affective syndromes, identified through the MEDLINE data base. RESULTS: Patients in manic or psychotic phases of schizoaffective or bipolar disorder were significantly more likely to respond to clozapine than patients with schizophrenia (p = .006) or severe depressive syndromes (unipolar, bipolar, and schizoaffective depression combined; p = .001). There was no significant difference in the side effect profile secondary to clozapine in patients with severe mood disorders compared to patients with schizophrenia. CONCLUSION: Clozapine appears to be effective and well-tolerated in the short-term and maintenance treatment of severe or psychotic mood disorders, particularly in the manic-excited phases of schizoaffective and bipolar disorders, even in patients who have not responded well to conventional pharmacotherapies.

Bipolar Disorder↗

Future of genetics of mood disorders research.

This report summarizes the deliberations of a panel with representation from diverse disciplines of relevance to the genetics of mood disorders. The major charge to the panel was to develop a strategic plan to employ the tools of genetics to advance the understanding, treatment, and outcomes for mood disorders. A comprehensive review of the evidence for the role of genetic factors in the etiology of mood disorders was conducted, and the chief impediments for progress in gene identification were identified. The National Institute of Mental Health (NIMH) portfolios in the Genetics Research Branch and the Division of Mental Disorders, Behavioral Sciences, AIDS, and all genetics training activities were reviewed. Despite some promising leads, there are still no confirmed linkage findings for mood disorders. Impediments to gene finding include the lack of phenotypic validity, variation in ascertainment sources and methodology across studies, and genetic complexity. With respect to linkage, the committee recommended that a large-scale, integrated effort be undertaken to examine existing data from linkage and association studies of bipolar disorders using identical phenotypes and statistical methods across studies to determine whether the suggestive linkage findings at some loci can be confirmed. Confirmation would justify more intensive approaches to gene finding. The committee recommended that the NIMH support continued efforts to identify the most heritable subtypes and endophenotypes of major depression using the tools of genetic epidemiology, neuroscience, and behavioral science. The field of genetic epidemiology was identified as an important future direction because population-based, epidemiologic studies of families and unrelated affected individuals assume increasing importance for common chronic diseases. To prepare for shifts to more complex genetic models, the committee recommended that the NIMH develop new interdisciplinary training strategies to prepare for the next generation of genetics research.

Genetic Linkage↗

Psychosensory features in mood disorder: a preliminary report.

The purpose of this study was to determine the prevalence of psychosensory features in mood disorder patients, and to investigate the relationship between psychosensory features and classic psychopathology. We evaluated 50 mood disorder patients (39 bipolar, 11 schizoaffective) for the presence of psychosensory features and psychopathology. We assessed psychosensory features separately using the Profile of Psychomotor Symptoms. We obtained additional information regarding each patient's psychiatric and drug history, family history, and electroencephalogram. Seven (14.0%) experienced three or more recent psychosensory features, and 12 (24.0%) reported three or more past psychosensory features. The presence of alcohol and drug abuse, number of medications, and electroencephalographic abnormality had no effect on the prevalence of psychosensory features. Psychosensory features significantly (rs = .53, P < .001) correlated with hallucinations, but not with other psychopathology (P > NS). Psychosensory features are not uncommon in mood disorders and have a strong relationship with hallucinations. Our findings also suggest that the presence of psychosensory features in mood disorder suggests episode severity and not a specific subgroup.

Adult↗

Signaling networks in the pathophysiology and treatment of mood disorders.

Over the past decade, the focus of research into the pathophysiology of mood disorders (bipolar disorder and unipolar depression in particular) has shifted from an interest in the biogenic amines to an emphasis on second messenger systems within cells. Second messenger systems rely on cell membrane receptors to relay information from the extracellular environment to the interior of the cell. Within the cell, this information is processed and altered, eventually to the point where gene and protein expression patterns are changed. There is a preponderance of evidence implicating second messenger systems and their primary contact with the extracellular environment, G proteins, in the pathophysiology of mood disorders. After an introduction to G proteins and second messenger pathways, this review focuses on the evidence implicating G proteins and two second messenger systems-the adenylate cyclase (cyclic adenosine monophosphate, cAMP) and phosphoinositide (protein kinase C, PKC) intracellular signaling cascades-in the pathophysiology and treatment of bipolar disorder and unipolar depression. Emerging evidence implicates changes in cellular resiliency, neuroplasticity and additional cellular pathways in the pathophysiology of mood disorders. The systems discussed within this review have been implicated in neuroplastic processes and in modulation of many other cellular pathways, making them likely candidates for mediators of these findings.

Adenylyl Cyclases↗

Differentiating childhood-onset schizophrenia from psychotic mood disorders.

OBJECTIVE: The authors systematically examined a sample of patients who were referred to an ongoing National Institute of Mental Health (NIMH) study of childhood-onset schizophrenia (COS), but who received diagnoses of mood disorders at the NIMH, to analyze the reliability of these research-setting diagnoses and to characterize the patients clinically. Pilot data regarding the clinical course of these patients over a 2- to 7-year follow-up period were also obtained. METHOD: Thirty-three cases were selected from the 215 pediatric patients who had been screened in person from 1991 to 1999 for admission to the COS study. These 33 patients had been excluded from the COS study on the basis of a day-long evaluation, including a structured diagnostic interview, which yielded a diagnosis of a mood disorder rather than schizophrenia. This subgroup, together with six COS subjects (for a total N= 39), were included in a diagnostic reliability study in which they were reevaluated by three psychiatrists who were blind to the initial research diagnosis. In addition, pilot follow-up data regarding current function and treatment status were obtained for 25 of the 33 patients with mood disorders. RESULTS: Overall, the interrater reliability of the three raters was excellent (kappa = 0.90). Global reliability between these raters and the NIMH research diagnoses was good (average kappa across diagnoses = 0.61), and agreement for those patients who had mood disorders was good (86% agreement; kappa = 0.60). Pilot follow-up data indicate that none of the subjects with a diagnosed mood disorder developed a clinical course resembling schizophrenia. CONCLUSIONS: Many of the patients referred to the NIMH COS study with clinical diagnoses of schizophrenia had psychotic mood disorders diagnosed on the basis of a comprehensive research evaluation including structured diagnostic interviews, and these research diagnoses were reliable. The diagnosis of COS is difficult and requires a time-consuming evaluation process.

Adolescent↗

Developing novel treatments for mood disorders: accelerating discovery.

This review was generated from discussions by the Pharmacologic and Somatic Treatments Section of the National Institute of Mental Health Strategic Plan for Mood Disorders Committee on advancing novel pharmacologic and somatic treatments for mood disorders. The opening section of the article summarizes in broad strokes, current pharmacologic treatments, and new directions in the field. Thereafter the topics focus on specific research initiatives that could advance the current therapeutics for mood disorders including new basic and clinical research in vivo human imaging procedures, somatic therapeutics, and the vast new area of pharmacogenetics. New scientific and technical opportunities exist today based on advances in basic neuroscience, opportunities in clinical testing, industry interest in advancing central nervous system therapeutics, and on active consumer advocacy groups. The question of how to bring all of these positive forces together to accelerate discovery in mood disorder thera-peutics is the topic of this article.

Animals↗

Does lithium reduce the mortality of recurrent mood disorders?

Numerous follow-up studies have shown that patients with mood disorders who do not receive prophylactic medication are at increased risk of death, particularly from suicide. After 11 years follow-up we compared the mortality of 103 patients attending a lithium clinic with that expected on the basis of age/sex/year-specific rates for England and Wales. Only 10 patients died during the study, although the expected number of deaths was 18.31 (P = 0.052, two-tailed) and no deaths from suicide were observed. After correcting for the prevalence of mood disorder in the general population, the relative risk was 0.60 (95% CI 0.29-1.12) which suggests that lithium reverses the excess mortality associated with recurrent mood disorders, including that from suicide.

Bipolar Disorder↗

Serotonin transporter gene (5-HTTLPR) is not associated with depressive symptomatology in mood disorders.

Disturbances of the serotoninergic neutrotransmitter system have been implicated in the pathogenesis of mood disorders. A functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) has been recently reported to be associated with both unipolar and bipolar disorder. In this study, we investigated the possibility that the 5-HTTLPR might be associated with depressive symptomatology in a sample of mood disorder subjects. One hundred and thirty-two psychiatric inpatients affected by major depressive (n = 67) and bipolar (n = 65) disorder (DSM-IV) were assessed at admission by the Hamilton Depression Rating Scale (HAMD-21, divided into Core, Sleep, Activity, Psychic anxiety, Somatic anxiety and Delusion clusters) and were typed using PCR techniques. The only prior treatment permitted was low dose benzodiazepines (<5 mg diazepam or equivalent); no prior (<2 weeks) antidepressant or neuroleptic treatment was allowed. 5-HTTLPR variants were not associated with total depressive symptomatology as measured by HAMD. The short 5-HTTLPR variant was marginally associated with higher psychic anxiety scores (F = 7.11, d.f. = 1,262, P = 0.008). The association was stronger among bipolars and early onset subjects. 5-HTTLPR variants were not associated with the remaining symptom clusters. The upstream regulatory region of the serotonin transporter gene has not, therefore, a major influence on the depressive symptomatology in mood disorder subjects.

Alleles↗

Behavior in degenerative dementias: mood disorders, psychotic symptoms and predictive value of neuropsychological deficits.

We studied mood disorders (MD) and psychotic symptoms (PS) in patients with fronto -temporal dementia (FTD) and Alzheimer's disease (AD) by means of different diagnostic instruments. These were: a subjective scale (subsets of survey psychiatric assessment schedule: SPAS), an objective scale (subsets of neuropsychiatric inventory: NPI) and a projective task (Wartegg completion task: WCT). A general tendency of NPI to over estimate the presence of symptoms compared to SPAS was observed, but distribution and severity of symptoms were quite homogeneous in the two dementia-groups, independently of the diagnostic scales. At variance with the scales, the WCT showed a more severe impairment in FTD than in AD. The regression analysis selected neuropsychological models able to predict behavioral disorders only in FTD, in particular, a planning deficit predicted PS. These data confirm the hypothesis that a damage in the frontal areas constitutes the neurobiological basis of PS in degenerative brain diseases. Furthermore, they suggest that mostly in FTD, behavioral disorders, as well as cognitive deficits, should be considered a direct expression of neural damage.

Aged↗

Serotonin2A receptor gene polymorphism in mood disorders.

Genes that regulate the serotonin (5-HT) system including 5-HT receptors may be involved in mood disorders. We studied 5-HT2A receptor exons and the adjacent intron regions in 102 patients with mood disorders (71 depressive disorders and 31 bipolar disorders). In 34 mood disorder cases, the gene encoding the 5-HT1A receptor had been sequenced, but no disease-specific polymorphism was found. The substitution of C for T at position 102 in exon 1, which had been reported by Warren et al., was confirmed. The corresponding amino acid, serine, did not change. The allele frequency of C [corrected] at position 102 was significantly higher in patients with depressive disorders than in those with bipolar disorders and healthy control subjects. Furthermore, the mean age of onset in the patients heterozyous for the T and C alleles was lower than that in those homozygous for the C allele. No other polymorphism in the gene was found.

Adolescent↗