Underlying Mood Disorders Research Articles

Role of Brain-Derived Neurotrophic Factor in the Aetiology of Depression

Brain-derived neurotrophic factor (BDNF) is a critical mediator of activity-dependent neuronal plasticity in the cerebral cortex. Deficits in neurotrophic factors have been proposed to underlie mood disorders. However, recent evidence suggests that mood disorders may be produced by abnormalities in the adaptation of neural networks to environmental conditions. Antidepressants may act by enhancing neuronal plasticity, which allows environmental inputs to modify the neuronal networks to better fine tune the individual to the outside world. Recent observations in the visual cortex directly support this idea. According to the network hypothesis of depression, changes in the levels of neurotrophins including BDNF may not directly produce depression or an antidepressant effect, but neurotrophins may act as critical tools in the process whereby environmental conditions guide neuronal networks to better adapt to the environment. This hypothesis suggests that antidepressant drugs should not be used alone but should always be combined with rehabilitation to guide the plastic networks within the brain.

Antidepressant Use During Pregnancy and the Risk of Preterm Delivery and Fetal Growth Restriction

The associations between prenatal exposure to antidepressants and preterm delivery and fetal growth restriction are controversial and poorly understood. We studied the relation between antidepressant use and these outcomes. Analysis included women with nonmalformed infants interviewed in the Slone Epidemiology Center Birth Defects Study between 1998 and 2008. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for premature and small-for-gestational age (SGA) offsprings, adjusting for sociodemographic, lifestyle, medical, and reproductive factors. The frequencies of preterm delivery were 7.3% among the 5710 nonusers (reference), 8.9% among the 192 selective serotonin reuptake inhibitor (SSRI) users (OR, 1.1; 95% CI, 0.6-2.0), and 15.3% among the 59 non-SSRI antidepressant users (OR, 2.2; 95% CI, 1.0-4.9); the respective frequencies of delivering an SGA offspring were 7.2%, 10.9% (OR, 1.7; 95% CI, 1.0-2.7), and 13.6% (OR, 2.2; 95% CI, 1.0-4.9). Compared with nonusers, the frequencies of preterm delivery (7.6%) and SGA offspring (5.7%) were not increased among the 106 women who discontinued SSRIs before the end of the first trimester. Among women who continued SSRIs beyond the first trimester, 10.5% delivered a preterm infant (OR, 1.3; 95% CI, 0.6-2.8) and 17.4% had an SGA offspring (OR, 3.0; 95% CI, 1.7-5.5). Women treated with SSRIs late in pregnancy had a higher frequency of delivering SGA infants, and women receiving non-SSRI antidepressants were more likely to deliver premature and SGA offsprings. The findings suggest an effect of underlying mood disorder or an effect common to both drug classes. In any case, prenatal antidepressant use may help identify women at elevated risks of delivering preterm and SGA infants.

Malignant Catatonia in a Patient with Bipolar Disorder, B12 Deficiency, and Neuroleptic Malignant Syndrome

A Case is presented of a 23-year-old woman with progressive onset of paranoid psychosis and catatonia, who was ultimately found to have both vitamin B12 deficiency and a family history of bipolar disorder. The patient was initially diagnosed with schizophrenia and treated with the antipsychotic medication ziprasidone. Her condition rapidly worsened to a state consistent with either neuroleptic malignant syndrome or malignant catatonia. Work-up then revealed vitamin B12 deficiency and a family history of bipolar disorder. Her symptoms improved rapidly but partially with benzodiazepines and electrocon-vulsive therapy, and completely with addition of valproic acid, vitamin B12 replacement, and re-introduction of antipsychotic medication in the form of olanzapine. The authors discuss the differential diagnosis of catatonia as reflecting a high likelihood of underlying mood disorder; the evaluation and management of malignant catatonia and malignant neuroleptic syndrome; and the role of vitamin B12 deficiency in precipitating psychotic symptoms. The case also illustrates the problems of diagnosing and managing a multifactorial disorder with psychiatric, general medical, and perhaps iatrogenic components.

Depression and Suicide in Children and Adolescents

1. Laura M. Prager, MD* 1. *Assistant Professor, Child Psychiatry, Massachusetts General Hospital, Boston, Mass After completing this article, readers should be able to: 1. Discuss the clinical presentation and diagnostic criteria of depression. 2. Describe clinical management strategies for depression. 3. Recognize risk factors for suicide and self-destructive behaviors. 4. Understand how to assess and treat the suicidal patient. Depressive disorders in children and adolescents are common and often disabling. They can interfere with normal growth and development, academic performance, and interpersonal relationships, and they are a significant risk factor for suicide. These disorders fall on a spectrum that ranges from mild symptoms of depressed mood, which might occur in response to an acute stressor, to pervasive sad or irritable mood accompanied by problems with sleep, appetite, social isolation, and sometimes, suicidal ideas, plans, and intent. Prevalence rates for depression range from 1% to 2% of prepubertal children to 3% to 8% of adolescents. Depression in prepubertal children and bipolar disorder in any age group are equally common in both sexes. However, unipolar depressive disorders in adolescents are more common in girls than in boys (ratio of 3:1), and early onset of puberty in girls increases the risk for depression. (1) Depressed children and adolescents manifest a variety of signs and symptoms. They can be sad, irritable, or angry and may present with school or behavioral problems. They can demonstrate somatic complaints (eg, headache, stomachache, muscle weakness), decreased or increased appetite, fatigue, insomnia, hypersomnia, or disturbed sleep-wake cycles. Some children and adolescents develop psychotic features consistent with their mood symptoms, such as paranoid delusions or auditory hallucinations with self-deprecatory content. Some develop self-injurious behaviors or suicidal ideation, plan, and intent. Anxiety symptoms may be present and may predate the development of depressive symptoms. Behavioral problems ranging from oppositional defiance to frank conduct disorder may occur in conjunction with an underlying mood disorder. Depressive disorders vary in degree …

Focal Subcortical Biophysical Abnormalities in Patients Diagnosed With Type 2 Diabetes and Depression

Major depressive disorder has been consistently identified in patients with type 2 diabetes. Despite its high prevalence and clinical effect, the neurobiological substrates underlying depression in patients with diabetes remain largely unknown. To examine the biophysical integrity of proteins in critical white and gray matter regions in patients with type 2 diabetes and major depression to understand the pathophysiology of depression in diabetes. A cross-sectional magnetization transfer study using magnetic resonance imaging. Regions examined included the anterior cingulate, corpus callosum, frontal and occipital white matter, and the caudate and lenticular nuclei. A tertiary care university hospital. We studied 16 patients diagnosed with type 2 diabetes and major depression, 22 patients diagnosed with diabetes without depression (diabetic controls), and 30 controls without diabetes or major depression (healthy controls). Magnetization transfer ratios, a measure of the biophysical structure of proteins in the gray and white matter. Magnetization transfer ratios were significantly lower bilaterally in the head of the caudate nucleus in the group with diabetes and depression compared with the other 2 groups (P < .001). Diabetic controls had values between the depressed diabetic and healthy control groups. There were no significant differences in magnetization transfer ratios between groups in the other regions examined. These data indicate that there is an important subcortical biophysical component to depression in patients with type 2 diabetes. This finding has broad implications for the neuronal circuitry underlying mood disorders.

Selective Serotonin Reuptake Inhibitor Use and Risk of Gestational Hypertension

The purpose of this study was to assess the effects of treatment with selective serotonin reuptake inhibitors (SSRIs) on the risks of gestational hypertension and preeclampsia. The authors analyzed data from 5,731 women with nonmalformed infants and no underlying hypertension who participated in the Slone Epidemiology Center Birth Defects Study from 1998 to 2007. Gestational hypertension was defined as incident hypertension diagnosed after 20 weeks of pregnancy, with and without proteinuria (i.e., with and without preeclampsia). The risks of gestational hypertension and preeclampsia were compared between women who did and did not receive SSRI treatment during pregnancy. Relative risks and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards model, adjusting for prepregnancy sociodemographic, lifestyle, reproductive, and medical factors. Gestational hypertension was present in 9.0% of the 5,532 women who were not treated with SSRIs and 19.1% of the 199 women who were treated with SSRIs. Among women who received treatment, gestational hypertension was present in 13.1% of the 107 women who received treatment only during the first trimester and in 26.1% of the 92 women who continued treatment beyond the first trimester. The occurrence of preeclampsia was 2.4% among women who were not treated with SSRIs, 3.7% among women who were exposed to SSRIs only during the first trimester, and 15.2% among women who continued SSRI treatment beyond the first trimester. Relative to women who did not receive treatment, the adjusted relative risk of preeclampsia was 1.4 for women who discontinued treatment and 4.9 for women who continued treatment. SSRI exposure during late pregnancy-whether a causal factor or not-might identify women who are at an increased risk for gestational hypertension and preeclampsia. Further investigation is needed in order to separate the effects of treatment with SSRIs from those of underlying mood disorders.

Is daytime napping a healthy habit in adolescents?

Introduction: Napping is a commonly observed phenomenon, seen due to increase in daytime drowsiness and is usually perceived as a part of circadian rhythm dip in level of alertness. Whether such brief periods of sleep are just a habit, a sign of sleep deprivation or underlying mood disorder is a matter of debate. This study was conducted to see the relationship of napping with various aspects of mood & performance.

Approaching the Molecular Pathology of Suicide

uicide risk and personality traits associated with suicidal behavior are often related to childhood maltreatment and other “environmental” stressors (1). Therefore, the pathohysiology of suicide is likely to involve molecular mechanisms hat are not necessarily related to genetic factors (defined here as hanges in DNA sequence), albeit this hypothesis is difficult to est conclusively. Somatic cells (including neurons) employ a wide array of olecular mechanisms to alter and regulate gene expression nd function without changing the sequence of the genomic NA itself. These include (but are not limited to) “epigenetic” echanisms, which are commonly defined by a chemical odification of the DNA and/or the histone proteins associted with it. For example, the methylation of DNA cytosine esidues at the sites of CpG dinucleotides within gene prooters is an epigenetic mark typically associated with represion or downregulation of RNA transcription (2). In addition, ene expression is also regulated by a rich set of postranslational modifications of specific histone residues; these nclude lysine acetylation, methylation, SUMOylation and biquitinylation, arginine methylation, serine phosphorylaion, and proline isomerization (2). Now, two provocative articles, one by Poulter et al. in this ournal (3) and the other one by McGowan et al. in PLoS ONE 4), provide evidence for DNA methylation changes in the frontal ortex (3) and hippocampus of suicide victims (4). Poulter et al. (3) focused on the promoter of the ionotropic -aminobutyric acid (GABA)-A a1 receptor subunit, which acording to their previous work is expressed at decreased levels in he anterior prefrontal cortex of suicide victims (5). However, it hould be noted that another study, conducted in anterior ingulate—which is in close proximity to the prefrontal cortex— eported a consistent increase in GABA-A a1 expression in ompleted suicides (6). The clinical cohorts in both studies were efined by an underlying diagnosis of mood disorder, and herefore the discrepancy remains to be resolved. If not exlained by demographic differences, medication history, postortem variables, and other confounds, one interesting hypothsis would be that levels of GABA-A a1 transcript show opposing lterations in different subdivisions of the frontal lobe of suicidal ubjects. In any case, Poulter et al. (3) now report that a small ubset of CpG dinucleotides at the proximal GABA-A a1 prooter are hypermethylated in prefrontal cortex of 10 male uicide victims diagnosed with major depression, compared with on-psychiatric control subjects who died from other causes. The ethylation levels in control subjects ranged from 6% to 10% but ere as high as 38% in suicide victims. When taken together with heir previous finding of decreased GABA-A a1 messenger RNA

Men and Therapy

Socialization influences may result in a masking of men's symptoms of depression. This masking renders assessment a challenge for most clinicians, who are often sidetracked by more-immediate presenting concerns (relationship or job loss, developmental transitions, or alcohol or substance abuse). Clinicians may overlook a longer-term and more pernicious underlying mood disorder. This case presentation describes the assessment and treatment of a 53-year-old White male in both group and individual therapy. He initially sought a men's therapy group for support for developmental transitions but was actually suffering from a more severe underlying depression. The theoretical rationale and treatment implications for working with masked depression in men are presented.

Vitamin B12 Deficiency Manifested as Mania

Sir: Multiple psychiatric symptoms may precede pernicious anemia. Only 1 case of full manic syndrome secondary to B12 deficiency has been reported.1 Case report. Ms. A was a 35-year-old woman with no personal or family history of psychiatric disorders, who was admitted to the hospital in February of 2005 with a 3-week history of episodes of manic symptoms of several hours' duration, including grandiosity, hyperactivity, sexual indiscretion, hyperphagia, irritable mood, reckless behavior, flight of ideas, and overbearing manner. These episodes had a sudden onset and conclusion, and the patient was able to remember them. No hallucinations were reported at any time. At admission, she was oriented in all spheres, but was easily distractible. Full manic syndrome (DSM-IV criteria) was present and there was no coexisting delirium. All these psychiatric symptoms disappeared after 1 hour, without any medical intervention. An examination revealed the presence of a left Babinski's reflex and ataxia, as well as a bilateral loss of proprioception, vibration, and sensation of light touch and pain in the lower extremities. Strength and reflex in the lower extremities were diminished. The results of general blood chemistries, a thyroid function test, and a comprehensive drug screen were within normal limits. Although the results of electroencephalogram (EEG) and brain magnetic resonance imaging were normal, the duration, as well as the sudden onset and conclusion of episodes, suggested an epileptic cause for this patient's mania.2 Ms. A was treated with valproic acid for 3 weeks with no improvement. Serum vitamin B12 level was measured and was found to be markedly diminished––less than 60 pg/mL. Vitamin B12 (1000 µg/day) was administered intravenously for 1 week. After the third day of B12 replacement therapy, our patient did not experience new manic episodes. Therapy was continued with 1000 µg intramuscular injections weekly for 1 month and then with monthly intramuscular injections as maintenance treatment. Within 1 month, neurologic symptoms had improved. One year after B12 vitamin replacement started, her mental status was still normal. Although many psychiatric symptoms have been considered to be related to B12 deficiency,3,4 this is the first report of short duration episodes of manic symptoms secondary to B12 deficiency. The absence of previous psychiatric or medical disorders, coupled with her continued clinical remission while she was receiving B12 alone, argues that B12 deficiency was the most likely cause of her psychiatric disorder. Our case could also raise the hypothesis of different neuro-biological mechanisms underlying mood disorders and the importance of B12 and folate in their genesis.5

Baclofen-Induced Psychosis

To report a case of psychosis induced by therapeutic doses of baclofen. A 32-year-old Hindu man was prescribed oral baclofen 10 mg twice daily for relief of muscular spasms secondary to tetanus. After 4 weeks of baclofen use, he presented to the psychiatry emergency facility with a 4 day history of third-person auditory hallucinations and persecutory and referential delusions without underlying mood symptoms. These symptoms resolved within 1 week of discontinuing baclofen. Rechallenge with baclofen resulted in reemergence of psychotic symptoms, which disappeared after discontinuing baclofen. Reemergence of psychotic symptoms after rechallenge with baclofen suggests baclofen-induced psychosis. Use of the Naranjo probability scale indicates a probable association of baclofen with this patient's psychosis. The absence of underlying mood disorder makes this case different from previously reported ones. Baclofen may be associated with the occurrence of psychosis. Clinicians should consider baclofen-induced psychosis as a differential diagnosis in patients presenting with psychosis during treatment with this drug.

Subsyndromal depression in the elderly: underdiagnosed and undertreated

Major depressive illness is present in about 5.7% of US residents aged ≥65 years, whereas clinically significant nonmajor or “subsyndromal” depression affects approximately 15% of the ambulatory elderly. Risk of developing subsyndromal depression increases as elderly people get older. Because they have numerous distressing ailments, everyday life can be burdensome for many elderly persons. Almost one third of Americans aged 75 years or older rate their health as “fair to poor.” Yet, the physical discomforts experienced by so many elderly individuals are unlikely to generate a clinically significant depression unless other ingredients such as loneliness, impairment of mobility, loss of a spouse, a serious financial reverse, and—probably most important—genetic susceptibility are added to the psychophysiological mix. Because depression damages quality of life and is usually eminently treatable, it is essential that physicians and other health professionals be trained to recognize true depression and distinguish it from confounding conditions caused by medications, organic brain disease, or short-term grief reactions. In the medically ill elderly, depressive symptoms may be overlooked because of the assumption that they are a part of the concurrent medical illness. Diagnosis of depression in the elderly can be greatly assisted by use of age-specific screening instruments such as the Geriatric Depression Scale. Ultimately, brain imaging and biochemical and physiological measurements may prove useful in diagnosis. The presence of somatic concomitants of depression such as severe neck and low back pain should alert the clinician to the possibility of an underlying mood disorder. Suicide and suicide attempts occur all too frequently in the depressed elderly; therefore, screening for late-life depression is urgently required among the elderly in primary and residential health care settings.

TEMPS-A: progress towards validation of a self-rated clinical version of the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire

Background Our aim was to validate the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A) in a clinical population. Methods The study was conducted in two Memphis mood clinics involving 398 affectively ill patients with young to middle index age (42 years±13 S.D.), who were 95% white, 62% female, and 51% bipolar spectrum. A subset of 157 of the entire sample were retested in 6–12 months, and the entire sample was then subjected to factor analysis (PCA extraction method with varimax rotation). Results We obtained high test–retest reliability ranging from 0.58 for the irritable, to 0.68, 0.69 and 0.70, respectively, for the cyclothymic, dysthymic and hyperthymic. The hypothesized four-factor structure of the TEMPS-A was upheld, with the cyclothymic explaining 14% of the variance, followed by the irritable, hyperthymic, and dysthymic together accounting for another 14%. Internal consistency was excellent, with Chronbach alphas ranging from 0.76 for the dysthymic to 0.88 for the cyclothymic. Exploratory factor analysis revealed 2 super factors, Factor I loading on cyclothymic, irritable, and dysthymic temperaments, and Factor II loading heavily on the hyperthymic. The 50-item TEMPS-A-Clinical Version was constructed by using a cutoff of alpha ≥0.4 for traits loading exclusively on their original temperaments. We also proposed a longer 69-item version for future study, in which we permitted a greater number of traits based on clinical considerations (alpha cutoff 0.30). Limitation The sample was preponderantly white, and may not generalize to other U.S. ethnic groups. This earlier version of TEMPS-A did not include the anxious temperament. Conclusions We psychometrically validated the TEMPS-A in affectively ill outpatients, leading to an instrument suitable for use in psychiatric, especially affectively ill, populations. It is noteworthy that in this clinically ill population we succeeded in measuring traits which could make subjects vulnerable to affective episodes, as well as those of adaptive nature. For instance, the dysthymic emerged as bound to routine, self-blaming, shy-nonassertive, sensitive to criticism, yet self-denying, dependable, and preferring to work for someone else rather than be the boss. The hyperthymic had the highest number of “positive” traits: upbeat, fun-loving, outgoing, jocular, optimistic, confident, full of ideas, eloquent, on the go, short-sleeper, tireless, who likes to be the boss, but single-minded, risk-taker, and unlikely to admit to his/her meddlesome nature. The cyclothymic emerged as labile with rapid shifts in mood; unstable in energy, self-esteem and socialization; unevenly gifted and dilettante; yet keen in perception, intense in emotions, and romantic. The irritable emerged as skeptical and critical (which might be considered intellectual virtues), but otherwise having the “darkest” nature of all temperaments: grouchy, complaining, dissatisfied; anger- and violence-prone, and sexually jealous. The foregoing temperament attributes, observed in a moderately severe group of patients with affective disorders, nonetheless testify to the evolutionary context of these disorders—“submissive” behavior, territoriality, romantic charm, and last, but not least, sexually jealous with its associated specter of violence. We hypothesize that the putative social and limbic mechanisms underlying mood disorders appear to have archaic origins on an evolutionary scale. We finally submit that the traits underlying affective disorders are very much part of human nature.

Genetics of Childhood Disorders: XXXIX. Stem Cell Research, Part 3: Regulation of Neurogenesis by Stress and Antidepressant Treatment

Mood disorders continue to be major medical problems that affect up to 17% of the population at some point in life and can result in loss of life. Although effective treatments exist, not all patients respond to available medications and there is a time lag of weeks to months in the therapeutic response to antidepressants. The pathophysiology underlying mood disorders has not been identified. Recent advances in neurobiology provide a new conceptual framework for investigating both the pathophysiology and the treatment of mood disorders.

Evaluation and management of insomnia in menopause.

Insomnia is a problem with complex and multifactorial etiologies that requires both standardized and individualized treatment interventions. Specific targets of treatment may include hyperarousal, poor sleep habits, underlying mood disorders, sedative overuse, pain and general medical problems, circadian dysrhythmias, sleep apnea, and restless legs syndrome. Optimal treatment also will incorporate stress management, coping strategies, enhancement of relationships, and promoting lifestyle changes that facilitate sleep.

Fire-setting, pyromania and self-mutilation in female remanded prisoners

A co-morbid history of fire-setting and self-mutilation in a sample of female remanded prisoners identified a subgroup with severe personality disorder, early onset of behavioural disorder, and extensive criminality. The relationship between fire-setting and self-mutilation in these subjects was mediated through antisocial personality disorder and an underlying mood disorder. The phenomenology of fire-setting and self-mutilating behaviour was identical in women with pyromania.

Suicidal behavior on and off lithium prophylaxis in a group of patients with prior suicide attempts.

One hundred patients who had attempted suicide before commencing lithium prophylaxis were followed up. Outcome was analyzed in terms of attempted or completed suicide after a mean of 10 years since admission to the lithium clinics. Of 10 patients who committed suicide, 9 had discontinued adequate lithium prophylaxis for a period ranging from 2 weeks to 7 years before death. Having discontinued lithium therapy was associated with suicide also in the subgroup of patients for whom lithium had not completely prevented episodes during lithium treatment. Suicide risk was 24 times as high during periods off compared with periods on adequate lithium prophylaxis. Incidence of attempting suicide was similar during the periods before receiving or after discontinuing lithium treatment, whereas it was 5 to 6 times lower during prophylaxis. Continuous and adequate lithium prophylaxis should be considered in the presence of high suicide risk, even if the prophylactic effect on the underlying mood disorder may be incomplete.

Sleep and mood disorders.

Mood disorders are found in one-third to one-half of patients with chronic sleep problems. Likewise, most patients with mood disorders experience insomnia, but a minority obtain significantly increased amounts of sleep. Although mood disorders cause significant morbidity and mortality, they often go undiagnosed. Attention to sleep complaints could lead to better identification of mood disorders. Management of sleep problems in patients with mood disorders should focus on treating underlying mood disorders with attention to the nature of the sleep complaint. Patients with depression show characteristic abnormalities in sleep continuity, slow-wave sleep and REM sleep patterns. Differences in sleep patterns cannot reliably distinguish patients with depression from those with other psychiatric disorders, but sleep changes may provide a window on neurobiologieal abnormalities in depression.

Prevalence and clinical correlates of pathological affective display in Alzheimer's disease.

This study examined the prevalence and correlates of pathological affect in Alzheimer's disease. A consecutive series of 103 patients with Alzheimer's disease were examined with a comprehensive psychiatric assessment that included the pathological laughing and crying scale (PLACS). Forty patients (39%) showed pathological affect: 25% showed crying episodes, and 14% showed laughing or mixed (laughing and crying) episodes. Patients with pathological affect crying showed significantly higher depression scores and a significantly higher frequency of major depression and dysthymia than patients with no pathological affect. Patients with mixed pathological affect showed significantly more subcortical atrophy on CT than patients with pathological affect crying. Forty seven per cent of the patients with pathological affect had no congruent mood disorder, and they showed a significantly longer duration of illness and more severe anosognosia than patients with pathological affect that was congruent with an underlying mood disorder. The study validates the PLACS, and shows the high prevalence of pathological affect in Alzheimer's disease.