Abnormalities of cAMP signaling in affective disorders: implication for pathophysiology and treatment

Objective: During the last decade, much attention has been given to the role of signal transduction pathways in affective disorders. This review describes the possible role of the cAMP signaling in such disorders.

Methods: Among the components of cAMP signaling, this review focuses on the cAMP-dependent phosphorylation system. We analyzed the basic components of the cAMP-dependent phosphorylation system and the preclinical evidence supporting their involvement in the biochemical action of antidepressants and mood stabilizers. The clinical data available until now, concerning the possible link between the cAMP-dependent phosphorylation system and the pathophysiology of affective disorders, are also reviewed.

Results: The studies herein presented demonstrated that the levels and the activity of cAMP-dependent protein kinase are altered by antidepressants and mood stabilizers. Furthermore, these medications are able to modify the phosphorylation state, as well as the levels of some of the cAMP-dependent protein kinase substrates. More recently, clinical studies have reported abnormalities in the cAMP-dependent phosphorylation system in both peripheral cells and the postmortem brain of patients with affective disorders.

Conclusions: Overall, these studies support an involvement of cAMP signaling in affective disorders. The precise knowledge of the findings has the potential to improve the understanding of pharmacotherapy and to provide directions for the development of novel biochemical and genetic research strategies on the pathogenesis of affective disorders.     

Approximate entropy of symptoms of mood: an effective technique to quantify regularity of mood

Objectives:  Several psychiatric conditions are associated with lability of affect. In this study, we investigated regularity of mood using APEN (Approximate Entropy) on daily subjective ratings using a Visual Analog Scale with 11 items pertaining to mood.
Methods:  APEN was applied to the data in a double-blind placebo controlled investigation on the effects of fluoxetine (n=19), pemoline (n=18) and placebo (n=20) in normal controls. These subjects rated their subjective feelings daily at the end of each day. We analysed 56 data point time series (each value was obtained on each day) after the three experimental conditions.
Results:  While the mean or the SD of all the 56 points was not significantly different among the three conditions, APEN was highly and significantly lower for pemoline compared with fluoxetine and placebo. There was no significant correlation between average APEN and mean or SD (standard deviation). The one symptom that explained most of this difference among the groups after drug administration was the feeling of 'happiness'.
Conclusions:  This result indicates that there was a more consistent subjective sense of happiness during the 8-week period of pemoline administration compared with the other two drugs. Though this study was not designed to address the efficacy of mood stabilizing drugs, such daily subjective ratings may be useful in future studies that evaluate the stability of mood. APEN has been used in several different fields of research with small data sets and this study extends its possible use to evaluate changes in mood in certain populations such as patients with bipolar disorders.     

Cognitive deficits in schizophrenia and affective disorders: evidence for a final common pathway disorder

This study was designed to determine whether patients with schizophrenia and those with affective disorders display a common pattern of cognitive deficits. Cognitive performance was assessed with a neuropsychological test battery in consecutively admitted in-patients with schizophrenia (n= 100) and affective disorders (n= 100). The two groups of patients showed a similar pattern of cognitive deficits, especially in tests focusing on attentional capacities. The groups only differed significantly in their performance on the Wisconsin Card Sorting Test (WCST), with the schizophrenic patients performing less well. These results suggest that, with the exception of the deficit as measured by the WCST, similar cognitive impairments exist in schizophrenia and affective disorders, even at very early stages of the illness. Therefore, patients with schizophrenia and those with affective disorders cannot be qualitatively distinguished with sufficient reliability. We postulate that the cognitive deficit pattern represents a final common pathway disorder in the two groups of patients.     

Neuroprotective treatment strategies for poststroke mood disorders: A minireview on atypical neuroleptic drugs and selective serotonin re-uptake inhibitors

In our minireview we summarize the neuroprotective effect of atypical antipsychotic and selective serotonin re-uptake inhibitors after cerebral ischemia. In regard of increasing rate of poststroke mood disorders and current evidences indicating to an increased rate of cerebrovascular accidents after neuroleptic usage by the elderly population we also reviewed the clinical relevance of the neuroprotective and mood stabilizing effect of atypical antipsychotic agents in the light of basic pathophysiology of stroke.     

High-affinity 3H-imipramine binding in platelets of children and adolescents with major affective disorders

High-affinity ³H-imipramine binding to platelet membranes was evaluated in 12 untreated children and adolescents aged 11–17 years who met the DSM-III criteria for major affective disorders. The affective patients were compared to 13 nonaffective subjects and 15 normal controls of similar ages. No significant difference in the maximal binding of ³H-imipramine (B_max) and K_d values could be found among the three groups. ³H-imipramine binding values failed to discriminate between patients with major depression and those with bipolar disorder, depressed type. No association between a positive family history of major affective disorders and ³H-imipramine binding values was detected.     

Skating to where the puck is going to be: a plan for clinical trials and translation research in mood disorders.

As part of the National Institute of Mental Health Strategic Plan for Mood Disorders Research effort, the Clinical Trials and Translation Workgroup was asked to define priorities for clinical trials in mood disorders and for research on how best to translate the results of such research to clinical practice settings.Through two face-to-face meetings and a series of conference calls, we established priorities based on the literature to date and what was known about research currently in progress in this area.We defined five areas of priority that cut across developmental stages, while noting that research on adult mood disorders was at a more advanced stage in each of these areas than research on child or geriatric disorders. The five areas of priority are: 1) maximizing the effectiveness and cost-effectiveness of initial (acute) treatments for mood disorders already known to be efficacious in selected populations and settings when they are applied across all populations and care settings; 2) learning what further treatments or services are most likely to reduce symptoms and improve functioning when the first treatment is delivered well, but the mood disorder does not remit or show adequate improvement; 3) learning what treatments or services are most cost-effective in preventing recurrence or relapse and maintaining optimal functioning after a patient's mood disorder has remitted or responded maximally to treatment; 4) developing and validating clinical, psychosocial, biological, or other markers that predict: a) which treatments are most effective, b) course of illness, c) risk of adverse events/tolerability and acceptability for individual patients or well-defined subgroups of patients; 5) developing clinical trial designs and methods that result in lower research costs and greater generalizability earlier in the treatment development and testing process. A rationale for the importance of each of these priorities is provided.     

BDNF and BMI effects on brain structures of bipolar offspring: results from the global mood and brain science initiative

Objective

To compare brain‐derived neurotrophic factor (BDNF) levels between offspring of individuals with bipolar disorders (BD) and healthy controls (HCs) and investigate the effects of BDNF levels and body mass index (BMI) on brain structures.

Method

Sixty‐seven bipolar offspring and 45 HCs were included (ages 8‐28). Structural images were acquired using 3.0 Tesla magnetic resonance imaging. Serum BDNF levels were measured using enzyme‐linked immunosorbent assay. Multivariate and univariate analyses of covariance were conducted.

Results

Significantly higher BDNF levels were observed among bipolar offspring, relative to HCs (P > 0.025). Offspring status moderated the association between BDNF and BMI (F₁=4.636, P = 0.034). After adjustment for relevant covariates, there was a trend for a significant interaction of group and BDNF on neuroimaging parameters (Wilks’λ F_56,94=1.463, P = 0.052), with significant effects on cerebellar white matter and superior and middle frontal regions. Brain volume and BDNF were positively correlated among HCs and negatively correlated among bipolar offspring. Interactions between BDNF and BMI on brain volumes were non‐significant among HCs (Wilks’λ F_28,2=2.229, P = 0.357), but significant among bipolar offspring (Wilks’λ F_28,12=2.899, P = 0.028).

Conclusion

Offspring status and BMI moderate the association between BDNF levels and brain structures among bipolar offspring, underscoring BDNF regulation and overweight/obesity as key moderators of BD pathogenesis.     

New directions for the treatment of depression: Targeting the photic regulation of arousal and mood (PRAM) pathway

Both preclinical and clinical studies demonstrate that depression is strongly associated with reduced light availability, which in turn contributes to decreased function of brain regions that control mood. Here, we review findings that support a critical pathway for the control of mood that depends upon ambient light. We put forward a novel hypothesis, functionally linking retina to locus coeruleus (LC) in depression, and discuss the role of norepinephrine in affective disease. Finally, we discuss how utilizing the chemogenetic tool Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to precisely control this retina–LC circuit may be used as a novel therapeutic to treat depression.     

Prevalence, diagnosis, and pharmacological treatment of mood disorders in HIV disease.

Human immunodeficiency virus seropositive (HIV+) individuals are at a heightened risk of developing mood disorders and related syndromes. Over the past several decades, increased rates of mood disorders, including depression and mania, have been reported among HIV+ individuals. Because alterations in mood may impact on quality of life and perhaps reduce adherence to antiretroviral treatment regimens that are critical for preventing disease progression, recognition and effective treatment of mood disorders is essential. There are accumulating data showing that antidepressants and mood stabilizers, as well as other novel agents, might benefit HIV+ individuals suffering from a concomitant mood disturbance. This review highlights the relevant studies that have examined prevalence rates of mood disorders in HIV+ individuals, characteristics of HIV disease that influence the diagnosis and psychopharmacologic treatment of mood disorders, including complex interactions with antiretroviral medications, as well as the available evidence regarding the efficacy of agents used to treat depression and mania in the context of HIV disease.     

单相抑郁与双相情感障碍遗传效应及方式的对照研究

为寻找情感性障碍可能是一组异源性疾病的根据，调查了１７例单相抑郁和９６例双相情感障碍患者一、二级亲属中的情感性障碍患病率，并对二组亚型的遗传效应及方式作了对照分析。结果显示，单相抑郁的家族聚集性明显高于双相情感障碍。单相抑郁和双相情感障碍的加权平均遗传率分别为１３１．２％和８８．９％。单相抑郁和双相情感障碍都符合多基因遗传，但单相抑郁的遗传率明显高于双相情感障碍，且单相抑郁的二级亲属同病者均集中在母系。提示两者可能属异源性疾病。     

Caregiver distress in schizophrenia and mood disorders: the role of illness-related stressors and caregiver-related factors

Background: Studies using the stress-appraisal-coping model to examine caregiving in schizophrenia and mood disorders are limited.

Aim: This study attempted to examine psychological distress among caregivers of persons with schizophrenia and mood disorders using the framework of the stress-coping theory. The impact of illness-related stressors and caregiver-related factors on caregiver-distress was also explored.

Methods: In this cross-sectional study, 176 of the 238 selected outpatients with remitted schizophrenia, bipolar and recurrent depressive disorders identified over a 1-year period underwent standardized assessments of psychopathology and functioning. Assessments of burden, appraisal, coping, social support, neuroticism, familial–cultural variables and psychological distress (as an index of caregiving-outcome) were also carried out among family-caregivers of these persons.

Results: High levels of caregiver-burden and caregiver-distress and a mix of positive and negative appraisal, adaptive and maladaptive coping, and high and low levels of perceived support among caregivers characterized the caregiving experience. Univariate analyses revealed that both illness-related stressors (symptom-severity, level of functioning, objective burden) and caregiver-related factors (subjective burden, appraisal, coping, perceived support, family-cohesion, neuroticism, time spent in caregiving) influenced caregiver-distress. However, multivariate analyses demonstrated that caregiver-related factors such neuroticism, perceived support, time spent in caregiving, subjective burden and negative appraisal had a much greater influence on caregiver-distress than illness-related stressors.

Conclusions: Although interactions between illness-related stressors and caregiver attributes appear to determine caregiver-distress, subjective perceptions and other attributes of caregivers may have a greater impact on distress. Therefore, interventions to reduce caregiver-distress should place equal, if not more emphasis on caregiver-related factors which influence distress.     

Suicidal and violent behaviour in mood disorders: A major public health problem. A review for the clinician

Abstract

Suicide attempt, and particularly completed suicide are relatively rare events in the community, but they are very common among psychiatric patients. Since over 90% of suicide victims suffer from (mostly untreated) current major mental disorders (particularly from major depressive episode), psychiatric risk factors are the clinically most useful predictors, especially if psychosocial and demographic risk factors are also pesent. Violent behaviours associated with mood disorders constitute a related yet independently also important aspect of this illness, and assessment and management of violence is a key component of everyday psychiatric practice. While most people with current mental disorder are not violent, violence is more common among seriously mentally ill individuals than in healthy persons. This is particularly true for untreated schizophrenics and untreated patients with major mood disorders, first of all in the cases of comorbid substance use disorders, mainly among those with current mania or postpartum depression. Although specific clinical studies are lacking, it is very lilely that successful acute and long-tem treatment of mood disorders can reduce the risk of violent behaviour in this patient population.     

Childhood trauma and cognitive functioning in mood disorders: A systematic review

Background

Cognitive impairment is a core feature of mood disorders and has been identified as an important treatment target. A better understanding of the factors contributing to cognitive impairment in mood disorders would be beneficial in developing interventions to address cognitive impairment. One key factor is childhood trauma. The aim of this review was to systematically synthesise and review research examining associations between reported childhood trauma and cognitive functioning in mood disorders.

Methods

Studies in adult samples examining the relationship between objective cognitive function and reported childhood trauma in major depressive disorder and/or bipolar disorder (in-episode or euthymia) were identified. Searches were conducted on PubMed, Embase and PsycINFO until January 2022. A narrative review technique was used due to the heterogeneity of group comparisons, cognitive tests and data analysis across studies.

Results

Seventeen studies met the criteria for inclusion (mood disorders N = 1723, healthy controls N = 797). Evidence for childhood trauma being related to poorer cognitive functioning was consistent across global cognitive functioning and executive function domains for euthymic patients and psychomotor speed for in-episode patients. There was mixed evidence for verbal learning and memory and executive function for in-episode patients. Identification of patterns within other domains was difficult due to limited number of studies.

Conclusion

Findings from this review suggest childhood trauma is associated with poorer cognitive functioning in people with mood disorders. Targeted interventions to improve cognition may be warranted for this group.     

Neuroendocrine and psychopathological measures in anorexia nervosa: Resemblances to primary affective disorders

Clinical and biochemical data suggest a link between anorexia nervosa (AN) and primary affective disorders (PAD). In 14 female patients, aged 15–40 years, with 7-month to 11-year histories of AN, we studied circadian cortisol periodicity, response to the dexamethasone suppression test (DST), and plasma levels of β-endorphin and β-lipotropin before and after desimipramine therapy. Possible correlations were sought among neuroendocrine impairments, weight loss, and depressive symptomatology. Impaired circadian cortisol periodicity, blunted DST response, and increased β-endorphin plasma levels, observed in a subgroup of patients, could not be related to weight loss, either before or after therapy. Instead, a trend toward a relationship between neuroendocrine impairments and depressive symptoms was observed before and after treatment.     

Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders.

BACKGROUND: The objective of the current study was to examine possible clinical predictors of positive response to lamotrigine or gabapentin monotherapy in treatment-refractory affectively ill patients. METHODS: Forty-five patients with treatment refractory bipolar (n = 35) or unipolar (n = 10) affective disorder participated in a clinical study evaluating six weeks of treatment with lamotrigine, gabapentin, or placebo monotherapy given in a double-blind, randomized fashion with two subsequent cross-overs to the other agents. Patients received daily mood ratings and weekly cross-sectional scales. Much or very much improved on the Clinical Global Impression scale modified for bipolar illness was considered a positive response. Degree of response was correlated with a number of baseline demographic and course of illness variables in a univariate analysis and then by linear regression. RESULTS: Response rates to lamotrigine (51%) exceeded those to gabapentin (28%) and placebo (21%). A positive response to lamotrigine monotherapy was associated with a bipolar diagnosis; fewer hospitalizations; fewer prior medication trials; and male gender (of which the latter two variables survived logistic regression). For gabapentin, degree of response correlated with shorter duration of illness; younger age; and lower baseline weight (with the latter two surviving linear regression). CONCLUSIONS: In this highly treatment-refractory population, lamotrigine appeared most effective for male patients with fewer prior medication trials. Gabapentin monotherapy, although not better than placebo, appeared most effective in those with younger age and lower baseline weight. These preliminary data in a treatment refractory subgroup may help in the further definition of the range of clinical utility of these widely used anticonvulsants.     

Increased incidence of affective disorders, anxiety disorders, and non-natural mortality in women after breast cancer diagnosis: a nation-wide cohort study in Denmark

OBJECTIVE: To investigate whether breast cancer patients have increased incidence of psychiatric admission with affective disorders, anxiety disorders, or non-natural mortality compared with the general female population. METHOD: Register-linkage between nation-wide registries: The Danish Psychiatric Central Register, The Danish Cancer Registry, and The Danish National Register of Causes of Death. A total of 61 709 women registered with primary invasive breast cancer between 1970 and 1993 were included and 356 023 person-years were accrued. RESULTS: The standardized incidence ratio of first-ever psychiatric admission with affective disorder was 1.49 (95% CI: 1.35-1.63) and with anxiety disorder 1.25 (95% CI: 1.06-1.46). The standardized non-natural mortality ratio during the first year after breast cancer diagnosis was 1.54 (95% CI: 1.27-1.87). All analyses were adjusted for age, calendar period, and place of residence. CONCLUSION: Breast cancer patients have significantly increased incidence of psychiatric admission with affective disorders, anxiety disorders, and non-natural mortality.     

A comparison of the medical lethality of suicide attempts in bipolar and major depressive disorders

Objectives:  Among mood disorders, bipolar disorder (BPD) is often noted to involve the highest rates of suicide attempts and possibly of completion. This study sought to determine whether suicide attempters with BPD exhibit suicide attempts with higher lethality than attempters with major depressive disorder (MDD) and to explore differences in clinical features associated with suicidal acts.
Methods:  Mood disordered suicide attempters were interviewed about Axis I and II diagnoses, lifetime history of suicide attempts, suicidal intent, suicidal ideation, the medical lethality of their most severe suicide attempt, severity of depression, hopelessness, lifetime aggression, and impulsivity.
Results:  The maximum lethality of suicidal acts tended to be higher among BPD attempters compared with those with MDD. However, there were no differences in the number of suicide attempts, intent to die or suicidal ideation. Suicide attempters with BPD reported higher levels of aggression and impulsivity but less hopelessness compared with MDD attempters. These differences could not be explained by Cluster B personality disorder comorbidity. Of note, within the BPD group, but not the MDD group, males reported suicidal acts with higher lethality. Multivariate analyses suggested that risk for more lethal suicide attempts is associated with BPD and male sex and that bipolar males appear to be especially vulnerable to these behaviors.
Conclusions:  Males with BPD make more lethal suicide attempts than females with BPD, an effect not observed among the MDD sample. Our findings suggest that higher rates of suicidal behavior in BPD may be due to a specific effect of BPD on males, leading to more dangerous suicidal behaviors. This effect, together with the larger proportion of males in the BPD group compared with the MDD group may lead to higher rates of reported attempted and completed suicide.