Inflammatory proteins and miRNA-144-5p in patients with depression, anxiety, or stress- and adjustment disorders after psychological treatment.

Both inflammatory proteins and microRNAs (miRNA) have been reported to be associated with various psychiatric disorders. However, the association between inflammatory proteins and miRNAs remains largely unknown, especially for patients with depression, anxiety, or stress- and adjustment disorders. In this study, we analyzed plasma levels of 92 inflammatory proteins from 178 patients with depression, anxiety, or stress- and adjustment disorders at baseline and after 8-week psychological treatments which resulted in a significant decrease in the Montgomery Åsberg Depression Rating Scale (MADRS-S) score. We investigated the response of the proteins after treatment and the correlation with miR-144-5p. After Benjamini-Hochberg correction for multiple testing, a total of 36 inflammatory proteins changed significantly after 8-week psychological treatments. Among the 36 significantly changed proteins, 21 proteins showed a decrease, and 17/21 proteins were inversely associated with plasma miR-144-5p levels at baseline. In addition, decreases in these proteins were associated with increases in miR-144-5p after treatment. The findings were similar after stratification by use of medications. The associations between the proteins and depression at baseline, measured by MADRS-S, as well as the change in protein levels and treatment response were, however, less clear. These findings need to be examined in future studies.

Reactive Depression: Lost in Translation!

The old classification of depression as reactive and endogenous, which are still observed in clinical practice, both cannot be accommodated under the current rubric of major depression. This is because psychiatric nosology under the Diagnostic and Statistical Manual of Mental Disorders (DSM) and its latest fifth edition (DSM-V) is still descriptive and not etiologic. The aim of this review was to revisit reactive and endogenous categories of depression from the perspective of today's understanding of etiological pathways. From an epigenetic perspective, the old dichotomy of reactive versus endogenous is interrelated through the impact of the environment (e.g., stress). This includes familial or prenatal depression, where the environmental impact is before birth, or childhood depression, where the early life stress is the precipitating factor to genetic susceptibility. In conclusion, searching for both environmental impact (e.g., stressors) and genetic predispositions in depression, even at a clinical level, could help clinicians with better therapeutic decisions.

The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder.

BACKGROUND: Traditional diagnoses of major depressive disorder (MDD) suggested that the presence or absence of stress prior to onset results in either 'reactive' or 'endogenous' subtypes of the disorder, respectively. Several lines of research suggest that the biological underpinnings of 'reactive' or 'endogenous' subtypes may also differ, resulting in differential response to treatment. We investigated this hypothesis by comparing the gene-expression profiles of three animal models of 'reactive' and 'endogenous' depression. We then translated these findings to clinical samples using a human post-mortem mRNA study. METHODS: Affymetrix mouse whole-genome oligonucleotide arrays were used to measure gene expression from hippocampal tissues of 144 mice from the Genome-based Therapeutic Drugs for Depression (GENDEP) project. The study used four inbred mouse strains and two depressogenic 'stress' protocols (maternal separation and Unpredictable Chronic Mild Stress) to model 'reactive' depression. Stress-related mRNA differences in mouse were compared with a parallel mRNA study using Flinders Sensitive and Resistant rat lines as a model of 'endogenous' depression. Convergent genes differentially expressed across the animal studies were used to inform candidate gene selection in a human mRNA post-mortem case control study from the Stanley Brain Consortium. RESULTS: In the mouse 'reactive' model, the expression of 350 genes changed in response to early stresses and 370 in response to late stresses. A minimal genetic overlap (less than 8.8%) was detected in response to both stress protocols, but 30% of these genes (21) were also differentially regulated in the 'endogenous' rat study. This overlap is significantly greater than expected by chance. The VAMP-2 gene, differentially expressed across the rodent studies, was also significantly altered in the human study after correcting for multiple testing. CONCLUSIONS: Our results suggest that 'endogenous' and 'reactive' subtypes of depression are associated with largely distinct changes in gene-expression. However, they also suggest that the molecular signature of 'reactive' depression caused by early stressors differs considerably from that of 'reactive' depression caused by late stressors. A small set of genes was consistently dysregulated across each paradigm and in post-mortem brain tissue of depressed patients suggesting a final common pathway to the disorder. These genes included the VAMP-2 gene, which has previously been associated with Axis-I disorders including MDD, bipolar depression, schizophrenia and with antidepressant treatment response. We also discuss the implications of our findings for disease classification, personalized medicine and case-control studies of MDD.

Testing a diathesis-stress model: potential genetic risk factors for development of distress in context of acute leukemia diagnosis and transplant.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals and may be implicated in the etiology of mood-related phenotypes, specifically in the context of stressful life events. We hypothesized that this single-nucleotide polymorphism will predict the development of psychological distress among patients diagnosed with acute leukemia and preparing for hematopoietic stem cell transplant (HSCT). We also explored the relationship of other genetic factors to psychological distress, including 5HTTLPR and STin2, FKBP5, and the CRHR1 TAT haplotype. METHOD: In a retrospective cohort design, 107 adult acute leukemia survivors preparing for HSCT at a major medical center completed a pre-HSCT psychological evaluation and volunteered to donate blood to the HSCT Cell and Serum Research Repository for future research studies. RESULTS: There was evidence of a potential association between BDNF (Val66Met) and psychological distress. More specifically, rs6265 was related to both personal mental health history (P = 0.09, 0.06 adjusted) and diagnosis of depression/adjustment disorder at time of pre-transplant evaluation (P = 0.11, 0.09 adjusted). Other genetic factors were unrelated to distress. CONCLUSION: The BDNF Val66Met polymorphism may contribute to development of depressive symptomatology in patients undergoing stressful life events, such as diagnosis of acute leukemia and preparation for HSCT. The SNPs in BDNF might be applicable in identifying patients at risk for developing psychological distress and depression in the context of coping with stressful medical conditions. Polymorphism in other genes (FKBP5, CRHR1, and 5HTT) did not show any significant relationships. Replication studies are needed with larger samples of people undergoing similar significant life stressors.

Should the diagnosis of major depression be made independent of or dependent upon the psychosocial context?

BACKGROUND: The diagnosis of certain psychiatric syndromes (e.g. panic attacks, post-traumatic stress disorder) is crucially dependent on the psychosocial context in which they arise. For other syndromes (e.g. schizophrenia), the context is generally irrelevant. Should the diagnosis of major depression (MD) be made dependent upon or independent of the psychosocial context in which it occurs? METHOD: Twins were selected from a population-based registry who, on personal interview, reported developing a full depressive syndrome either 'out of the blue' or in response to stressful life events (SLEs) rated objectively as having mild, low moderate, high moderate or severe long-term contextual threat (LTCT). RESULTS: In these depressed subjects, no relationship was found between the level of adversity associated with onset and most indices of liability to depression, including risk of MD in co-twin and parents, level of neuroticism, risk for future depressive episodes, co-morbidity with other internalizing disorders and history of sexual abuse. Compared to the remainder of this epidemiologic cohort, subjects developing depression in response to the severe threat events had substantially elevated levels of all the examined indices of liability to MD. CONCLUSIONS: Individuals who develop a full depressive syndrome in response to high-threat events do not have an appreciably lower liability to MD than those developing depression after exposure to low adversity and have much higher liability to depression than observed in their population cohort. These results support the hypothesis that, in general, MD can be diagnosed independently of the psychosocial context in which it arises.

Psychiatric disorders in the biological and adoptive families of adopted individuals with affective disorders.

To investigate the contribution of genetic and environmental factors in the etiology of mood disorders, a study was initiated to examine the frequency of psychiatric disorders in the biological and adoptive relatives of adult adoptees with mood disorders and in matched normal adoptees. Psychiatric evaluations of the relatives were made on the basis of independent blind diagnoses based on mental hospital and other official records. Analysis of the data showed an eightfold increase in unipolar depression among the biological relatives of the index cases and a 15-fold increase in suicide among the biological relatives of the index cases. These data demonstrate a significant genetic contribution to unipolar depression and suicide. They fail to disclose a significant contribution of family-associated transmission in the genesis of the mood disorders.

Differentiation of primary affective illness from situational, symptomatic, and secondary depressions.

Analysis of family history and antidepressant drug response variables of 100 "neurotic" depressives followed up prospectively over three to four years disclosed that primary depressions (unipolar and bipolar) could be distinguished from nonprimary cases by (1) the early occurrence of "pharmacological-hypomania;" (2) family history of bipolar illness; (3) family history for affective disorder in two or three consecutive generations, especially when "loaded." Although each of these variables alone occurred in only one fifth to one third of the primary group, they individually displayed better than 95% specificity for it. Thus, the confidence with which the diagnosis of primary affective illness could be made in the presence of any of these variables ranged from 88% to 100%. These findings argue for considering such nonsymptomatological variables for their potential in strengthening the phenomenologic diagnostic criteria for depressive illness.

Genetic factors in moderately severe and mild affective disorders.

The aim of this study was to investigate the contribution of hereditary factors in the development of affective and depressive adjustment disorders. I interviewed 151 index twins with moderately severe and mild affective illness, as well as their co-twins. The analysis of concordance rates indicates that hereditary factors may be important in the development of bipolar disorder and in major depression, except in non-psychotic, hysterical individuals. Furthermore, hereditary factors may not play any role in dysthymic disorder and depressive adjustment disorder. These findings are tentative and should be viewed against the methodologic limitations of this study, which include small sample size of the subgroups and the use of the Present State Examination as the basis for the DSM-III diagnoses.

Secondary depression: familial, clinical, and research perspectives.

The authors evaluate the clinical and research significance of the diagnosis of secondary depression by comparing 48 cases of primary and 26 cases of secondary depression. The patients with secondary depression have a higher familial prevalence of alcoholism, affective disorder, and drug abuse. The groups differ somewhat on a few sociodemographic, behavioral, and attitudinal variables but are similar in symptomatology, sex ratio, onset and duration of symptoms, treatment received, and response to treatment. These results suggest that the distinction between primary and secondary depression should be retained in research that examines neurochemistry or genetics. Primary and secondary depression appear to be identical from the persepctive of clinical care. Management of these patients should emphasize the diagnosis of depression rather than antecedent diagnoses.

A family study of generalized anxiety disorder.

The frequency of generalized anxiety disorder was higher among first-degree relatives of probands with generalized anxiety (N = 20) than among the relatives of control subjects (N = 20), but it was not higher among relatives of probands with panic disorder (N = 40) or agoraphobia (N = 40). Also, the frequency of panic disorder was higher among relatives of probands with panic disorder than among control relatives but was not higher among relatives of generalized anxiety probands. Relatives of probands with generalized anxiety who had the same disorder had a mild, stress-related illness. The results confirm the separation between generalized anxiety disorder and panic disorder but challenge the distinction between generalized anxiety and adjustment disorders.

Suicide pact in a depressed elderly couple: case report.

An elderly depressed couple with multiple physical problems decided that death was preferable to their present lifestyle, and made a suicide pact. At the last minute the wife felt unable to go through with it and the couple entered a psychiartic hosptial. During their 3-week stay they were treated appropriately with amitriptyline and psychotherapy. Since discharge they have been followed closely for two years. Some psycho- and socio-dynamic and therapeutic aspects are discussed.

Lack of association between suicide attempt and a polymorphism at the dopamine receptor D4 locus.

Dopaminergic neurotransmission has been implicated in suicidal behaviour. The 48 bp-repeat polymorphism in the gene coding for dopamine receptor D4 was investigated in a sample of suicide attempters (n = 165) and healthy control subjects (n = 99). No association between suicide attempts and this polymorphism was observed. Neither did any significant differences emerge in comparison with control subjects when the suicide attempters were grouped into different diagnostic categories: unipolar (n = 45), anxiety (n = 23), adjustment (n = 37) and personality disorders, cluster B (n = 36). The results suggest that alleles defined by the investigated polymorphism do not have a major impact on suicidal behaviour.

Search for association between suicide attempt and serotonergic polymorphisms.

Serotonergic neurotransmission has been implicated in suicidal behavior. Polymorphisms in the genes coding for tryptophan hydroxylase, serotonin receptor 2A and serotonin transporter were investigated in a sample of suicide attempters (n = 165) and healthy control subjects (n = 99). No significant differences were found for any of the investigated polymorphisms. Neither did any significant differences emerge in comparison with control subjects when the suicide attempters were grouped into different diagnostic categories: unipolar disorder (n = 45), adjustment disorder (n = 37), substance use disorder (n = 37) and personality disorder, cluster B (n = 36). The results suggest that alleles defined by the investigated polymorphisms do not represent a major determinant in suicide attempt. However, a highly significant (P = 0.001; odds ratio, 1.47; 99% confidence interval, 1.42-1.53) allelic association between tryptophan hydroxylase and suicide attempt is indicated after pooling our data with literature data. In light of previous data, a possible association between the tryptophan hydroxylase polymorphism and a phenotype that may become differently stratified within differently selected samples of suicide attempters is discussed.

The impact of diagnostic misclassification on the pattern of familial aggregation and coaggregation of psychiatric illness.

Family studies in psychiatry have traditionally been interpreted as if psychiatric diagnoses were made without error. This is unlikely to be true. The first section of this paper presents a model, based on several simplifying assumptions, which examines the impact of diagnostic misclassification on patterns of familial aggregation and coaggregation of two disorders. In the second section, the model is illustrated by examining the effect of varying misclassification rates on the patterns of aggregation and coaggregation in four simulated family studies of psychotic illness. Misclassification is considered which is equal or unequal for the two disorders, which is the same in probands and relatives or greater in relatives and which occurs between disorders of similar or quite different population risk. Misclassification in the range which commonly occurs in psychiatry can produce substantial effects on the observed pattern of familial aggregation and coaggregation. Furthermore, the proportion of diagnosed cases which are misclassified varies widely depending upon whether an affected individual is from the general population or is a relative of an individual affected with the same or a different psychiatric disorder. The third section of the paper illustrates a method for examining the fit of the proposed model to observed data and "correcting" for the effects of misclassification in family studies. For example, the familial coaggregation between bipolar illness and schizophrenia in a recent large family study can be entirely explained by the observed rates of diagnostic misclassification between the two disorders. The results of the proposed model strongly suggest that diagnostic misclassification should be considered in the interpretation of family studies of psychiatric illness.

Family (genetic) studies in neurotic depression.

Neurotic depression may be defined as a depression that occurs in the context of a long standing history of personality difficulties or neurotic symptoms. Two types of conditions fit this definition: (1) depressions secondary to personality disorder, neuroses or substance abuse; and (2) primary depressions with a family history of alcoholism. Depressions so defined show familial relationships with secondary depression, anxiety disorders, alcoholism, and depressions with personality disorders. The data suggest that these cluster in the same family and are related to the definition of neurotic depression given above. Whether these familial relationships are genetic awaits further research.

Hazard, heredity and depression. A family study.

The relationship between proband characteristics and familial aggregation of depression was assessed in an interview study of 83 families ascertained via probands who had a recent onset of depression. Contrary to expectations and to previous reports in the literature there were no differences between the frequencies of depression in the first degree relatives of probands who had or had not experienced adversity prior to the onset of their illness. Depression was actually slightly more common among the first degree relatives of probands who had experienced a threatening life event compared with the relatives of those who had not. Early onset of depression (before 32 yr) and a neurotic pattern of symptoms in probands were associated with significantly higher rates of current illness in relatives. However, both these differences disappeared when lifetime prevalence or morbid risk to age 65 were considered. Indeed the morbid risk of severe depression in the relatives of endogenously depressed probands was nearly twice that in the relatives of neurotic probands.

The genetics of neurotic-reactive depression: a reanalysis of Shapiro's (1970) twin study using diagnostic criteria.

The present study explored the role of genetic factors in the development of neurotic depression. Case studies of 16 monozygotic (MZ) and 14 same-sex dizygotic (DZ) twins from Robert Shapiro's 1970 study of non-endogenous depression were rediagnosed by two raters blind to the zygosity and identity of each twin. Diagnoses were made using Research Diagnostic Criteria (RDC) and George Winokur's 1985 criteria for neurotic-reactive depression. When neurotic depression was operationally defined using Winokur's criteria plus RDC major or definite minor depression, the concordance rate for MZ twins was significantly greater than that for DZ twins. Our results contrast with Shapiro's negative findings, probably due to our use of formal diagnostic criteria and Shapiro's requirement that cotwins be hospitalized to be considered concordant. The present results suggest that genetic factors play a role in the etiology of at least some forms of neurotic depression.

Recurrently situational (reactive) depression: a study of course, phenomenology and familial psychopathology.

Probands with non-bipolar major depressive disorder (MDD) were grouped according to the consistency across episodes with which depression appeared to arise from situational factors. Situational depression showed significant diagnostic stability across the second and third recurrences in a 10-year follow-up. The relatives of recurrently situational probands had higher neuroticism scores, higher lifetime rates of MDD and, when depressed, fewer endogenous symptoms than did the relatives of non-situational probands. This study joins two others in finding an association between stress-related depression and high familial loadings for MDD. It also illustrates the value of diagnostic consistency across episodes as a means of refining groups for the study of diagnostic subtypes.

Morbidity risk for psychiatric disorders in families of probands with affective disorders divided according to levels of platelet MAO activity.

In a series comprising 166 subjects with affective disorders, the lowest and highest quartiles in the male and female platelet monoamine oxidase (MAO) distribution, respectively, were included. The morbidity risk in the first-degree relatives (parents and siblings) of these low and high platelet MAO subjects was determined. First-degree relatives of low platelet MAO probands were found to have an increased morbidity risk for neurotic-reactive depressions and for alcoholism. The results seem to be in line with the biological high-risk paradigm, indicating that platelet MAO could be a biological marker for increased vulnerability. First-degree relatives of high platelet MAO probands were found to have an increased morbidity risk for bipolar affective disorders.

Peer status and the directionality of symptomatic behavior: prime social competence predictors of outcome for vulnerable children.

Social competence data from four target groups of vulnerable children--children of schizophrenic mothers; children of neurotic mothers; clinic children with externalizing symptomology; clinic children with internalizing symptomology--and from a large control group of their public school classmates, strongly suggest that peer-rated social incompetence and presence of externalizing behavior disorders are the best predictors of which vulnerable children run the greatest risk of poor adult outcome.