Lysosomal dysfunction in diabetic cardiomyopathy.

Diabetes is a major risk factor for a variety of cardiovascular complications, while diabetic cardiomyopathy, a disease specific to the myocardium independent of vascular lesions, is an important causative factor for increased risk of heart failure and mortality in diabetic populations. Lysosomes have long been recognized as intracellular trash bags and recycling facilities. However, recent studies have revealed that lysosomes are sophisticated signaling hubs that play remarkably diverse roles in adapting cell metabolism to an ever-changing environment. Despite advances in our understanding of the physiological roles of lysosomes, the events leading to lysosomal dysfunction and how they relate to the overall pathophysiology of the diabetic heart remain unclear and are under intense investigation. In this review, we summarize recent advances regarding lysosomal injury and its roles in diabetic cardiomyopathy.

Metformin Inhibits Autophagy, Mitophagy and Antagonizes Doxorubicin-Induced Cardiomyocyte Death.

The antidiabetic drug metformin has been shown to reduce cardiac injury under various pathological conditions, including anticancer drug doxorubicin (DOX)-induced cardiotoxicity, which makes metformin a prime candidate for repurposing. However, the mechanisms that mediate the cardioprotective effects of metformin remain highly controversial. In this study, we tested a prevailing hypothesis that metformin activates autophagy/mitophagy to reduce DOX cardiotoxicity. FVB/N mice and H9C2 cardiac myoblasts were treated with metformin, respectively. Autophagy/mitophagy was determined by Western blot analysis of microtubule-associated protein light chain 3, form-II (LC3-II), a well-established marker of autophagic vesicles. Although metformin had minimal effects on basal LC3-II levels, it significantly inhibited the accumulation of LC3-II levels by the lysosomal protease inhibitors pepstatin A and E64d in both total cell lysates and mitochondrial fractions. Also, dual fluorescent autophagy/mitophagy reporters demonstrated that metformin slowed the degradation rate of autophagic cargos or mitochondrial fragments in the lysosomes. These surprising results suggest that metformin inhibits rather than stimulates autophagy/mitophagy, sharply contrasting the popular belief. In addition, metformin diminished DOX-induced autophagy/mitophagy as well as cardiomyocyte death. Together, these results suggest that the cardioprotective effects of metformin against DOX cardiotoxicity may be mediated by its ability to inhibit autophagy and mitophagy, although the underlying molecular mechanisms remain to be determined.

The gender difference in depressive prevalence is due to high prevalence of somatic depression among women who do not have depressed relatives.

BACKGROUND: Given that several studies have found the gender difference in depression to be rooted in psychosocial forces and others have shown the difference to be due to a gender difference in somatic depression, we compared the gender difference in somatic depression among respondents who reported no relative depressed with that of all other depressed respondents. METHODS: Respondents in a representative sample from the Zurich study who met criteria for somatic depression and reported no relatives (first-degree, or parents, or mothers, or fathers in separate analyses) with depression were compared to other depressed respondents as to gender. RESULTS: The gender difference in the prevalence of depression among respondents with somatic depression who reported no relatives with depression (whether the relatives were all first-degree, or any parent, or mothers only or fathers only) was significantly greater than the gender difference in depression among other respondents LIMITATIONS: The measure of depression among relatives was based upon reports of the respondents. CONCLUSION: All or almost all of the gender difference in depression in this representative sample.is due to a gender difference in somatic depression among respondents who reported no depressed relative. Somatic depression may be a disorder distinct from depression without significant additional somatic symptomatology. If so, it is likely that it should be treated differently.

Evidence for Broadening Criteria for Atypical Depression Which May Define a Reactive Depressive Disorder.

Objective. Arguing that additional symptoms should be added to the criteria for atypical depression. Method. Published research articles on atypical depression are reviewed. Results. (1) The original studies upon which the criteria for atypical depression were based cited fatigue, insomnia, pain, and loss of weight as characteristic symptoms. (2) Several studies of DSM depressive criteria found patients with atypical depression to exhibit high levels of insomnia, fatigue, and loss of appetite/weight. (3) Several studies have found atypical depression to be comorbid with headaches, bulimia, and body image issues. (4) Most probands who report atypical depression meet criteria for "somatic depression," defined as depression associated with several of disordered eating, poor body image, headaches, fatigue, and insomnia. The gender difference in prevalence of atypical depression results from its overlap with somatic depression. Somatic depression is associated with psychosocial measures related to gender, linking it with the descriptions of atypical depression as "reactive" appearing in the studies upon which the original criteria for atypical depression were based. Conclusion. Insomnia, disordered eating, poor body image, and aches/pains should be added as criteria for atypical depression matching criteria for somatic depression defining a reactive depressive disorder possibly distinct from endogenous melancholic depression.

Differences in the developmental patterns of depression with and without additional somatic symptoms.

Depression accompanied by somatic symptoms ("somatic" depression) has been found to differ from depression without the additional symptoms ("pure" depression) in their gender ratio, their association with measures of perceived gender inequality taken from both respondents and their parents, and in their response to pharmacological treatment. Further evidence of the distinction between the two syndromes might come from differential patterns of development. Data on the annual incidence of new cases of depression exhibited by a representative sample of respondents aged 12-19 came from the National household survey on drug use and health. Between early adolescence (ages 12-14) and late adolescence (ages 15-19), female respondents exhibited a much larger increase in somatic depression than in pure depression. Males did not exhibit the same pattern. These results further support the hypothesis that somatic and pure depressions are two distinct disorders.

Poor response to antidepressant medication of patients with depression accompanied by somatic symptomatology in the STAR*D Study.

Studies suggest that the gender difference in the prevalence of depression results because women exhibit higher prevalence than men of a depressive phenotype associated with somatic symptoms. Because this phenotype has been found to be based in psychosocial forces, it may not respond well to antidepressant medication. In this study, data from the STAR*D Study were analyzed to compare remission rates in response to an SSRI and to several other antidepressants of patients exhibiting depression accompanied by somatic symptomatology versus other patients. Scores on the Clinician Rated Quick Inventory of Depressive Symptomatology were used to measure clinical remission in response to medication. Patients exhibiting depression accompanied by somatic symptomatology exhibited less remission to the SSRI Citalopram (31% versus 43%) and to the various medications administered in level 3 (14% versus 25%) than did other patients in STAR*D. The low rates of remission in response to medication of patients exhibiting somatic symptomatology were not due to the greater proportion of women, nor to the greater proportion of patients exhibiting anxiety disorders, among patients exhibiting somatic symptomatology. Remission rates were found to be related to exhibiting somatic symptomatology not to exhibiting nonsomatic symptoms.

Should additional symptoms be included in criteria for atypical depression?

Analyses of a systematic household sample of 750 respondents aged 11-22, 19 with atypical depression, find atypical depression associated with fear of fat, insomnia, headache, and fatigue. Other research suggests adding these symptoms to criteria for atypical depression, rendering them quite similar to criteria used in studies of somatic depression.

Atypical depressive syndromes in varying definitions.

BACKGROUND: Atypical depression (AD) exhibits distinct patterns of gender,bipolar-II disorder, genetic, and neuro-biological measures. Using prospective data from a community sample, this paper identifies criteria (and correlates) for an AD syndrome that maximizes the association with female sex and bipolar-II. METHODS: The Zurich cohort study is composed of 591 subjects selected from a population-based cohort of young adults in the canton of Zurich in Switzerland, screened in 1978 and followed with six interviews through 1999. Seven definitions of atypical depression were tested, using varying combinations of vegetative symptoms and mood reactivity. RESULTS: The atypical definitions using 2 of 3 (fatigue, overeating, oversleeping) or 2 of 2 (overeating, oversleeping) vegetative symptoms showed the strongest association with gender, bipolarity, and family history of mania. The 2/3 definition was chosen for further analysis due to its high sensitivity for identifying these characteristics. This syndrome had cumulated weighted prevalence of 16.4% (males 9.7%, females 23%); when associated with major depressive episodes, 8.2% (males 3.2%, females 15.1%). AD patients were characterized by high treatment rates, severity, and work impairment, early age of onset and long illness. AD was comorbid with social phobia, binge eating, neurasthenia, migraine headache, and subjective cognitive impairment.

Gender differences in the prevalence of somatic versus pure depression: a replication.

OBJECTIVE: Using data from the Epidemiologic Catchment Area (ECA) study, the author attempted to replicate the finding of the National Comorbidity Survey that the prevalence of depression associated with somatic symptoms was much higher among women than men. METHOD: The author reanalyzed data from the ECA study. He divided respondents into those who met criteria for major depression and exhibited appetite and sleep disturbances and fatigue (somatic depression) and those who met depression criteria but did not exhibit all of these somatic criteria (pure depression). RESULTS: The reanalysis revealed that the prevalence of somatic depression but not pure depression was much higher among women than men. Somatic depression was associated with high rates of pain; among women, it was associated with high rates of anxiety disorders and chronic dysphoria. CONCLUSIONS: The gender difference in depression may result from a difference in a specific type of depression-anxious somatic depression.