Globally, major depressive disorders (MDDs) and anxiety disorders are the two most burdensome psychiatric illnesses, with a significant negative impact on cognitive functioning, work-related attendance and productivity, and quality of life. As the second-leading cause of disability worldwide, MDD presents a high burden for both sexes as well as patients and caregivers. Considerable heterogeneity in clinical presentation, high rates of physical and psychiatric comorbidity, and variability in treatment response complicate the management of MDD. Specifically, less than half of MDD patients respond to the first antidepressant therapy, and treatment resistance is seen in up to 30% of treated MDD patients. Although depression is common globally, there are variations in symptomatic presentation and interpretation of symptoms across cultures.
CLINICAL PRESENTATION OF DEPRESSION ACROSS CULTURES
Culture may influence the regulation of emotion in several ways. Cultural ideologies, sanctions, and traditions may influence the sources of emotional stress, interpretation of feelings, strategies to cope with distress, help-seeking patterns, and societal response to the symptomatic expression of distress. For example, American society encourages open discussions about interpersonal and internal conflicts, including intimate events. By contrast, some cultures prioritize social harmony over individual needs and expressions; people living in such societies may view emotional problems as inappropriate foci for help-seeking and, instead, prefer to be “somatizers” focusing on physical symptoms such as pain or fatigue.
It is now well replicated that somatic presentations of depression and anxiety are widespread globally and not restricted to specific ethnocultural groups; however, many “somatizers” in primary care, when prodded, will acknowledge a psychological basis for their symptoms. This has implications for treatment: communicating a patient friendly and culturally compatible model of illness is more likely to enhance treatment adherence, clinical outcomes, and patient and caregiver satisfaction.
CLINICAL PRESENTATION OF DEPRESSION ACROSS GENDER
Depression phenomenology and presentation may also vary as a function of gender although again, these variations are inconsistent across settings. A prior Indian investigation revealed that depressed women experienced greater thoughts of death, an amplified sense of failure, and more social withdrawal compared to their male counterparts. Other findings included a higher frequency of psychotic symptoms in depressed female participants. Cultural explanations such as a lack of employment opportunities and a feeling of dependence leading to a greater sense of failure among women with mental illness were proposed by the authors to explain their findings.
Interestingly, stress may be more “depressogenic” in women; in other words, women experience depression at lower levels of cumulative stress. However, on closer examination, this relationship was true only in those with preexisting dysthymia or low-grade persistent depression. A plausible interpretation of these findings is that prior depression lowers the depressive threshold for those experiencing stress in women more than men. Certain types of life events, such as infertility, are more relevant in women probably owing to the associated sociocultural stigmatization. An older study found greater anger and hostility among depressed women but these have not been consistently replicated.
DIFFERENTIAL TREATMENT RESPONSE ACROSS CULTURES
Besides the high burden of treatment nonresponse in depression, as discussed earlier, there are also variations in antidepressant response rates between cultures. Not all these differences can be explained by genetic and epigenetic variations; indeed, social factors such as the extent and availability of social support and persistence of stress or occurrence of stressful life events during pharmacologic treatment may modulate response to treatment. These findings are consistent with those from a review that examined associations between specific cultural dimensions and antidepressant treatment responses across nations. Specifically, there was a positive association between antidepressant response and the dimension of power distance (extent to which less powerful individuals in the society accept and anticipate inequalities in power distribution) and, to a lesser extent, with dimensions such as masculinity (social penchant for assertiveness, competitiveness, and achievement) and indulgence (degree to which a society permits gratification of human instincts related to pleasure).
Differences in symptom presentation across cultures have also been linked to antidepressant response. In an interesting cross-national comparison of antidepressant response between Sweden and Turkey, authors observed that patients from Turkey showed a greater response to antidepressants. Possible explanations offered included greater patient–physician concurrence on the importance assigned to physical symptoms (pain) in clinical presentation and the greater proportion of Swedish patients with anxiety symptoms which are inherently less responsive to antidepressants. Intriguingly, even though there was no difference between countries in the proportion of those presenting with anxiety symptoms or their severity on symptom rating measures, Turkish physicians were more likely to coprescribe anxiolytics. Thus, the observed variation in antidepressant response may also have been due to variations in prescribing practices.
INTERPLAY BETWEEN CULTURE, ETHNICITY, AND BIOLOGICAL FACTORS
Cultural influences on symptom phenotypes and treatment responses do not happen in a vacuum. Rather, they are superimposed on biological factors, such as genetic and epigenetic variations that may influence the expression and functioning of the brain and drug-metabolizing enzymes. Ethnically determined differences in pharmacokinetic profiles of tricyclic antidepressants and benzodiazepines, evidence for the effectiveness of lower serum levels of lithium in Asians compared to Caucasians, ethnic pharmacogenetic variations in activity levels of key cytochrome enzymes such as CYP2D6 and CYP3A4, have all been well documented.
Finally, there are ethnic variations in sleep-related and neuroendocrine biomarkers for depression; specifically depressed patients of Afro-American descent showed lower rates of dexamethasone nonsuppression compared to their Caucasian counterparts. These imply that the biological causes of depression may vary across cultures and settings and contribute to variations in clinical symptoms. It also highlights the need to understand biological models of depression in the context of racial and ethnic variations across settings.
BIOLOGICAL MODELS OF DEPRESSION
Traditional biological theories of depression have emphasized the deficiency of monoamines, such as serotonin, norepinephrine, and dopamine, in the central nervous system as the cause of depression. However, a recent umbrella review concluded that there is little empirical evidence to support the traditional, and still influential, serotonin theory of depression, and by extension, the monoamine theory of depression. Further, a range of treatment approaches with novel therapeutic targets, such as anti-inflammatory agents and nutraceuticals are both effective and safe in enhancing antidepressant effects. These clinical observations and challenges in treating MDD have triggered a relook at its neurobiology and questioned our traditional understanding of what antidepressants are and how they may exert their therapeutic effects.
This is where alternate biological theories of depression may be helpful and are gaining clinical and research traction. These include neuroplasticity theory, immune-inflammatory theory, mitochondrial dysfunction theory, gut dysbiosis theory, etc. It is beyond the scope of this article to review all these models; however, an attempt is made to introduce some of the important, alternate, and biological models of depression.
Neuroplasticity refers to the innate ability of the neuronal networks in the brain to adaptively respond to internal and external stimuli. This theory postulates that depression occurs due to specific neurohistological changes in key brain areas that contribute to the clinical features of depression. In other words, depression is due to disordered hardwiring in the brain and not merely a state of chemical imbalance, and antidepressants may act by protecting against and reversing many of these changes.
Major lines of evidence supporting the neuroplasticity hypothesis of depression and antidepressant action come from human studies showing decreased neuron–synapse connections in the hippocampus and prefrontal cortex in the brain of subjects with depression, decreased concentration of neurotrophic factors during phases of depression, and rise in levels of neurotrophic factors (such as brain-derived neurotrophic factor) following antidepressant treatment. These trophic factors, in turn, activate the intracellular signaling cascade that stimulates neurogenesis, gliogenesis, new synapse formation, and cell survival in key brain regions such as the hippocampus and prefrontal cortex. These hardwiring changes in neural circuits involved in cognitive processing, behavioral response, and emotional expressions drive clinical response. Because it takes several weeks for these changes to happen, clinical response and recovery are often delayed in depression.
The immune-inflammatory model of depression posits that activation of the immune-inflammatory system triggers oxidative stress, excitotoxicity, and neuronal damage consistent with depression. This is backed by empirical evidence pointing to raised levels of inflammatory markers and cytokines in patients with depression, increased comorbidity between depression and inflammatory medical conditions such as psoriasis, and the depressogenic effects of cytokine-based immunotherapy in patients with hepatitis. Antidepressants have been shown to have anti-inflammatory properties and decrease cytokine levels following treatment. However, there have been inconsistencies in the relationship between changes in inflammatory marker levels and treatment response; specifically, the levels of some, but not all markers, changed with treatment, suggesting the importance of specific symptom subtypes in major depression.
Increased oxidative and nitrosative stress levels triggered by the immune-inflammatory response reduce mitochondrial oxidative phosphorylation, activate apoptotic factors, and trigger mitochondrial damage. Consequently, there is an impaired translocation of mitochondrial electron transport chain complexes leading to decreased adenosine triphosphate production. This energy deficit state caused by mitochondrial dysfunction adversely impacts neuronal transmission, neurogenesis, and synaptic plasticity because energy is required for all these processes. The net result is an inability of the brain to mount an adaptive stress response. Interestingly, different antidepressants have been found to have varying effects on mitochondrial functioning. Studying this in greater detail would improve efforts to personalize treatment for depression based on the unique bioenergetic profile of patients.
Chronic stress, allied with unhealthy lifestyle habits such as smoking and infections, can cause changes in gut microbiota. These changes can signal the brain through neural, immune, and chemical mechanisms, upsetting the normal bidirectional brain–gut axis signaling. These disruptions may trigger depressive symptoms by triggering central inflammation, oxidative stress, and neuronal death. A growing body of evidence highlights changes in gut microbiota composition in various psychiatric disorders, including depression. Moreover, antidepressant treatment has been found to normalize gut microbiota diversity, albeit incompletely. These persistent deficits following treatment may explain why depression begets depression, or in other words, the enduring vulnerability to future depressive episodes, an observation supported by both clinical experience and empirical evidence.
SUMMARY AND IMPLICATIONS
There are three main take-home messages here. First, the clinical presentation of depression is influenced by biological, cultural, and ethnic factors. It is important for clinicians to be aware of culture-specific presentations of depression because it will aid early diagnosis, improve adherence by developing patient-friendly models of illness that are culturally compatible and acceptable, and enhance clinical outcomes. Next, variations in clinical presentation have implications not only for diagnosis but also for treatment response; the latter is influenced by ethnocultural variations in pharmacokinetics, pharmacodynamics, and pharmacogenetics.
Finally, evidence from cross-cultural studies on depression-related biomarkers indicates that the biological underpinnings of depression may also vary within and across cultures. Evidence-based biological models of depression, such as neuroplasticity theory, offer a more complete explanation of pathophysiology of depression and mechanisms of antidepressant response. Understanding depression and antidepressant agents from these perspectives could be beneficial in identifying new treatment targets for alleviating the burden of depression. It may also contribute to developing personalized medicine approaches for managing depression.
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