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Mental Health

Major depressive disorder (MDD)

Mood disorder characterized by one or more major depressive episodes without a history of manic, mixed, or hypomanic episodes.

Mood disorder characterized by one or more major depressive episodes without a history of manic, mixed, or hypomanic episodes.

  • MDD is the #3 cause of the burden of disease worldwide (WHO, 2008)

Depressive disorders:

As per diagnostic Statistical Manual of Mental Disorders, fifth Edition (DSM-5)
  • Persistent depressive disorder (formerly known as dysthymia)
  • Disruptive mood dysregulation disorder 
  • Premenstrual dysphoric disorder
  • Substance/medication-induced depressive disorder
  • Depressive disorder due to another medical condition
  • Unspecified depressive disorder

Etiology

The etiology of major depressive disorder is multifactorial with both genetic and environmental factors playing a role. First-degree relatives of depressed individuals are about 3 times as likely to develop depression as the general population; however, depression can occur in people without family histories of depression.

Model of gene-environment interactions that lead to MDD
Model of gene-environment interactions that lead to MDD: The schematic depicts a model that is based on predisposing genetic vulnerabilities that interact with aversive and protective environmental factors in the development of major depressive disorder (MDD). At least some of the environmental effects are mediated through epigenetic mechanisms to produce the phenotype of MDD, which is characterized by alterations on a molecular level, on a brain network level and on a behavioural level | Otte, C., Gold, S., Penninx, B. et al. Major depressive disorder. Nat Rev Dis Primers 2, 16065 (2016). https://doi.org/10.1038/nrdp.2016.65

Risk factors:

  • Female gender
  • History of anxiety
  • History of eating disorders
  • First-degree relative with a history of depression
  • History of or current drug or alcohol abuse
  • History of or current sexual abuse or domestic violence

Co-morbidities:

patients with major medical conditions or with chronic medical conditions are at a greater risk of experiencing depressive symptoms.
  • Cardiac illnesses: Myocardial infarction, coronary artery atherosclerotic disease, and arrhythmias
  • Cerebrovascular disease (after a stroke or a transient ischemic attack)
  • Diabetes
  • Chronic lung/renal disease
  • Cancer
  • Chronic pain disorders

Pathophysiology

Biological systems involved in the pathophysiology of MDD
Biological systems involved in the pathophysiology of MDD: Clinical studies in major depressive disorder (MDD) and relevant animal models have identified pathophysiological features in the central nervous system, as well as the major stress response systems, such as the hypothalamic-pituitary-adrenal (HPA) axis, the autonomic nervous system, and the immune system. In the central nervous system, altered neurotransmission and reduced plasticity are evident. These could underlie functional changes in relevant brain circuits (for example, cognitive control and affective–salience networks), smaller regional brain volumes (for example, in the hippocampus), and neuroinflammation, as confirmed in neuroimaging studies. Beyond the central nervous system, chronic hyperactivity impairs feedback regulation of the HPA axis, which is one of the most consistently reported biological features of MDD. Within the immune system, substantial evidence supports increased levels of circulating cytokines and low-grade chronic activation of innate immune cells, including monocytes. However, other aspects of immunity seem to be impaired as exemplified by reduced natural killer (NK) cell cytotoxicity and Tcell proliferative capacity. Once it becomes chronic, both HPA axis hyperactivity and inflammation might converge with alterations in the autonomic nervous system to contribute to central nervous system pathobiology as well as cardiovascular and metabolic disease, which often co-occur with MDD. The sequence of events leading to changes in these interconnected systems and their exact relationship is not known. However, mechanistic studies in animals have shown that alterations in stress response systems can, directly and indirectly, affect the central nervous system. Conversely, chronic stress and associated changes in behaviour can reproduce many of the stress system alterations, including HPA feedback impairment and inflammation, which suggests a bidirectional link between central and peripheral biological features of MDD. | ACTH, adrenocorticotropin; CRH, corticotropin-releasing hormone; TNF, tumour necrosis factor. | Otte, C., Gold, S., Penninx, B. et al. Major depressive disorder. Nat Rev Dis Primers 2, 16065 (2016). https://doi.org/10.1038/nrdp.2016.65

Brain changes:

  • Structural MRI: Reduction in volume of cingulate cortex, prefrontal cortex, amygdala and hippocampus
  • Functional MRI:
    • Compromised function in prefrontal area during cognitive task
    • Hyperactivity of limbic system during an emotional task

Clinical features

Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnostic criteria:

Individual must have 5 symptoms, of which one must be a depressed mood or anhedonia causing social or occupational impairment, to be diagnosed with MDD.
  • Persistently low or depressed mood
  • Anhedonia (decreased interest in previously pleasurable activities)
  • Feelings of guilt or worthlessness
  • Lack of energy
  • Poor concentration
  • Appetite changes
  • Psychomotor retardation/agitation
  • Sleep disturbances
  • Suicidal thoughts

Complications:

Major depressive disorder: Complications

Diagnosis

Major depressive disorder is a clinical diagnosis; it is mainly diagnosed by the clinical history given by the patient and mental status examination. The clinical interview must include medical history, family history, social history, and substance use history along with the symptomatology. Collateral information from a patient’s family/friends is a very important part of psychiatric evaluation.

Screening tests:

  • Patient Health Questionnaire-9 (PHQ-9): Self-report, standardized depression rating scale is commonly used for screening, diagnosing, and monitoring treatment response for MDD
  • Hamilton Rating Scale for Depression (HAM-D) (hospital settings): Clinician-administered depression rating scale is commonly used for the assessment of depression
  • Other scales:
    • Montgomery-Asberg Depression Rating Scale (MADRS)
    • Beck Depression Inventory (BDI)
    • Zung Self-Rating Depression Scale
    • Raskin Depression Rating Scale
    • Ask Suicide-Screening Questions
Depression and Suicide Screening Tools
Depression and Suicide Screening Tools. On the Patient Health Questionnaire 2 (Panel A), a score of 3 or higher is 83% sensitive and 90% specific for a diagnosis of major depression. On the Ask Suicide-Screening Questions (Panel B), if the patient answers “no” to all four questions 1 through 4, the screening is complete and it is not necessary to ask question 5. No intervention is necessary (clinical judgment can always override a negative screening test). If the patient answers “yes” to any of questions 1 through 4 or declines to answer, the screening test is considered to be positive, and question 5 should be asked to assess severity. If the patient answers “yes” to question 5, the test is considered to be positive with an imminent risk identified. The patient requires immediate safety and a full mental health evaluation and cannot leave until he or she is evaluated for safety. Keep the patient in sight, remove all dangerous objects from the room, and alert the physician or clinician who is responsible for the patient’s care. If the patient answers “no,” the screening test is considered to be a positive test with a potential risk identified. He or she requires a brief suicide safety assessment to determine whether a full mental health evaluation is needed and cannot leave until he or she is evaluated for safety. Alert the physician or clinician who is responsible for the patient’s care. | Data adapted from www.nimh.nih.gov/labs-at-nimh/asq-toolkit-materials/index.shtml#outpatient. | Park, L. T., & Zarate, C. A., Jr (2019). Depression in the Primary Care Setting. The New England journal of medicine, 380(6), 559–568. https://doi.org/10.1056/NEJMcp1712493

Management

Stepped-care model:

The initial treatment of MDD includes medications or/and psychotherapy. Combination treatment, including both medications and psychotherapy, has been found to be more effective than either of these treatments alone. Electroconvulsive therapy is found to be more efficacious than any other form of treatment for severe major depression.
Stepped Care Approach to Managing Depression and Anxiety in Adults
Stepped Care Approach to Managing Depression and Anxiety in Adults (based on NICE guidelines). | CBT = cognitive behavioural therapy; GAD = generalised anxiety disorder. | The extra-articular impacts of rheumatoid arthritis: moving towards holistic care – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Stepped-Care-Approach-to-Managing-Depression-and-Anxiety-in-Adults-based-on-NICE_fig2_328612572 [accessed 9 Dec, 2020]

Pharmacotherapy:

  • Selective serotonin reuptake inhibitors (SSRIs): First-line for late-onset depression
    • Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, vilazodone, vortioxetine
  • Serotonin/norepinephrine reuptake inhibitors (SNRIs): In patients non-responsive to SSRIs and first-line agents in cases with significant fatigue/pain syndromes associated with depression
    • Venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran
  • Atypical antidepressants: Bupropion, mirtazapine, nefazodone, and trazodone
  • Serotonin-Dopamine Activity Modulators (SDAMs): Partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and as an antagonist at 5-HT2A and noradrenaline
    • Brexpiprazole and aripiprazole
  • Tricyclic antidepressants (TCAs): Amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine
  • Monoamine oxidase inhibitors (MAOIs): Isocarboxazid, phenelzine, selegiline, and tranylcypromine

Electroconvulsive therapy (ECT):

Treatment of choice for patients who do not respond to drug therapy, are psychotic, or are suicidal or dangerous to themselves.

Psychotherapy:

  • Cognitive behavior therapy (CBT): Structured, and didactic form of therapy that focuses on helping individuals identify and modify maladaptive thinking and behavior patterns (16-20 sessions).
  • Interpersonal therapy: Time-limited (typically 16 sessions) treatment for major depressive disorder which draws from attachment theory and emphasize the role of interpersonal relationships, focusing on current interpersonal difficulties.

Summary:

Major depressive disorder is a psychiatric condition that is characterized by persistent depressed mood, diminished interests, impaired cognitive function and vegetative symptoms
Major depressive disorder is a psychiatric condition that is characterized by persistent depressed mood, diminished interests, impaired cognitive function and vegetative symptoms. | Major depressive disorder. Nat Rev Dis Primers 2, 16066 (2016). https://doi.org/10.1038/nrdp.2016.66

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