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Depression

Updated : June 21, 2024





Background

Depression is a serious mental disease and mood disease. It is characterized by the prolonged sadness, feeling of hopelessness, and lack of pleasure or interest in the enjoyable activities. It can interfere with daily life, like school, work, and relationships. Depression affects 264 million people worldwide and lead to cause the disability. 

Depression occurs at any age, but mostly, it develops during the teenage or early adulthood. It is common in females than males. Depression may be a recurring disease, and people who have had one episode of depression are at risk of the other episodes.  

Epidemiology

Prevalence: As per the WHO, depression is a leading cause of the disability in world, and it affects 264 million people globally.  

Age and Gender: Depression can affect the people at any age, including older adults and children. The depression is common during the adolescence or early adulthood. The ratio of incidence of depression in females and males is about 2:1. 

Geographic Variations: The prevalence of depression may vary across the countries and regions. As per the study in the Journal of Affective Disorders, the prevalence of MDD is 0.5% in China and 21% in Ukraine.  

Mortality: Depression is also associated with mortality, especially from suicide. As per the WHO, suicide is a second leading cause of the death from people ages 15 to 29 years widely with a depression.  

Anatomy

Pathophysiology

Depression is a complex psychiatric disease. It contains multifactorial etiology and pathophysiology. Exact underlying cause is unclear. There are several factors which contribute to the depression.  

Monoamine Hypothesis 

The monoamine hypothesis shows that depression is caused by neurotransmitter imbalances like norepinephrine, serotonin, and dopamine. Low level of these neurotransmitters is linked to the symptoms of depression. 

Neurotrophic Hypothesis 

The neurotrophic hypothesis shows that depression is caused by low levels of neurotrophic factors like nerve growth factor and brain-derived neurotrophic factor. These factors are important for the growth, development, and maintenance of the neurons in the brain. A low level of these factors can lead to the atrophy and brain areas dysfunction which are involved in mood regulation. 

Inflammatory Hypothesis 

The inflammatory hypothesis suggests that the depression is caused by an increased level of pro inflammatory cytokines like IL-6, IL-1, and TNF-α. These cytokines are enhanced by the immune system in the response to inflammation and stress.  

HPA Axis Dysregulation Hypothesis 

The HPA axis dysregulation hypothesis shows that depression is caused by a dysregulation in HPA axis. The HPA axis is lead stress response in the body.  

Genetic Predisposition 

Multiple genes are involved in the development of depression. These include the neurotransmitter regulation, immune system function, and neurotrophic factor production. 

Etiology

Depression is caused by environmental, genetic, and psychological factors.  

Environmental factors: Environmental factors like stressful life, like losing a loved one. Divorce. Job loss and financial difficulties may trigger depression. 

Genetics: Genetic factors may be involved in the development of depression. Studies have shown that there is an increased incidence of depression in families who have a history of the disease.  

Neurotransmitter imbalances: Imbalance in the neurotransmitter like norepinephrine, dopamine, and serotonin are linked to depression. 

Medical conditions: Chronic pain, cancer, heart disease, and stroke can lead to depression.  

Substance abuse: Alcohol and drug can lead to development of depression. 

Medications: Medications like beta-blockers, hormonal therapies, and corticosteroids can lead to depression.  

Hormonal imbalances: Imbalance in hormones during pregnancy, postpartum, and menopause can lead to depression.  

Cognitive factors: Negative thoughts, low self-belief can lead to development of depression. 

Genetics

Prognostic Factors

Severity of depression: Patients who have a severe depression may have a poorer diagnosis than the one who have a mild symptom of depression.  

Co-occurring medical or psychiatric conditions: Patients who have a depression along with other conditions like substance abuse or anxiety may have a worse prognosis of depression.  

Age: Old patients may have a worse prognosis than the younger ones.  

Social support: Patients who have adequate social support may have a better prognosis than the one who are isolated from society.  

Treatment response: Patients who are responded well in the treatment may have a better prognosis than the one who are not responding well.  

Clinical History

A typical clinical evaluation for depression involves examining the physical signs of patients. Symptoms like feelings of sadness, hopelessness, worthlessness, and guilt lasting than 2 weeks are common. Other indicators may include loss of interest, changes in eating and sleeping habits, fatigue and trouble focusing. 

Moreover, the assessment may cover factors which are related to the risk of suicide like suicide attempts, suicidal thoughts and access to means of self-harm of patients. This information plays an important role in treatment plan that meets the individuals needs while minimizing the risk of harm. Clinicians might utilize tools or surveys to scale the severity of symptoms and progression of over time.  

Physical Examination

Vital Signs: Measurement of blood pressure, pulse rate, body temperature, and respiratory rate 

Neurological Examination: Evolution of reflexes, coordination, muscular strength, and sensation 

Gastrointestinal System: Examination of changes in appetite and weight 

Medicine and Substance Use: Discussion of current medications use including herbal supplement and substance used including the alcohol and drugs.  

Sleep Patterns: Discussion of sleep patterns and disturbances. 

There is also a need to perform a mental health status examination to evaluate the mood of patient, behavior, and though process. It includes the assessment of appearance of patients. Motor activity, speech, thought, and mood. It also includes the screening test like Patient Health Questionnaire-9 (PHQ-9) or Beck Depression Inventory (BDI). This can assess the severity of symptoms of depressions.  

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Major depressive disorder: Prolonged feelings of emptiness and sadness, loos of interest, feeling of worthlessness or guilt, fatigue, changes in sleep and appetite, and thoughts of death and suicide.  

Persistent Depressive Disorder or Dysthymia: Chronic depression with long-lasting and mild symptoms. It lasts for more than 2 years.  

Bipolar Diseases: Alteration of times of sadness with periods of hypomania or mania.  

Substance-Induced Mood Disorder: Substance abuse can mimic the symptoms of depression. It led to use of substances.   

Adjustment disorder: Stressor like divorce, job loss or disease may lead to depressed mood.  

Schizophrenia: It is a chronic mental disease that may present with depression. 

Personality disorders: Personality diseases like avoidant personality disorder and borderline personality disorder may lead to depression.  

Medical conditions: Medical conditions like vitamin deficiencies, neurological disorders, and thyroid diseases may lead to depression.  

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Assessment and Diagnosis: 

The following criteria are used to determine the first modality: 

Clinical evaluation 

Existence of any diseases 

Stress 

Patient’s selection 

Response to early medical treatment 

Psychotherapy 

Weekly sessions of 60 minutes are offered as a part of outpatient psychotherapy. It has a time limit and great variation of application.  

Medication:  

Medications which are used to treat the depression are SSRIs, SNRIs, agonists for serotonin (5HT)-1a, SDAMs, TCAs, depression relievers, MAOIs, NMDA receptors.  

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Lifestyle modifications in treating depression

Psychotherapy  

Cognitive-Behavioral Therapy (CBT): This method is a systematic approach to recognize and change the detrimental effects of behavior and thought patterns which are contribute to the depression.  

Interpersonal Therapy (IPT): IPT reduces depression symptoms by enhancing communication and relationships.  

Dialectical Behavioral Therapy (DBT): DBT treats the emotional dysregulations and interpersonal problems by combination of cognitive and behovioral methods.   

Use of tricyclic antidepressants to treat depression

Imipramine 

Imipramine is used to treat the depression. It increases the serotonin and norepinephrine level in brain and plays an important role in mood stability. 

Desipramine 

Desipramine is used to treat the depression. It increases the serotonin and norepinephrine level in brain to a lesser extent. It plays an important role in mood stability. 

Clomipramine:  

Clomipramine is primarily used to treat the OCD and MDD. It increases the serotonin level and some level of norepinephrine in the brain. It plays an important role in mood stability. 

Trimipramine 

Trimipramine is used to treat the depression. It increases the serotonin and norepinephrine level in brain and plays an important role in mood stability. 

Doxepin 

Doxepin is used to treat the depression. It increases the serotonin and norepinephrine level in brain and plays an important role in mood stability. It is also used to treat the sleep disease and anxiety.  

Amitriptyline 

Amitriptyline is used to treat the depression. It increases the serotonin and norepinephrine level in brain and plays an important role in mood stability. 

Nortriptyline:  

Nortriptyline is similar to amitriptyline. It is used to treat the depression. It increases the serotonin and norepinephrine level in brain and plays an important role in mood stability. 

Protryptyline:  

Protryptyline is used to treat the depression. It increases the level of norepinephrine, and some extend serotonin in the brain. It plays an important role in mood stability. 

Use of SSRI (Selective Serotonin Reuptake Inhibitors) to treat depression

Citalopram:  

Citalopram increases the serotonin level in brain and plays an important role in mood stability. 

Escitalopram 

Escitalopram and citalopram are closely related. Escitalopram is an active S-enantiomer of citalopram. It has more efficacy and decreased side effects than the citalopram. It elevates the serotonin levels in the brain.  

Fluvoxamine: 

Fluvoxamine increases the serotonin level in the brain and plays an important role in mood stability. 

Fluoxetine: 

Fluoxetine increases the serotonin level in the brain by blocking the reuptake of serotonin. It plays an important role in mood stability. 

Paroxetine 

Paroxetine increases the serotonin level in the brain by blocking the reuptake of serotonin. It plays an important role in mood stability. 

Sertraline 

Sertraline increases the serotonin level in the brain by blocking the reuptake of serotonin. It plays an important role in mood stability. 

Vilazodone 

Vilazodone increases the serotonin level in the brain and acts as a SRI. It also inhibits the activity of serotonin 5-HT1A receptors by acting as a partial agonist. It has two fold actions and plays an important role as an antidepressant.  

Vortioxetine: 

Vortioxetine is a serotonin modulator. It has a complicated action. It increases the serotonin level in the brain and acts as a SRI by blocking the reuptake of serotonin. It also affects the several serotonin receptors like 5- HT1B, 5- HT1A, and 5- HT1D in an antagonistic and agonistic manner. It plays an important role as an antidepressant.  

Use of serotonin/norepinephrine reuptake inhibitors (SNRI) to treat depression

Venlafaxine 

Venlafaxine prevents the brain from reabsorbing the serotonin and norepinephrine. It is contributing to anxiolytic and antidepressant properties. 

Desvenlafaxine 

Desvenlafaxine is used to treat the depression and mood disorders. It increases the level of serotonin and norepinephrine in the brain and plays an important role in mood regulation.  

Duloxetine:  

Duloxetine is used to treat the depression. It increases the level of serotonin and norepinephrine in the brain and plays an important role in the mood regulations.  

Levomilnacipram:

Levomilnacipram is used to treat the depression. It increases the level of serotonin and norepinephrine in the brain and plays an important role in the mood regulations.  

Use of serotonin 5HT-1A agonists to treat depression

Gepirone: 

Gepirone interact with the serotonin 5-HT1A receptors and act as a partial agonist. It activates the receptors which may influence the control of anxiety and mood. 

Use of atypical antidepressants to treat depression

Bupropion 

Bupropion role in not fully understood. It mainly impacts the level of dopamine and norepinephrine in the brain.  

Mirtazapine: 

Mirtazapine action is different. It elevates the release of neurotransmitters like norepinephrine and serotonin in the brain. It has an effect on particular serotonin receptors. It plays an important role in regulation of mood and reduced the symptoms of depression. 

Nefazodone 

Nefazodone enhances the release of neurotransmitters like norepinephrine and serotonin in the brain. 

Trazodone 

Trazodone action is unclear. It increases the level of serotonin in the brain. It helps to treat the insomnia. 

Use of modulators of serotonin-dopamine activity to treat depression

Brexipiperazole:  

Brexipiperazole acts as a partial agonist at serotonin 5-HT1A receptors and dopamine D2. It acts as an antagonist on the 5-HT2B and 5-HT2A serotonin receptors.  

Cariprazine 

Cariprazine reacts as a partial agonist at dopamine D3 and D2 and serotonin 5-HT1A receptors. It acts as an antagonist on the 5-HT2A serotonin receptors. It also used to treat the bipolar disorders and schizophrenia. 

Aripiprazole 

Aripiprazole reacts as a partial agonist at dopamine D2 and 5-HT1A receptors. It acts as an antagonist on the serotonin 5-HT2A receptors.  

Use of MAO inhibitors to treat depression

Isocarboxazid 

Monoamine oxidase is an enzyme which degrades the neurotransmitters like orepinephrine, serotonin, and dopamine in the brain. Isocarboxazid inhibits these neurotransmitters. It increases the level of neurotransmitters and blocks this enzymes. It has an antidepressant effects. 

Phenelzine 

Phenelzine prevents the degradation of neurotransmitters serotonin, norepinephrine, and dopamine in the brain. It increases the level of neurotransmitters and blocks this enzymes. It has an antidepressant effects. 

Selegiline 

Selegiline prevents the degradation of neurotransmitters serotonin, norepinephrine, and dopamine in the brain. It increases the level of neurotransmitters and blocks this enzymes. It has an antidepressant effects and anti-Parkinson’s effect. 

Tranylcypromine: 

Tranylcypromine prevents the degradation of neurotransmitters serotonin, norepinephrine, and dopamine in the brain. It increases the level of neurotransmitters and blocks this enzymes. It has an antidepressant effects. 

Use of NMDA antagonists to treat depression

Esketamine: 

Esketamine is an antagonist of the NMDA receptor. It modifies the glutamatergic system in the brain. It is useful to treat depression which are resistant to treatment in part. 

Use of St.John’s wort to treat depression

The action of St.John’s wort is unclear. It alters the level of neurotransmitters like serotonin in the brain. It has antioxidant and anti-inflammatory properties. 

Use of Psilocybin to treat depression

Psilocybin has drawn an interest in medical uses, it has some promising results in the ongoing studies to treat the conditions like anxiety, depression, and PTSD. 

Depression during pregnancy

As per the APA guidelines, psychotherapy used to treat the mildly depressed pregnant women. Electroconvulsive therapy can be fastest and safest treatment for the severe depression during the pregnancy especially in cases of agitation, severe retardation, and psychosis. Bright-white-light therapy was a significantly more effective than the placebo treatment to treat the depression during pregnancy in a double-blind study. 

Non-pharmacological therapy to treat depression

Behavioural Activation (BA) 

BA is depending on the early functional descriptions to treat the depression by Lewinsohn and Ferster. It focuses on the positive and negative reinforcement of depression. Modern BA treatments were developed in response to Jacobson et al. analysis. 

Cognitive Behavioural Therapy (CBT) 

CBT is time limited method. It requires 10 to 20 sessions. CBT is used in combination with BT to treat depression. 

Interpersonal Therapy (IPT) 

IPT is a time limited method. It focuses on the contemporary interpersonal factors. It gives the importance to the interpersonal relationships and attachment theory. 

Mindfulness-Based Cognitive Therapy (MBCT) 

MBCT integrated the CBT and mindfulness-based stress reduction (MBSR). It decreases the rate of relapse in patients who have had successful treatment of recurrent MDD episodes. 

Problem Solving Therapy (PST) 

PST enhances the problem-solving attitudes and behaviors of patients. It is used to treat MDD based on a model which describes the social problem solving as moderator and mediator of the relationship between depression and stress.  

Electroconvulsive therapy (ECT) to treat depression

ECT is a very successful treatment to treat depression. The benefits of the treatment may be felt within week of starting the treatment and the action is quicker than the other medications treatments. The patients who are not well respond to the other medications therapy, suicidal or psychotic are treated with ECT. It consists of 12 sessions. The indicators to use of the ECT is as below: 

Medications therapy failure 

Need an immediate action with the antidepressants  

Any history of positive response to ECT 

Selection of patients 

High suicide risk 

Increased risk of death and morbidity from medications 

Use of Bright-Light therapy (BLT) to treat depression

BLT is a treatment which is used for seasonal affective disorder. 10000 lux of BLT is given for 30 to 90 minutes daily. It can cause hypomanic or manic episodes in vulnerable individuals. The side effects of this treatment include headache, restlessness, and eye irritation. BLT is not effective as much as UV lights. Conventional antidepressants may be used to along with the BLT or without BLT. It is beneficial for older patients and pregnant women. 

Additional treatment for depression

Deep brain stimulation (DBS) is a promising and long-term treatment to treat the depression. It is used in cases of resistant to conventional treatments. Effectiveness of this treatment is still experimental. A double blind, randomized, controlled trail showed that the transcranial direct current stimulation (tDCS) and sertraline were more effective than the medication alone. The combination of the group has a significant difference in the depression rating scale score which is compared with the sertraline-only (Mean difference 8.5 points), tDCS-only (5.9 points), and placebo groups (11 points). 

Treatment of pediatric depression

Fluoxetine is the only medication which is approved by USFDA to treat the pediatric depression. 

Treatment of postpartum depression

Major depressive disorders treatment after childbirth leads to the same guidelines as any other depression to a better prognosis linked to earlier initiations. A Cochrane review showed that psychological and psychosocial interventions can significantly decrease the proportion of the postpartum depression in females. Interventions like intensive home visits, interpersonal psychotherapy, and peer-based support decreased the risk ratio by 0.78 compared to the standard care. The course of the postpartum blues is mild and resolves by its own. 6 to 12 months of treatment is suggested for the first episodes and for long-term management of the treat with an antidepressant for the recurrence. 

Use of antidepressants in lactation:  

Most of the antidepressants are safe to use while nursing but their long-term effects is still unknown. Pregnant women should approach a depression treatment with the same risk benefit analysis. Antidepressants are secreted into the breast milk,]] and the level may vary. There are a positive data presents for fluoxetine, TCAs, paroxetine, and sertraline with minimum or no antidepressants level presents in the breast milk.  

Use of antidepressants in geriatric population:  

Geriatric patients should start the antidepressants medications from a lower dosage approx. half of the recommended dosage and titrate more slowly than the adults. The standard method to adjust the dosage, changes the medications, or declaration of treatment failure is about 12 weeks. More research has been done during that 12 weeks of waiting time. Drug-drug interactions is a major concern with the SSRIs, fluvoxamine, paroxetine, and fluoxetine with a high risk.  

Hospitalization

Hospitalization must be initiated with the emergency commitment or consent of patients if suicidal idea is present. A child who has attempted suicide must be placed in a protected place until all the resources are utilized. Homicidal or suicidal idea into a significance of hospitalization in a mental health facilities. Other symptoms may include the extreme disorganization, deep depressive symptoms, inability to meet basic needs. 

Diet and activity

The MIND diet is a combination of DASH and Mediterranean diets. It has been shown to protect from the cognitive function and improve the mental health in depressed patients. The MIND diet improves the mental health and reduced the dementia risk.  

Tyramine rich foods must be avoided when MAOIs are prescribes. These foods include air-dried sausage, raisins, sauerkraut, shrimp paste, sour cream, caviar, tinned figs, avocados, meat tenderizer, beer, wine, aged cheese, and aged chicken or cow liver. Physical activities and exercise are necessary for the recovery. Stress reduction counselling must be provided to the patients.  

Consultations

Consultations is important in the treatment specifically in patients who have severe symptoms and requires intensive care. Physicians should consult a psychiatrist of they have utilized all the options. Somatic therapies, psychotherapy, and medication must be easily accessible specifically for patients who have suicidal idea, psychosis, mania. or physical health decline.  

Phases of Management

Evaluation, treatment, and maintenance are the 3 phases of depression management.  

Evaluation and Prognosis:  

Clinical Evaluation: A comprehensive examination by a medical professional usually by a primary care physician, psychiatrist, or psychologist.  

Screening Tools: Standardized questionnaires like the Patient Health Questionnaire-9 (PHQ-9) are used to diagnose and severity of evaluation. 

Treatment Plan: Various treatments like psychotherapy, medications, or combination are used to treat the depression. 

Treatment for the Acute Phase:  

The achievement of the acute phase is to reduce the most severe symptoms of depression.  

Drug therapy: It is necessary to prescribe the antidepressant medication to stabilize the mood and to reduce the symptoms. 

Psychotherapy: CBT, PT, and other therapies are used to treat the depression.  

Continuation phase treatment:   

The achievemnet of the continuation phase is to keep the depressive symptoms from returning to improvement in the acute phase. This phase lasts for 4 to 9 months. 

Medication: The patients should continue to take the therapeutic dosage of antidepressants.  

Psychotherapy: Ongoing treatment may support the reinforcement of healthy mechanisms.  

Treatment of Maintenance Phase:  

The goal of maintenance phase is to prevent the depressive episodes from happening again.  

Medications and Psychotherapy is used to treat the maintenance phase of depression.  

Medication

 

ephedrine

25 mg-50 mg IM or subcutaneously or 5 mg-25 mg IV administered slowly repeat the dose in 5-10 minutes as needed



paroxetine

20

mg

Orally 

every day

and increase up to 20-50 mg/day orally
The Maximum dose for a day is 50 mg



brexpiprazole 

0.5

mg

Tablet

Orally 

every day

Do not exceed 3mg/day



protriptyline 

Initial dose-10mg/day and increase the dose upward every 5-7 days then, 15-60mg/day orally every 6-8 hours
Do not exceed 60mg/day



nortriptyline 

25

mg

Capsule

Orally 

every 6 -8 hours

Do not exceed 150mg/day



5-htp 

The medication dosage of 150-300 mg orally once a day is prescribed for depression



isocarboxazid 

10 mg orally every 6-12 hours; increase the dose by 10-40 mg/kg divided every 6-12 hours by the end of the first week
Increase the dose by a maximum of 20 mg/week to 60 mg/day
After the 1st week, increase the dose from 20 mg/week to 60 mg/day
After achieving the maximum effect, decrease upto maintenance dose



phenelzine  

Initially, 15 mg orally every 8 hours; increase the dose to 60 mg/day with patient tolerance; do not exceed more than 20-30 mg every 8 hours
Continue the treatment with 60 mg for 4 weeks in the patients who do not show clinical response
Decrease the dose after the maximum response is achieved in 2-6 weeks
Maintain it as low as 15 mg each day or every other day
Monitor the blood pressure during the same



nefazodone 

100 mg orally every 12 hours
Increase the dose by 50-100 mg/dose
Maintenance dose- 300-600 mg orally each day
The dose is increased by 100-200 mg per day at an interval of a minimum of 1 week
Long-term patients require 52 weeks for the treatment



mirtazapine 

15 mg orally every night; increase the dose every 1-2 weeks
Do not exceed the dose of more than 45 mg orally each evening



amoxapine 

25 mg orally every 8-12 hours
Increase the dose to 200-300 mg orally every night after 5-7 days
If the dose exceeds more than 300 mg/day, divide the dose every 12 hours
Do not exceed the dose of 400 mg each day
Inpatients may need higher doses; administer up to 600 mg/day as divided doses twice daily



fluoxetine 

Indicated for depression because of Bipolar I Disorder
Initially, 20 mg fluoxetine with 5 mg olanzapine orally every evening
Dose Adjustment
According to the tolerance and efficacy, take 20-50 mg of fluoxetine and 5-12.5 mg of olanzapine



desipramine 

100 - 200

mg

Orally 

at bedtime or divided 2 times daily


may be increase up to 300 mg daily when severely ill



imipramine 

Outpatient:

75


75 orally daily; may be increase up to150 mg/day in divided doses do not exceed 200 mg a day
Inpatient:
100-150 mg orally daily
may increase up to 200 mg daily
after 2 weeks if there is no response, increase dose up to 250-300 mg
do not exceed 300 mg daily

the Maximum dose given is 50-100 mg orally daily



doxepin 

25

mg

daily; titrate gradually

5 - 7