Depression

Introduction

Depression is a serious medical illness. It’s more than just a feeling of being sad or “blue” for a few days. Symptoms of depression may include:

• Feeling sad or “empty”
• Loss of interest in favorite activities
• Overeating, or not wanting to eat at all
• Not being able to sleep, or sleeping too much
• Feeling very tired
• Feeling hopeless, irritable, anxious, or guilty
• Aches or pains, headaches, cramps, or digestive problems
• Thoughts of death or suicide

Depression is a disorder of the brain. There are a variety of causes, including genetic, biological, environmental, and psychological factors. Depression can happen at any age, but it often begins in teens and young adults. It is much more common in women. Women can also get postpartum depression after the birth of a baby. Some people get seasonal affective disorder in the winter. Depression is one part of bipolar disorder too.

Associated Anatomy

Scientific studies have found that numerous brain areas show altered activity in people with major depressive disorder, and this has encouraged advocates of various theories that seek to identify a biochemical origin of the disease, as opposed to theories that emphasize psychological or situational causes. Factors spanning these causative groups include nutritional deficiencies in magnesium, vitamin D, and tryptophan with situational origin but biological impact. Several theories concerning the biologically based cause of depression have been suggested over the years, including theories revolving around monoamine neurotransmitters, neuroplasticity, neurogenesis, inflammation and the circadian rhythm. Physical illnesses, including hypothyroidism and mitochondrial disease, can also trigger depressive symptoms. Neural circuits implicated in depression include those involved in the generation and regulation of emotion, as well as in reward. Abnormalities are commonly found in the lateral prefrontal cortex whose putative function is generally considered to involve regulation of emotion. Regions involved in the generation of emotion and reward such as the amygdala, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and striatum are frequently implicated as well. These regions are innervated by a monoaminergic nuclei, and tentative evidence suggests a potential role for abnormal monoaminergic activity.

Causes

The specific cause of major depressive disorder is not known. As with most psychiatric disorders, major depressive disorder appears to be a multifactorial and heterogeneous group of disorders involving both genetic and environmental factors. Evidence from family and twin studies indicates that with depression that develops in early childhood, the transmission from parents to children appears to be related more to psychosocial influences than to genetics. Adolescent-onset and adult-onset depression, while more heritable than prepubertal depression, likewise reflect an interaction between genes and environmental stressors. As with many mental disorders, a variety of factors may be involved, such as:

• Biological differences. People with depression appear to have physical changes in their brains. The significance of these changes is still uncertain, but may eventually help pinpoint causes.
• Brain chemistry. Neurotransmitters are naturally occurring brain chemicals that likely play a role in depression. Recent research indicates that changes in the function and effect of these neurotransmitters and how they interact with neurocircuits involved in maintaining mood stability may play a significant role in depression and its treatment.
• Hormones. Changes in the body’s balance of hormones may be involved in causing or triggering depression. Hormone changes can result with pregnancy and during the weeks or months after delivery (postpartum) and from thyroid problems, menopause or a number of other conditions.
• Inherited traits. Depression is more common in people whose blood relatives also have this condition. Researchers are trying to find genes that may be involved in causing depression.

Differential Diagnosis

The differential diagnosis for depression includes a wide variety of medical disorders, such as the following:

• Central nervous system diseases (eg, Parkinson disease, dementia, multiple sclerosis, neoplastic lesions)
• Endocrine disorders (eg, hyperthyroidism, hypothyroidism)
• Drug-related conditions (eg, cocaine abuse, side effects of some CNS depressants)
• Infectious disease (eg, mononucleosis)
• Sleep-related disorders
• Related psychiatric disorders

Major depressive disorder must be differentiated from dysthymia. Patients with dysthymia present with low mood for at least 2 years as a primary symptom; they have insufficient symptoms to meet criteria for major depressive disorder. However, dysthymia may predate a depressive episode. Misdiagnosis of bipolar disorder as recurrent unipolar depression may occur if the clinician does not identify the presence of hypomania between depressive episodes. This leads to inadequate treatment and, theoretically, could lead to a precipitation of a hypomanic, manic, or mixed episode. Patients with anxiety disorders are at higher risk for developing comorbid depression. In such patients, it is important to identify the anxiety disorder, because affected individuals often require specific treatment approaches. Commonly encountered anxiety disorders include the following:

• Generalized anxiety disorder
• Obsessive-compulsive disorder
• Panic disorder
• Phobic disorders
• Posttraumatic stress disorder

Patients with certain personality disorders (eg, borderline personality disorder) may present with mood changes as a prominent symptom. The presence of a personality disorder can be difficult to determine in the setting of active affective symptoms. Many depressed patients who appear labile, demanding, or pathologically dependent look dramatically different once the depressive episode has been treated adequately. People with eating disorders also have a high rate of comorbid major depressive disorder and require specific treatment approaches. These disorders include bulimia, anorexia nervosa, and eating disorder not otherwise specified. A large percentage of individuals in this last group have binge-eating disorder.

Drugs

Drugs used for the treatment of depression include the following:

• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin/norepinephrine reuptake inhibitors (SNRIs)
• Atypical antidepressants
• Serotonin-Dopamine Activity Modulator (SDAMs)
• Tricyclic antidepressants (TCAs)
• Monoamine oxidase inhibitors (MAOIs)
• N-methyl-D-aspartate (NMDA) receptor antagonists
• St. John’s wort (Hypericum perforatum)

Antidepressants SSRIs:

Citalopram (Celexa)

Citalopram enhances serotonin activity as a result of selective reuptake inhibition at the presynaptic neuronal membrane. It has minimal effects on norepinephrine and dopamine. Although it has FDA approval only for depression, citalopram is commonly prescribed for other psychiatric disorders, including obsessive-compulsive disorder, generalized anxiety disorder, panic disorder, and premenstrual dysphoric disorder. The FDA advises that the dose of citalopram not exceed 40 mg/day because of the risk of potentially fatal QT prolongation. Furthermore, higher doses have not been shown to be more effective in treating depression.

Escitalopram (Lexapro)

Escitalopram is an SSRI and S-enantiomer of citalopram used for the treatment of depression. The mechanism of action is thought to be potentiation of serotonergic activity in the central nervous system resulting from inhibition of CNS neuronal reuptake of serotonin. Escitalopram has little or no effect on norepinephrine and dopamine reuptake. Onset of depression relief may occur after 1-2 wk, but individual responses vary, and a full effect may not be seen until 8-12 weeks.

Fluoxetine (Prozac)

Fluoxetine is a commonly used SSRI and was the first of the SSRIs to become available in the United States. It selectively inhibits presynaptic serotonin reuptake with minimal or no effect on reuptake of norepinephrine or dopamine. It is commonly prescribed for many indications that are not FDA approved, including fibromyalgia, posttraumatic stress disorder, Raynaud phenomenon, social anxiety disorder, and selective mutism.

Fluvoxamine (Luvox)

Fluvoxamine enhances serotonin activity due to selective reuptake inhibition at the neuronal membrane. It does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors and thus has fewer side effects than tricyclic antidepressants. Fluvoxamine is a strong inhibitor of cytochrome P-450. Although fluvoxamine is FDA approved only for obsessive-compulsive disorder, it is commonly prescribed for other psychiatric disorders, including social anxiety disorder, posttraumatic stress disorder, pain disorder, and major depression.

Paroxetine (Paxil, Pexeva)

Paroxetine is a potent selective inhibitor of neuronal serotonin reuptake and also has a weak effect on norepinephrine and dopamine neuronal reuptake. It has slight anticholinergic effects and may cause more weight gain than other SSRIs. Paroxetine is sometimes prescribed for indications that are not FDA approved, such as eating disorders and the relief of vasomotor symptoms of menopause.

Sertraline (Zoloft)

Sertraline selectively inhibits presynaptic serotonin reuptake. It has very minimal effects on norepinephrine and dopamine neuronal uptake. Sertraline is sometimes prescribed for indications that are not FDA approved, such as eating disorders, generalized anxiety disorder, and panic disorder.

Vilazodone (Viibryd)

Vilazodone’s mechanism of antidepressant effect is related to serotonergic activity in the CNS through selective inhibition of serotonin reuptake. This agent is also a partial agonist at serotonergic 5-HT1A receptors, although the contribution of this activity to the drug’s antidepressant effect is unknown. Vilazodone is indicated for major depressive disorder. The dose should be adjusted when this agent is given with moderate or strong CYP3A4 inhibitors.

Vortioxetine (Trintellix)

Vortioxetine enhances serotonergic activity through 5-HT reuptake inhibition. It also modulates serotonin receptor activity through 5-HT1A receptor agonism and 5-HT3 receptor antagonism, although the contribution of these activities to the antidepressant effect is not fully understood. It is approved to treat major depressive disorder in adults.

Antidepressants, SNRIs

Desvenlafaxine (Pristiq, Khedezla)

Desvenlafaxine is an SNRI that is indicated for the treatment of major depressive disorder.

Duloxetine (Cymbalta)

Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine uptake, and antidepressant action is thought to be due to serotonergic and noradrenergic potentiation in the central nervous system.

Reference/links:

https://emedicine.medscape.com/article/286759-overview
https://www.mayoclinic.org/diseases-conditions/depression/symptoms-causes/syc-20356007
https://medlineplus.gov/depression.html#cat_92
https://www.wikidoc.org/index.php/Clinical_depression
https://clinicaltrials.gov/ct2/results?cond=Depression&Search=Clear&age_v=&gndr=&type=&rslt=

 

Reference/links:

https://emedicine.medscape.com/article/286759-overview
https://www.mayoclinic.org/diseases-conditions/depression/symptoms-causes/syc-20356007
https://medlineplus.gov/depression.html#cat_92
https://www.wikidoc.org/index.php/Clinical_depression
https://clinicaltrials.gov/ct2/results?cond=Depression&Search=Clear&age_v=&gndr=&type=&rslt=

 

Possible Treatment

A wide range of effective treatments is available for major depressive disorder. Medication alone  and psychotherapy (e.g., cognitive-behavioral therapy, interpersonal therapy) alone can relieve depressive symptoms. There is also empirical support for the ability of psychotherapy (CBT) to prevent relapse. In children and adolescents, however, pharmacotherapy by itself is insufficient treatment. Moreover, in all patient populations, the combination of medication and psychotherapy generally provides the quickest and most sustained response. Combination therapy has also been associated with significantly higher rates of improvement in depressive symptoms; increased quality of life; and better treatment compliance, especially when treatment is needed for longer than 3 months.

Medications

Usually, 2–12 weeks at a therapeutic dose, with assumed adherence to the regimen, are needed for a clinical response to become evident. The choice of medication should be guided by anticipated safety and tolerability, which aid in compliance; physician familiarity, which aids in patient education and anticipation of adverse effects; and history of previous treatments. Often, treatment failures are caused by medication noncompliance, inadequate duration of therapy, or inadequate dosing. According to the 2008 American College of Physicians (ACP) guideline (the most recent release of the guideline) on using second-generation antidepressants to treat depressive disorders, patient preferences should be given serious consideration when choosing the best course of pharmacotherapy for patients with depressive disorders. The patient may want to avoid use of a particular antidepressant if he or she had a previous negative experience with the drug. The 2008 ACP guideline advises that treatment for major depressive disorder should be altered if the patient does not have an adequate response to pharmacotherapy within 6–8 weeks. Once satisfactory response is achieved, treatment should be continued for 4–9 months in patients with a first episode of major depression that was not associated with significant suicidality or catastrophic outcomes. In those who have had 2 or more episodes of depression, a longer course of maintenance treatment may prove beneficial. In 2011, the American Psychiatric Association (APA) updated its Practice Guideline for the Treatment of Patients with Major Depressive Disorder. The 2011 APA guideline emphasizes the need to customize a treatment plan for each patient based on a careful assessment of symptoms, including rating scale measurements administered by a clinician or the patient, as well as an analysis of therapeutic benefits and side effects. Treatment should maximize patient function within specific and realistic goals. The initial modality should be chosen on the basis of the following:

• Clinical assessment
• Presence of other disorders
• Stressors
• Patient preference
• Reactions to previous treatment

Psychotherapy

Psychotherapy is often conducted on an outpatient basis with weekly, 60-minute sessions. Although there is wide variation in practice, psychotherapy tends to be time-limited (e.g., 16 sessions). In the 1990s, The American Psychological Association’s Division 12 Task Force on Promotion and Dissemination of Psychological Procedures developed criteria for evaluating the empirical support for psychological treatments. Chambless and Hollon refined these guidelines such that a therapy is considered efficacious and specific if there is evidence from high-quality studies in two or more settings indicating that it is superior to a pill or psychological placebo or to another bonafide treatment. A treatment is considered efficacious if there is evidence from two or more settings that it is superior to no treatment. A therapy is considered to be possibly efficacious if there is research support from one or more studies in a single setting. It is recommended that individuals seeking psychotherapy for depression receive one with empirical support.

Primary Prevention

The following may help in preventing a depressed mood:

• Get more exercise
• Maintain good sleep habits
• Seek out activities that bring you pleasure
• Volunteer or get involved in group activities
• Talk to someone you trust about how you are feeling
• Try to be around people who are caring and positive
• Alcohol and illegal drugs should be avoided. These substances can make depression worse and might lead to thoughts of suicide.

Secondary Prevention

Healthy lifestyle habits can help prevent depression, and reduce the chances of it coming back. Talk therapy and antidepressant medication can also make you less likely to become depressed again. Talk therapy may help you through times of grief, stress, or low mood. Family therapy may help teens who feel sad. Keeping close contact with other people is important for preventing depression.

Risk factors

Depression often begins in the teens, 20s or 30s, but it can happen at any age. More women than men are diagnosed with depression, but this may be due in part because women are more likely to seek treatment. Factors that seem to increase the risk of developing or triggering depression include:

• Certain personality traits, such as low self-esteem and being too dependent, self-critical or pessimistic
• Traumatic or stressful events, such as physical or sexual abuse, the death or loss of a loved one, a difficult relationship, or financial problems
• Blood relatives with a history of depression, bipolar disorder, alcoholism or suicide
• Being lesbian, gay, bisexual or transgender, or having variations in the development of genital organs that aren’t clearly male or female (intersex) in an unsupportive situation
• History of other mental health disorders, such as anxiety disorder, eating disorders or post-traumatic stress disorder
• Abuse of alcohol or recreational drugs
• Serious or chronic illness, including cancer, stroke, chronic pain or heart disease
• Certain medications, such as some high blood pressure medications or sleeping pills (talk to your doctor before stopping any medication)

Signs or Symptoms

Although depression may occur only once during your life, people typically have multiple episodes. During these episodes, symptoms occur most of the day, nearly every day and may include:

• Feelings of sadness, tearfulness, emptiness or hopelessness
• Angry outbursts, irritability or frustration, even over small matters
• Loss of interest or pleasure in most or all normal activities, such as sex, hobbies or sports
• Sleep disturbances, including insomnia or sleeping too much
• Tiredness and lack of energy, so even small tasks take extra effort
• Reduced appetite and weight loss or increased cravings for food and weight gain
• Anxiety, agitation or restlessness
• Slowed thinking, speaking or body movements
• Feelings of worthlessness or guilt, fixating on past failures or self-blame
• Trouble thinking, concentrating, making decisions and remembering things
• Frequent or recurrent thoughts of death, suicidal thoughts, suicide attempts or suicide
• Unexplained physical problems, such as back pain or headaches

For many people with depression, symptoms usually are severe enough to cause noticeable problems in day-to-day activities, such as work, school, social activities or relationships with others. Some people may feel generally miserable or unhappy without really knowing why.

Studies

Active Not Recruiting

Number of studies: 258 Link

Completed

Number of studies: 3, 556 Link

Enrolling by Invitation

Number of studies: 85 Link

Not Yet Recruiting

Number of studies: 281 Link

Recruiting

Number of studies: 1, 033 Link

Results Available

Number of studies: 923 Link

Results Not available

Number of studies: 5, 366 Link

Suspended

Number of studies: 15 Link

Terminated

Number of studies: 325 Link

Withdrawn

Number of studies: 132 Link

Typical Test

Screening Tests

The U.S. Preventive Services Task Force (USPSTF) recommends screening for depression in the general adult population, including older adults and pregnant and postpartum women. It is important to understand that the results obtained from the use of any depression rating scales are imperfect in any population, especially the geriatric population. The simplest screening test is a single question: Are you depressed? A pooled analysis found that single-question screening had a specificity of 97% but an overall sensitivity of 32% and, thus, would identify only 3 of every 10 patients with depression in primary care. The following 2-question test addresses depressed mood and anhedonia:

• During the past month, have you been bothered by feeling down, depressed, or hopeless?
• During the past month, have you been bothered by little interest or pleasure in doing things?

In a cross-sectional study, these 2 screening questions showed a sensitivity of 97% and a specificity of 67%. Longer self-report screening instruments for depression include the following:

• PHQ-9 – The 9-item depression scale of the Patient Health Questionnaire; each item is scored 0 to 3, providing a 0 to 27 severity score
• Beck Depression Inventory (BDI) or Beck Depression Inventory-II (BDI-II) – 21-question symptom-rating scales
• BDI for primary care – A 7-question scale adapted from the BDI
• Zung Self-Rating Depression Scale – A 20-item survey
• Center for Epidemiologic Studies-Depression Scale (CES-D) – A 20-item instrument that allows patients to evaluate their feelings, behavior, and outlook from the previous week.

Given that the commonly atypical presentation of depression in the elderly population can challenge even the most experienced clinician, rating scales in the elderly should be used and interpreted only in the context of a more thorough examination for depression. Patients with major depressive disorder often complain of poor memory or concentration. This may be due to the depression itself or to an underlying dementia. In older patients with established dementia, the Cornell Scale for Depression in Dementia (see the image below) can be used to determine the category and severity of depression. The clinician completes the scale on the basis of prior observation and interviews with the patient and the patient’s caregiver.

Laboratory Studies to Rule Out Organic Causes

Depression is a clinical diagnosis, based on the history and physical findings. No diagnostic laboratory tests are available to diagnose major depressive disorder, but focused laboratory studies may be useful to exclude potential medical illnesses that may present as major depressive disorder. These laboratory studies might include the following:

• Complete blood cell (CBC) count
• Thyroid-stimulating hormone (TSH)
• Vitamin B-12
• Rapid plasma reagin (RPR)
• HIV test
• Electrolytes, including calcium, phosphate, and magnesium levels
• Blood urea nitrogen (BUN) and creatinine
• Liver function tests (LFTs)
• Blood alcohol level
• Blood and urine toxicology screen
• Arterial blood gas (ABG)
• Dexamethasone suppression test (Cushing disease, but also positive in depression)
• Cosyntropin (ACTH) stimulation test (Addison disease)

Neuroimaging

Neuroimaging can help clarify the nature of the neurologic illness that may produce psychiatric symptoms, but these studies are costly and may be of questionable value in patients without discrete neurologic deficits. Computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain should be considered if organic brain syndrome or hypopituitarism is included in the differential diagnosis. Positron emission tomography (PET) imaging provides the means for the study of receptor binding of certain ligands and the effect a compound may have on receptors. However, PET scanning is problematic for use with children and adolescents because it requires complex equipment and uses radiation. Using single-photon emission computed tomography (SPECT) scanning, Tutus et al reported significant differences between the perfusion index values of untreated adolescents with depression and those of control patients. The researchers found that adolescents with major depressive disorder may have regional blood flow deficits in the left anterofrontal and left temporal cortical regions, with greater right-left perfusion asymmetry than healthy control patients.

Reference/links:

https://emedicine.medscape.com/article/286759-overview
https://www.mayoclinic.org/diseases-conditions/depression/symptoms-causes/syc-20356007
https://medlineplus.gov/depression.html#cat_92
https://www.wikidoc.org/index.php/Clinical_depression
https://clinicaltrials.gov/ct2/results?cond=Depression&Search=Clear&age_v=&gndr=&type=&rslt=

 

Possible Treatment

A wide range of effective treatments is available for major depressive disorder. Medication alone  and psychotherapy (e.g., cognitive-behavioral therapy, interpersonal therapy) alone can relieve depressive symptoms. There is also empirical support for the ability of psychotherapy (CBT) to prevent relapse. In children and adolescents, however, pharmacotherapy by itself is insufficient treatment. Moreover, in all patient populations, the combination of medication and psychotherapy generally provides the quickest and most sustained response. Combination therapy has also been associated with significantly higher rates of improvement in depressive symptoms; increased quality of life; and better treatment compliance, especially when treatment is needed for longer than 3 months.

Medications

Usually, 2–12 weeks at a therapeutic dose, with assumed adherence to the regimen, are needed for a clinical response to become evident. The choice of medication should be guided by anticipated safety and tolerability, which aid in compliance; physician familiarity, which aids in patient education and anticipation of adverse effects; and history of previous treatments. Often, treatment failures are caused by medication noncompliance, inadequate duration of therapy, or inadequate dosing. According to the 2008 American College of Physicians (ACP) guideline (the most recent release of the guideline) on using second-generation antidepressants to treat depressive disorders, patient preferences should be given serious consideration when choosing the best course of pharmacotherapy for patients with depressive disorders. The patient may want to avoid use of a particular antidepressant if he or she had a previous negative experience with the drug. The 2008 ACP guideline advises that treatment for major depressive disorder should be altered if the patient does not have an adequate response to pharmacotherapy within 6–8 weeks. Once satisfactory response is achieved, treatment should be continued for 4–9 months in patients with a first episode of major depression that was not associated with significant suicidality or catastrophic outcomes. In those who have had 2 or more episodes of depression, a longer course of maintenance treatment may prove beneficial. In 2011, the American Psychiatric Association (APA) updated its Practice Guideline for the Treatment of Patients with Major Depressive Disorder. The 2011 APA guideline emphasizes the need to customize a treatment plan for each patient based on a careful assessment of symptoms, including rating scale measurements administered by a clinician or the patient, as well as an analysis of therapeutic benefits and side effects. Treatment should maximize patient function within specific and realistic goals. The initial modality should be chosen on the basis of the following:

• Clinical assessment
• Presence of other disorders
• Stressors
• Patient preference
• Reactions to previous treatment

Psychotherapy

Psychotherapy is often conducted on an outpatient basis with weekly, 60-minute sessions. Although there is wide variation in practice, psychotherapy tends to be time-limited (e.g., 16 sessions). In the 1990s, The American Psychological Association’s Division 12 Task Force on Promotion and Dissemination of Psychological Procedures developed criteria for evaluating the empirical support for psychological treatments. Chambless and Hollon refined these guidelines such that a therapy is considered efficacious and specific if there is evidence from high-quality studies in two or more settings indicating that it is superior to a pill or psychological placebo or to another bonafide treatment. A treatment is considered efficacious if there is evidence from two or more settings that it is superior to no treatment. A therapy is considered to be possibly efficacious if there is research support from one or more studies in a single setting. It is recommended that individuals seeking psychotherapy for depression receive one with empirical support.

Primary Prevention

The following may help in preventing a depressed mood:

• Get more exercise
• Maintain good sleep habits
• Seek out activities that bring you pleasure
• Volunteer or get involved in group activities
• Talk to someone you trust about how you are feeling
• Try to be around people who are caring and positive
• Alcohol and illegal drugs should be avoided. These substances can make depression worse and might lead to thoughts of suicide.

Secondary Prevention

Healthy lifestyle habits can help prevent depression, and reduce the chances of it coming back. Talk therapy and antidepressant medication can also make you less likely to become depressed again. Talk therapy may help you through times of grief, stress, or low mood. Family therapy may help teens who feel sad. Keeping close contact with other people is important for preventing depression.

Risk factors

Depression often begins in the teens, 20s or 30s, but it can happen at any age. More women than men are diagnosed with depression, but this may be due in part because women are more likely to seek treatment. Factors that seem to increase the risk of developing or triggering depression include:

• Certain personality traits, such as low self-esteem and being too dependent, self-critical or pessimistic
• Traumatic or stressful events, such as physical or sexual abuse, the death or loss of a loved one, a difficult relationship, or financial problems
• Blood relatives with a history of depression, bipolar disorder, alcoholism or suicide
• Being lesbian, gay, bisexual or transgender, or having variations in the development of genital organs that aren’t clearly male or female (intersex) in an unsupportive situation
• History of other mental health disorders, such as anxiety disorder, eating disorders or post-traumatic stress disorder
• Abuse of alcohol or recreational drugs
• Serious or chronic illness, including cancer, stroke, chronic pain or heart disease
• Certain medications, such as some high blood pressure medications or sleeping pills (talk to your doctor before stopping any medication)

Signs or Symptoms

Although depression may occur only once during your life, people typically have multiple episodes. During these episodes, symptoms occur most of the day, nearly every day and may include:

• Feelings of sadness, tearfulness, emptiness or hopelessness
• Angry outbursts, irritability or frustration, even over small matters
• Loss of interest or pleasure in most or all normal activities, such as sex, hobbies or sports
• Sleep disturbances, including insomnia or sleeping too much
• Tiredness and lack of energy, so even small tasks take extra effort
• Reduced appetite and weight loss or increased cravings for food and weight gain
• Anxiety, agitation or restlessness
• Slowed thinking, speaking or body movements
• Feelings of worthlessness or guilt, fixating on past failures or self-blame
• Trouble thinking, concentrating, making decisions and remembering things
• Frequent or recurrent thoughts of death, suicidal thoughts, suicide attempts or suicide
• Unexplained physical problems, such as back pain or headaches

For many people with depression, symptoms usually are severe enough to cause noticeable problems in day-to-day activities, such as work, school, social activities or relationships with others. Some people may feel generally miserable or unhappy without really knowing why.

Studies

Active Not Recruiting

Number of studies: 258 Link

Completed

Number of studies: 3, 556 Link

Enrolling by Invitation

Number of studies: 85 Link

Not Yet Recruiting

Number of studies: 281 Link

Recruiting

Number of studies: 1, 033 Link

Results Available

Number of studies: 923 Link

Results Not available

Number of studies: 5, 366 Link

Suspended

Number of studies: 15 Link

Terminated

Number of studies: 325 Link

Withdrawn

Number of studies: 132 Link

Typical Test

Screening Tests

The U.S. Preventive Services Task Force (USPSTF) recommends screening for depression in the general adult population, including older adults and pregnant and postpartum women. It is important to understand that the results obtained from the use of any depression rating scales are imperfect in any population, especially the geriatric population. The simplest screening test is a single question: Are you depressed? A pooled analysis found that single-question screening had a specificity of 97% but an overall sensitivity of 32% and, thus, would identify only 3 of every 10 patients with depression in primary care. The following 2-question test addresses depressed mood and anhedonia:

• During the past month, have you been bothered by feeling down, depressed, or hopeless?
• During the past month, have you been bothered by little interest or pleasure in doing things?

In a cross-sectional study, these 2 screening questions showed a sensitivity of 97% and a specificity of 67%. Longer self-report screening instruments for depression include the following:

• PHQ-9 – The 9-item depression scale of the Patient Health Questionnaire; each item is scored 0 to 3, providing a 0 to 27 severity score
• Beck Depression Inventory (BDI) or Beck Depression Inventory-II (BDI-II) – 21-question symptom-rating scales
• BDI for primary care – A 7-question scale adapted from the BDI
• Zung Self-Rating Depression Scale – A 20-item survey
• Center for Epidemiologic Studies-Depression Scale (CES-D) – A 20-item instrument that allows patients to evaluate their feelings, behavior, and outlook from the previous week.

Given that the commonly atypical presentation of depression in the elderly population can challenge even the most experienced clinician, rating scales in the elderly should be used and interpreted only in the context of a more thorough examination for depression. Patients with major depressive disorder often complain of poor memory or concentration. This may be due to the depression itself or to an underlying dementia. In older patients with established dementia, the Cornell Scale for Depression in Dementia (see the image below) can be used to determine the category and severity of depression. The clinician completes the scale on the basis of prior observation and interviews with the patient and the patient’s caregiver.

Laboratory Studies to Rule Out Organic Causes

Depression is a clinical diagnosis, based on the history and physical findings. No diagnostic laboratory tests are available to diagnose major depressive disorder, but focused laboratory studies may be useful to exclude potential medical illnesses that may present as major depressive disorder. These laboratory studies might include the following:

• Complete blood cell (CBC) count
• Thyroid-stimulating hormone (TSH)
• Vitamin B-12
• Rapid plasma reagin (RPR)
• HIV test
• Electrolytes, including calcium, phosphate, and magnesium levels
• Blood urea nitrogen (BUN) and creatinine
• Liver function tests (LFTs)
• Blood alcohol level
• Blood and urine toxicology screen
• Arterial blood gas (ABG)
• Dexamethasone suppression test (Cushing disease, but also positive in depression)
• Cosyntropin (ACTH) stimulation test (Addison disease)

Neuroimaging

Neuroimaging can help clarify the nature of the neurologic illness that may produce psychiatric symptoms, but these studies are costly and may be of questionable value in patients without discrete neurologic deficits. Computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain should be considered if organic brain syndrome or hypopituitarism is included in the differential diagnosis. Positron emission tomography (PET) imaging provides the means for the study of receptor binding of certain ligands and the effect a compound may have on receptors. However, PET scanning is problematic for use with children and adolescents because it requires complex equipment and uses radiation. Using single-photon emission computed tomography (SPECT) scanning, Tutus et al reported significant differences between the perfusion index values of untreated adolescents with depression and those of control patients. The researchers found that adolescents with major depressive disorder may have regional blood flow deficits in the left anterofrontal and left temporal cortical regions, with greater right-left perfusion asymmetry than healthy control patients.

Reference/links:

https://emedicine.medscape.com/article/286759-overview
https://www.mayoclinic.org/diseases-conditions/depression/symptoms-causes/syc-20356007
https://medlineplus.gov/depression.html#cat_92
https://www.wikidoc.org/index.php/Clinical_depression
https://clinicaltrials.gov/ct2/results?cond=Depression&Search=Clear&age_v=&gndr=&type=&rslt=

 

Doxepin increases the concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake at the presynaptic neuronal membrane. These effects are associated with a decrease in the symptoms of depression. It has the highest affinity for H1 receptors of all TCAs and, thus, is very sedating and can cause weight gain.

Trimipramine (Surmontil)

Trimipramine inhibits reuptake of norepinephrine and serotonin at the presynaptic neuron and elicits strong anticholinergic effects. It has a high affinity for the H1 receptor and is thus very sedating, but it is useful for gastroesophageal reflux.

Amoxapine

Amoxapine inhibits reuptake of norepinephrine and, to a lesser extent, serotonin at the presynaptic neuron. It also blocks dopamine receptors, causing it to have antipsychotic activity, as well.

Antidepressants, MAO Inhibitors

Selegiline transdermal patch (Emsam)

Selegiline inhibits MAOb at lower doses and both forms at higher doses. Because it does not inhibit MAOa, it does not require dietary restrictions at lower doses. Lower doses of oral selegiline (Eldepryl) appear to lack antidepressant properties and are usually prescribed to treat Parkinson disease. Higher doses are used to treat major depressive disorder, and the selegiline transdermal patch is FDA approved for this indication. Selegiline is sometimes used off-label to treat attention-deficit/hyperactivity disorder. Dietary restrictions are not required for the 6 mg/24 hour patch because there is no risk of hypertensive crisis with this dose, given the lack of MAOa inhibition. Higher doses require dietary restrictions. The patch may be beneficial to those that cannot take oral medications. To avoid serotonin syndrome, initiating and stopping selegiline must be handled carefully.

Tranylcypromine (Parnate)

Tranylcypromine is used to treat major depression. It binds irreversibly to MAOa and to a lesser extent to MAOb, thereby reducing monoamine breakdown and enhancing synaptic availability. Clinical effects are not normally seen for 2-4 weeks. It has similar side effects as other MAOIs, but it is more likely to cause insomnia.

Phenelzine (Nardil)

Phenelzine is used to treat depression. It irreversibly inhibits both MOAa and MOAb. Side effects are similar to those of other MAOIs, but anticholinergic side effects are more common. Phenelzine causes less insomnia than tranylcypromine but is more likely to cause sedation, weight gain, and sexual dysfunction.

Isocarboxazid (Marplan)

Isocarboxazid is a nonselective hydrazine MAOI that is indicated for the treatment of depression. The mechanism by which MAOIs act as an antidepressant is not fully understood, but it is thought to be that these drugs increase the CNS concentrations of norepinephrine, dopamine, and serotonin.

Augmenting Agents

Lithium carbonate (Lithobid)

Lithium carbonate can be used as an effective augmenting agent in combination with an antidepressant in cases of treatment-resistant depression. It can also be used to treat or prevent episodes of depression. Lithium is contraindicated in patients with significant renal impairment. It is important to note that lithium interacts with many drugs. Use of lithium often requires monitoring of lithium levels and renal and thyroid function tests.

Buspirone

Buspirone is marketed as an antianxiety medication; however, it may have antidepressant effects at doses above 45 mg/day. The antidepressant effects may increase when buspirone is used in combination with SSRIs and TCAs in patients with treatment-resistant depression. Buspirone is a partial 5-HT1A agonist with serotonergic and some dopaminergic effects in the CNS. It has anxiolytic effects but may take up to 2-3 weeks for full efficacy.

Serotonin-Dopamine Activity Modulators

Brexpiprazole (Rexulti)

Serotonin-dopamine activity modulator (SDAM) indicated as an adjunct treatment for major depressive disorder. Dosage modifications are necessary with renal or hepatic impairment. Dosage modifications are also needed for individuals who are poor metabolizers of CYP2D6, or if coadministered drugs alter metabolism by CYP2D6 or CYP3A4.

Aripiprazole (Abilify, Abilify Discmelt)

Serotonin-dopamine activity modulator (SDAM) indicated as an adjunct treatment for major depressive disorder. Dosage modifications are also needed for individuals who are poor metabolizers of CYP2D6, or if coadministered drugs alter metabolism by CYP2D6 or CYP3A4. No dosage adjustment is required for renal or hepatic impairment.

Antidepressants, Other

Bupropion (Wellbutrin, Aplenzin, Forfivo XL)

Bupropion inhibits neuronal dopamine reuptake and decreases the rate of norepinephrine activity. In addition to major depressive disorder, the indications for bupropion include smoking cessation. Off-label indications include attention-deficit/hyperactivity disorder and depression associated with bipolar disorder. Common side effects include headache and mild weight loss. Unlike other antidepressants, bupropion does not cause sexual dysfunction.

Mirtazapine (Remeron, Remeron SolTab)

Mirtazapine blocks both presynaptic and postsynaptic alpha-2 receptors but has low affinity for alpha-1 receptors. It also blocks serotonin receptors 5HT2 and 5HT3. Common side effects include sedation, weight gain, and dry mouth.

Trazodone (Oleptro)

Trazodone is effective in the treatment of major depression. It inhibits reuptake of serotonin and modulates serotonergic neurotransmission. It also significantly blocks histamine (H1) receptors. Its most common side effect is sedation, and thus, it has an off-label indication as a hypnotic. It can be very rarely associated with priapism, a medical emergency and a dangerous side effect of this drug in men. It is often used at a low dosage (25 to 50 mg) as an adjunct to SSRIs to treat insomnia.

Esketamine intranasal (Spravato)

Esketamine, the S-enantiomer of racemic ketamine, is a nonselective, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist (NMDA is an ionotropic glutamate receptor). The mechanism by which esketamine exerts its antidepressant effect is unknown. It is indicated for treatment-resistant depression in conjunction with an oral antidepressant.

Stimulants

Dextroamphetamine (Dexedrine, ProCentra, Zenzedi)

This is an augmenting agent in resistant depression. It has been studied most for treating patients who are medically ill and depressed. It is available as a sustained-release preparation.

Methylphenidate (Ritalin, Aptensio XR, Concerta, Daytrana, Metadate ER, Quillivant ER)

Methylphenidate has been mostly studied for treating patients who are medically ill and depressed. It is available as a sustained-release preparation.

Thyroid Products

Liothyronine (Liothyronine T3, Cytomel, Triostat)

This synthetic salt of endogenous thyroid hormone may convert nonresponders (ie, nonresponders to antidepressants) to responders by increasing receptor sensitivity and enhancing the effects of TCAs.

Herbal products

Hypericum perforatum (St John’s Wort)

St John’s wort is believed to act as an antidepressant by increasing concentrations of CNS neurotransmitters, including serotonin. The common dosage is 300 mg 3 times a day with meals to prevent GI upset. If no clinical response occurs after 3-6 months, encouraging the use of another medication is essential.

Epidemiology

The twelve-month prevalence of clinical depression is 7,000 per 100,000 (7%) of the overall population. In some countries, such as Australia, one in four women and one in six men will suffer from depression. In Canada, major depression affects approximately 1.35 million people, and in the United States approximately 14 million adults per year. An estimated 121 million people worldwide currently suffer from depression. People who have had one episode of depression may be more than normally likely to have more episodes in the future, so the first time a young person becomes depressed is important both as a personal and public health concern. About twice as many females as males report or receive treatment for clinical depression, though this imbalance is shrinking over the course of recent history; this difference seems to completely disappear after the age of 50–55. Clinical depression is currently the leading cause of disability in North America, and is expected to become the second leading cause of disability worldwide (after heart disease) by the year 2020, according to the World Health Organization. Recent studies suggest that the diagnostic criteria for depression are far too broad, resulting in diagnosis of clinical depression in people who are not truly suffering from the disorder and who have shown normal responses to negative events.

Prognosis

Major depressive disorder has significant potential morbidity and mortality, contributing as it does to suicide, incidence and adverse outcomes of medical illness, disruption in interpersonal relationships, substance abuse, and lost work time. With appropriate treatment, 70-80% of individuals with major depressive disorder can achieve a significant reduction in symptoms, although as many as 50% of patients may not respond to the initial treatment trial. A study of first-episode psychotic depression by Tohen et al found that most patients achieved syndromal remission (86%) and recovery (84%); however, only 35% recovered functionally. Earlier syndromal recovery was associated with subacute onset, lower initial depression scores, and lack of mood-incongruent psychotic features. Within 2 years, almost half the patients experienced new episodes. In 41% of patients, the diagnosis was changed, usually to bipolar or schizoaffective disorders.

Natural Progression

Major depressive disorder is a serious health problem and will be the second leading cause of burden of disease worldwide by 2030. In any given 12-month period, 10–20% of adults will visit their general practitioner (GP) for mental complaints, of which the majority are related to depression. The prevalence of depression in primary care is estimated to be between 4 and 18%. People presenting with depressive symptoms are mainly seen in primary care; however, treatment guidelines are mainly based upon data from hospital settings or the general population. Few studies have examined the course and outcome of MDD in primary care over a greater period of time. In one study, 32% of the primary care patients who were depressed at baseline were not depressed after 12 months and 47% were not depressed after 3.5 years. A recent study showed that of the 79 primary care patients diagnosed with MDD at baseline, 25% persisted and 49% suffered from residual symptoms or recurrences after 18 months. These data suggest that the majority of adult patients with depression in primary care do not recover in the medium-term, but also that some patients do recover.

Pathophysiology

The underlying pathophysiology of major depressive disorder has not been clearly defined. Current evidence points to a complex interaction between neurotransmitter availability and receptor regulation and sensitivity underlying the affective symptoms. Clinical and preclinical trials suggest a disturbance in central nervous system serotonin (5-HT) activity as an important factor. Other neurotransmitters implicated include norepinephrine (NE), dopamine (DA), glutamate, and brain-derived neurotrophic factor (BDNF). However, drugs that produce only an acute rise in neurotransmitter availability, such as cocaine or amphetamines, do not have the efficacy over time that antidepressants do. The role of CNS 5-HT activity in the pathophysiology of major depressive disorder is suggested by the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs). In addition, studies have shown that an acute, transient relapse of depressive symptoms can be produced in research subjects in remission using tryptophan depletion, which causes a temporary reduction in CNS 5-HT levels. However, the effect of SSRIs on 5HT reuptake is immediate, but the antidepressant effect requires exposure of several weeks’ duration. Also, some antidepressants have no effect on 5HT (eg, desipramine), and the antidepressant tianeptine enhances 5HT uptake. All this, together with preclinical research findings, implies a role for neuronal receptor regulation, intracellular signaling, and gene expression over time, in addition to enhanced neurotransmitter availability. Seasonal affective disorder is a form of major depressive disorder that typically arises during the fall and winter and resolves during the spring and summer. Studies suggest that seasonal affective disorder is also mediated by alterations in CNS levels of 5-HT and appears to be triggered by alterations in circadian rhythm and sunlight exposure. Vascular lesions may contribute to depression by disrupting the neural networks involved in emotion regulation—in particular, frontostriatal pathways that link the dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate, and dorsal cingulate. Other components of limbic circuitry, in particular the hippocampus and amygdala, have been implicated in depression.

Brain structures

Functional neuroimaging studies support the hypothesis that the depressed state is associated with decreased metabolic activity in neocortical structures and increased metabolic activity in limbic structures. Serotonergic neurons implicated in affective disorders are found in the dorsal raphe nucleus, the limbic system, and the left prefrontal cortex. A meta-analysis comparing brain structures in patients with major depression, in healthy controls, and in patients with bipolar disorder demonstrated associations between depression and increased lateral ventricle size, larger cerebrospinal fluid volume, and smaller volumes of the basal ganglia, thalamus, hippocampus, frontal lobe, orbitofrontal cortex, and gyrus rectus. Patients experiencing a depressive episode had smaller hippocampal volume than those in remission. In one study, positron emission tomographic (PET) images showed abnormally diminished activity in an area of the prefrontal cortex in patients with unipolar depression and bipolar depression. This region is related to emotional response and has widespread connections with other areas of the brain, including the areas that appear to be responsible for the regulation of DA, noradrenaline (locus ceruleus), and 5-HT (raphe nuclei). Both functional and structural abnormalities were found in the same brain region during a major depressive episode. Sacher et al found increases in glucose metabolism in the right subgenual and pregenual anterior cingulate cortices and decreased gray matter volumes in the amygdala, dorsal frontomedian cortex, and right paracingulate cortex.

Aging

An integrative model of late-onset depression posits that age-related brain changes and disease-related changes (eg, cerebrovascular disease), coupled with physiologic vulnerabilities (eg, genetic risk factors, personal history of depression) and psychosocial adversity, lead to disruptions in the functional circuitry of emotion regulation—namely, hypometabolism of cortical structures and hypermetabolism of limbic structures. Endocrine changes in depression are evident across the life span, but some are unique to aging. Women with a previous history of depression are at higher risk of developing depression during menopause, although estrogen replacement does not relieve depression; low testosterone levels have been associated with depression in older men.

Possible Complications

Twenty percent of individuals with major depressive disorder untreated at 1 year will continue to meet criteria for the diagnosis, whereas an additional 40% will have a partial remission. Pretreatment irritability and psychotic symptoms may be associated with poorer outcomes. Partial remission and/or a history of prior chronic major depressive episodes are risk factors for recurrent episodes and treatment resistance.

Recurrence of early depression

According to the American Academy of Childand Adolescent Psychiatry (AACAP) practice parameters for depressive disorders in childhood and adolescence, a history of a previous depressive episode, subsyndromal symptoms of depression, dysthymia, and anxiety disorders increase the risk for future depression. In a study of an epidemiologic sample of 776 adolescents by Pine and associates, symptoms of majordepressioninadolescencestrongly predicted episodes of major depression in adulthood. 

Late-onset depression

The prognosis for patients with late-onset depression is felt to be poorer than that for younger patients, and it appears to be dependent on physical disability or illness and lack of social support. Of particular importance is the increasing risk of death by suicide, particularly among elderly men. The length of a depressive episode in the aging population is approximately 18 months, whereas in people 20–55 years of age, the length of an episode is 18 to 24 weeks. In older patients, depression is frequently comorbid with chronic medical conditions and can lead to worsening medical outcomes, including mortality. For example, coronary artery disease is a risk factor for the development of depression, and depression is an independent risk factor for the development of coronary disease. Patients with both conditions are more likely to die than those with coronary artery disease alone. Both behavioral and physiologic explanations are likely for these associations. 

Suicide

Depression plays a role in more than one half of all suicide attempts, whereas the lifetime risk of suicide among patients with untreated depressive disorder is nearly 20%. According to Centers for Disease Control and Prevention (CDC) data, suicide was the 10th leading cause of death in the United States in 2009, accounting for 36,909 deaths; it was the second leading cause of death in people 25-34 years of age, the third leading cause in people aged 10-24 years, and the fourth leading cause at ages 35-54.  However, despite these data and the fact that depression is more often diagnosed in women, the highest suicide rate is in men older than 75 years (see the graph below); more men than women die from suicide by a factor of 4.5:1. White men complete more than 78% of all suicides, and 56% of suicide deaths in males involve firearms. Poisoning is the predominant method among females. Attempted suicide is more frequent in women. In addition to older age and male sex, risk factors for suicide include the following:

• Diagnosis of major depression
• Previous history of suicide attempts
• Depressive symptoms with agitation or distress
• Burden of medical disease and the presence of a current serious medical condition (although this risk may be mediated by a diagnosis of depression)
• Recent stressful life events, especially family discord
• Lack of social support
• Being widowed or divorced
• The presence of a gun in the home
• Unexplained weight loss
• High levels of anxiety
• Lack of a reason not to commit suicide
• Presence of a specific plan that can be carried out
• Rehearsal of the plan

The relationship between use of antidepressants and risk of suicide varies with patient age. Treatment with antidepressants has been associated with increased suicidality in children, adolescents, and young adults 18 to 24 years of age. There is no evidence of increased risk for adults older than 24 years of age; for adults 65 years of age or older, the risk is actually decreased.

Possible Treatment

A wide range of effective treatments is available for major depressive disorder. Medication alone  and psychotherapy (e.g., cognitive-behavioral therapy, interpersonal therapy) alone can relieve depressive symptoms. There is also empirical support for the ability of psychotherapy (CBT) to prevent relapse. In children and adolescents, however, pharmacotherapy by itself is insufficient treatment. Moreover, in all patient populations, the combination of medication and psychotherapy generally provides the quickest and most sustained response. Combination therapy has also been associated with significantly higher rates of improvement in depressive symptoms; increased quality of life; and better treatment compliance, especially when treatment is needed for longer than 3 months.

Medications

Usually, 2–12 weeks at a therapeutic dose, with assumed adherence to the regimen, are needed for a clinical response to become evident. The choice of medication should be guided by anticipated safety and tolerability, which aid in compliance; physician familiarity, which aids in patient education and anticipation of adverse effects; and history of previous treatments. Often, treatment failures are caused by medication noncompliance, inadequate duration of therapy, or inadequate dosing. According to the 2008 American College of Physicians (ACP) guideline (the most recent release of the guideline) on using second-generation antidepressants to treat depressive disorders, patient preferences should be given serious consideration when choosing the best course of pharmacotherapy for patients with depressive disorders. The patient may want to avoid use of a particular antidepressant if he or she had a previous negative experience with the drug. The 2008 ACP guideline advises that treatment for major depressive disorder should be altered if the patient does not have an adequate response to pharmacotherapy within 6–8 weeks. Once satisfactory response is achieved, treatment should be continued for 4–9 months in patients with a first episode of major depression that was not associated with significant suicidality or catastrophic outcomes. In those who have had 2 or more episodes of depression, a longer course of maintenance treatment may prove beneficial. In 2011, the American Psychiatric Association (APA) updated its Practice Guideline for the Treatment of Patients with Major Depressive Disorder. The 2011 APA guideline emphasizes the need to customize a treatment plan for each patient based on a careful assessment of symptoms, including rating scale measurements administered by a clinician or the patient, as well as an analysis of therapeutic benefits and side effects. Treatment should maximize patient function within specific and realistic goals. The initial modality should be chosen on the basis of the following:

• Clinical assessment
• Presence of other disorders
• Stressors
• Patient preference
• Reactions to previous treatment

Psychotherapy

Psychotherapy is often conducted on an outpatient basis with weekly, 60-minute sessions. Although there is wide variation in practice, psychotherapy tends to be time-limited (e.g., 16 sessions). In the 1990s, The American Psychological Association’s Division 12 Task Force on Promotion and Dissemination of Psychological Procedures developed criteria for evaluating the empirical support for psychological treatments. Chambless and Hollon refined these guidelines such that a therapy is considered efficacious and specific if there is evidence from high-quality studies in two or more settings indicating that it is superior to a pill or psychological placebo or to another bonafide treatment. A treatment is considered efficacious if there is evidence from two or more settings that it is superior to no treatment. A therapy is considered to be possibly efficacious if there is research support from one or more studies in a single setting. It is recommended that individuals seeking psychotherapy for depression receive one with empirical support.

Primary Prevention

The following may help in preventing a depressed mood:

• Get more exercise
• Maintain good sleep habits
• Seek out activities that bring you pleasure
• Volunteer or get involved in group activities
• Talk to someone you trust about how you are feeling
• Try to be around people who are caring and positive
• Alcohol and illegal drugs should be avoided. These substances can make depression worse and might lead to thoughts of suicide.

Secondary Prevention

Healthy lifestyle habits can help prevent depression, and reduce the chances of it coming back. Talk therapy and antidepressant medication can also make you less likely to become depressed again. Talk therapy may help you through times of grief, stress, or low mood. Family therapy may help teens who feel sad. Keeping close contact with other people is important for preventing depression.

Risk factors

Depression often begins in the teens, 20s or 30s, but it can happen at any age. More women than men are diagnosed with depression, but this may be due in part because women are more likely to seek treatment. Factors that seem to increase the risk of developing or triggering depression include:

• Certain personality traits, such as low self-esteem and being too dependent, self-critical or pessimistic
• Traumatic or stressful events, such as physical or sexual abuse, the death or loss of a loved one, a difficult relationship, or financial problems
• Blood relatives with a history of depression, bipolar disorder, alcoholism or suicide
• Being lesbian, gay, bisexual or transgender, or having variations in the development of genital organs that aren’t clearly male or female (intersex) in an unsupportive situation
• History of other mental health disorders, such as anxiety disorder, eating disorders or post-traumatic stress disorder
• Abuse of alcohol or recreational drugs
• Serious or chronic illness, including cancer, stroke, chronic pain or heart disease
• Certain medications, such as some high blood pressure medications or sleeping pills (talk to your doctor before stopping any medication)

Signs or Symptoms

Although depression may occur only once during your life, people typically have multiple episodes. During these episodes, symptoms occur most of the day, nearly every day and may include:

• Feelings of sadness, tearfulness, emptiness or hopelessness
• Angry outbursts, irritability or frustration, even over small matters
• Loss of interest or pleasure in most or all normal activities, such as sex, hobbies or sports
• Sleep disturbances, including insomnia or sleeping too much
• Tiredness and lack of energy, so even small tasks take extra effort
• Reduced appetite and weight loss or increased cravings for food and weight gain
• Anxiety, agitation or restlessness
• Slowed thinking, speaking or body movements
• Feelings of worthlessness or guilt, fixating on past failures or self-blame
• Trouble thinking, concentrating, making decisions and remembering things
• Frequent or recurrent thoughts of death, suicidal thoughts, suicide attempts or suicide
• Unexplained physical problems, such as back pain or headaches

For many people with depression, symptoms usually are severe enough to cause noticeable problems in day-to-day activities, such as work, school, social activities or relationships with others. Some people may feel generally miserable or unhappy without really knowing why.

Studies

Active Not Recruiting

Number of studies: 258 Link

Completed

Number of studies: 3, 556 Link

Enrolling by Invitation

Number of studies: 85 Link

Not Yet Recruiting

Number of studies: 281 Link

Recruiting

Number of studies: 1, 033 Link

Results Available

Number of studies: 923 Link

Results Not available

Number of studies: 5, 366 Link

Suspended

Number of studies: 15 Link

Terminated

Number of studies: 325 Link

Withdrawn

Number of studies: 132 Link

Typical Test

Screening Tests

The U.S. Preventive Services Task Force (USPSTF) recommends screening for depression in the general adult population, including older adults and pregnant and postpartum women. It is important to understand that the results obtained from the use of any depression rating scales are imperfect in any population, especially the geriatric population. The simplest screening test is a single question: Are you depressed? A pooled analysis found that single-question screening had a specificity of 97% but an overall sensitivity of 32% and, thus, would identify only 3 of every 10 patients with depression in primary care. The following 2-question test addresses depressed mood and anhedonia:

• During the past month, have you been bothered by feeling down, depressed, or hopeless?
• During the past month, have you been bothered by little interest or pleasure in doing things?

In a cross-sectional study, these 2 screening questions showed a sensitivity of 97% and a specificity of 67%. Longer self-report screening instruments for depression include the following:

• PHQ-9 – The 9-item depression scale of the Patient Health Questionnaire; each item is scored 0 to 3, providing a 0 to 27 severity score
• Beck Depression Inventory (BDI) or Beck Depression Inventory-II (BDI-II) – 21-question symptom-rating scales
• BDI for primary care – A 7-question scale adapted from the BDI
• Zung Self-Rating Depression Scale – A 20-item survey
• Center for Epidemiologic Studies-Depression Scale (CES-D) – A 20-item instrument that allows patients to evaluate their feelings, behavior, and outlook from the previous week.

Given that the commonly atypical presentation of depression in the elderly population can challenge even the most experienced clinician, rating scales in the elderly should be used and interpreted only in the context of a more thorough examination for depression. Patients with major depressive disorder often complain of poor memory or concentration. This may be due to the depression itself or to an underlying dementia. In older patients with established dementia, the Cornell Scale for Depression in Dementia (see the image below) can be used to determine the category and severity of depression. The clinician completes the scale on the basis of prior observation and interviews with the patient and the patient’s caregiver.

Laboratory Studies to Rule Out Organic Causes

Depression is a clinical diagnosis, based on the history and physical findings. No diagnostic laboratory tests are available to diagnose major depressive disorder, but focused laboratory studies may be useful to exclude potential medical illnesses that may present as major depressive disorder. These laboratory studies might include the following:

• Complete blood cell (CBC) count
• Thyroid-stimulating hormone (TSH)
• Vitamin B-12
• Rapid plasma reagin (RPR)
• HIV test
• Electrolytes, including calcium, phosphate, and magnesium levels
• Blood urea nitrogen (BUN) and creatinine
• Liver function tests (LFTs)
• Blood alcohol level
• Blood and urine toxicology screen
• Arterial blood gas (ABG)
• Dexamethasone suppression test (Cushing disease, but also positive in depression)
• Cosyntropin (ACTH) stimulation test (Addison disease)

Neuroimaging

Neuroimaging can help clarify the nature of the neurologic illness that may produce psychiatric symptoms, but these studies are costly and may be of questionable value in patients without discrete neurologic deficits. Computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain should be considered if organic brain syndrome or hypopituitarism is included in the differential diagnosis. Positron emission tomography (PET) imaging provides the means for the study of receptor binding of certain ligands and the effect a compound may have on receptors. However, PET scanning is problematic for use with children and adolescents because it requires complex equipment and uses radiation. Using single-photon emission computed tomography (SPECT) scanning, Tutus et al reported significant differences between the perfusion index values of untreated adolescents with depression and those of control patients. The researchers found that adolescents with major depressive disorder may have regional blood flow deficits in the left anterofrontal and left temporal cortical regions, with greater right-left perfusion asymmetry than healthy control patients.

Reference/links:

https://emedicine.medscape.com/article/286759-overview
https://www.mayoclinic.org/diseases-conditions/depression/symptoms-causes/syc-20356007
https://medlineplus.gov/depression.html#cat_92
https://www.wikidoc.org/index.php/Clinical_depression
https://clinicaltrials.gov/ct2/results?cond=Depression&Search=Clear&age_v=&gndr=&type=&rslt=

 

Venlafaxine (Effexor XR)

Venlafaxine and its active metabolite inhibit neuronal serotonin and norepinephrine reuptake. They are weak inhibitors of dopamine reuptake. In addition, it causes beta-receptor down-regulation. Venlafaxine is sometimes prescribed for non–FDA-approved indications, such as obsessive-compulsive disorder, hot flashes, neuropathic pain, attention-deficit/hyperactivity disorder, and posttraumatic stress disorder.

Levomilnacipran (Fetzima)

Levomilnacipran is the active enantiomer milnacipran and should be administered once daily. It is a potent inhibitor of neuronal serotonin and norepinephrine reuptake, and inhibits norepinephrine uptake with approximately 3-fold higher potency in vitro than serotonin without directly affecting the uptake of dopamine or other neurotransmitters.

Antidepressants, TCAs

Amitriptyline (Elavil)

Amitriptyline inhibits the reuptake of norepinephrine and, more potently, serotonin at the presynaptic neuronal membrane, which increases concentration in the CNS. It has a high affinity for histamine H1 and muscarinic M1 receptors. Amitriptyline can cause weight gain, sedation, and anticholinergic side effects. It is often used for non–FDA-approved indications, such as chronic pain management, diabetic neuropathy, migraine prophylaxis, and posttraumatic stress disorder.

Desipramine (Norpramin)

Desipramine inhibits the reuptake of serotonin and, more potently, norepinephrine at the presynaptic neuronal membrane. It is a commonly used TCA that is relatively less sedating and tends to have fewer anticholinergic and antihistaminic adverse effects than other TCAs. It is sometimes used for off-label indications such as peripheral neuropathy and attention-deficit/hyperactivity disorder.

Imipramine (Tofranil)

Imipramine is one of the oldest agents available for the treatment of depression. It is demethylated in the liver to desipramine. Imipramine inhibits the reuptake of norepinephrine and, more potently, serotonin at the presynaptic neuronal membrane. It has a strong affinity for alpha-adrenergic, H1, and M1 receptors. Common side effects include orthostasis, sedation, weight gain, and anticholinergic effects. It is also used off-label in the treatment of panic disorder, posttraumatic stress disorder, and attention deficit/hyperactivity disorder.

Clomipramine (Anafranil)

Clomipramine potently inhibits the reuptake of serotonin at the presynaptic neuronal membrane. It has strong affinities to both H1 and M1 receptors, which results in sedation, weight gain, and anticholinergic side effects. Although clomipramine is FDA approved only for obsessive-compulsive disorder, it has also been prescribed for depression, panic attacks, and chronic pain.

Nortriptyline (Pamelor)

Nortriptyline blocks the reuptake of serotonin and, more potently, norepinephrine at the presynaptic neuronal membrane. It has less affinity for H1 and M1 receptors and, thus, is better tolerated than other TCAs. Although nortriptyline is FDA approved only for depression, it has also been prescribed for chronic pain, myofascial pain, anxiety disorders, and attention-deficit/hyperactivity disorder. As with desipramine, there is a therapeutic window for nortriptyline

Protriptyline (Vivactil)

Protriptyline increases the synaptic concentration of norepinephrine in the CNS by inhibiting reuptake at the presynaptic neuronal membrane. It has less affinity for H1 and M1 receptors and, thus, is better tolerated than tertiary amine TCAs.

Doxepin

Doxepin increases the concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake at the presynaptic neuronal membrane. These effects are associated with a decrease in the symptoms of depression. It has the highest affinity for H1 receptors of all TCAs and, thus, is very sedating and can cause weight gain.

Trimipramine (Surmontil)

Trimipramine inhibits reuptake of norepinephrine and serotonin at the presynaptic neuron and elicits strong anticholinergic effects. It has a high affinity for the H1 receptor and is thus very sedating, but it is useful for gastroesophageal reflux.

Amoxapine

Amoxapine inhibits reuptake of norepinephrine and, to a lesser extent, serotonin at the presynaptic neuron. It also blocks dopamine receptors, causing it to have antipsychotic activity, as well.

Antidepressants, MAO Inhibitors

Selegiline transdermal patch (Emsam)

Selegiline inhibits MAOb at lower doses and both forms at higher doses. Because it does not inhibit MAOa, it does not require dietary restrictions at lower doses. Lower doses of oral selegiline (Eldepryl) appear to lack antidepressant properties and are usually prescribed to treat Parkinson disease. Higher doses are used to treat major depressive disorder, and the selegiline transdermal patch is FDA approved for this indication. Selegiline is sometimes used off-label to treat attention-deficit/hyperactivity disorder. Dietary restrictions are not required for the 6 mg/24 hour patch because there is no risk of hypertensive crisis with this dose, given the lack of MAOa inhibition. Higher doses require dietary restrictions. The patch may be beneficial to those that cannot take oral medications. To avoid serotonin syndrome, initiating and stopping selegiline must be handled carefully.

Tranylcypromine (Parnate)

Tranylcypromine is used to treat major depression. It binds irreversibly to MAOa and to a lesser extent to MAOb, thereby reducing monoamine breakdown and enhancing synaptic availability. Clinical effects are not normally seen for 2-4 weeks. It has similar side effects as other MAOIs, but it is more likely to cause insomnia.

Phenelzine (Nardil)

Phenelzine is used to treat depression. It irreversibly inhibits both MOAa and MOAb. Side effects are similar to those of other MAOIs, but anticholinergic side effects are more common. Phenelzine causes less insomnia than tranylcypromine but is more likely to cause sedation, weight gain, and sexual dysfunction.

Isocarboxazid (Marplan)

Isocarboxazid is a nonselective hydrazine MAOI that is indicated for the treatment of depression. The mechanism by which MAOIs act as an antidepressant is not fully understood, but it is thought to be that these drugs increase the CNS concentrations of norepinephrine, dopamine, and serotonin.

Augmenting Agents

Lithium carbonate (Lithobid)

Lithium carbonate can be used as an effective augmenting agent in combination with an antidepressant in cases of treatment-resistant depression. It can also be used to treat or prevent episodes of depression. Lithium is contraindicated in patients with significant renal impairment. It is important to note that lithium interacts with many drugs. Use of lithium often requires monitoring of lithium levels and renal and thyroid function tests.

Buspirone

Buspirone is marketed as an antianxiety medication; however, it may have antidepressant effects at doses above 45 mg/day. The antidepressant effects may increase when buspirone is used in combination with SSRIs and TCAs in patients with treatment-resistant depression. Buspirone is a partial 5-HT1A agonist with serotonergic and some dopaminergic effects in the CNS. It has anxiolytic effects but may take up to 2-3 weeks for full efficacy.

Serotonin-Dopamine Activity Modulators

Brexpiprazole (Rexulti)

Serotonin-dopamine activity modulator (SDAM) indicated as an adjunct treatment for major depressive disorder. Dosage modifications are necessary with renal or hepatic impairment. Dosage modifications are also needed for individuals who are poor metabolizers of CYP2D6, or if coadministered drugs alter metabolism by CYP2D6 or CYP3A4.

Aripiprazole (Abilify, Abilify Discmelt)

Serotonin-dopamine activity modulator (SDAM) indicated as an adjunct treatment for major depressive disorder. Dosage modifications are also needed for individuals who are poor metabolizers of CYP2D6, or if coadministered drugs alter metabolism by CYP2D6 or CYP3A4. No dosage adjustment is required for renal or hepatic impairment.

Antidepressants, Other

Bupropion (Wellbutrin, Aplenzin, Forfivo XL)

Bupropion inhibits neuronal dopamine reuptake and decreases the rate of norepinephrine activity. In addition to major depressive disorder, the indications for bupropion include smoking cessation. Off-label indications include attention-deficit/hyperactivity disorder and depression associated with bipolar disorder. Common side effects include headache and mild weight loss. Unlike other antidepressants, bupropion does not cause sexual dysfunction.

Mirtazapine (Remeron, Remeron SolTab)

Mirtazapine blocks both presynaptic and postsynaptic alpha-2 receptors but has low affinity for alpha-1 receptors. It also blocks serotonin receptors 5HT2 and 5HT3. Common side effects include sedation, weight gain, and dry mouth.

Trazodone (Oleptro)

Trazodone is effective in the treatment of major depression. It inhibits reuptake of serotonin and modulates serotonergic neurotransmission. It also significantly blocks histamine (H1) receptors. Its most common side effect is sedation, and thus, it has an off-label indication as a hypnotic. It can be very rarely associated with priapism, a medical emergency and a dangerous side effect of this drug in men. It is often used at a low dosage (25 to 50 mg) as an adjunct to SSRIs to treat insomnia.

Esketamine intranasal (Spravato)

Esketamine, the S-enantiomer of racemic ketamine, is a nonselective, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist (NMDA is an ionotropic glutamate receptor). The mechanism by which esketamine exerts its antidepressant effect is unknown. It is indicated for treatment-resistant depression in conjunction with an oral antidepressant.

Stimulants

Dextroamphetamine (Dexedrine, ProCentra, Zenzedi)

This is an augmenting agent in resistant depression. It has been studied most for treating patients who are medically ill and depressed. It is available as a sustained-release preparation.

Methylphenidate (Ritalin, Aptensio XR, Concerta, Daytrana, Metadate ER, Quillivant ER)

Methylphenidate has been mostly studied for treating patients who are medically ill and depressed. It is available as a sustained-release preparation.

Thyroid Products

Liothyronine (Liothyronine T3, Cytomel, Triostat)

This synthetic salt of endogenous thyroid hormone may convert nonresponders (ie, nonresponders to antidepressants) to responders by increasing receptor sensitivity and enhancing the effects of TCAs.

Herbal products

Hypericum perforatum (St John’s Wort)

St John’s wort is believed to act as an antidepressant by increasing concentrations of CNS neurotransmitters, including serotonin. The common dosage is 300 mg 3 times a day with meals to prevent GI upset. If no clinical response occurs after 3-6 months, encouraging the use of another medication is essential.

Epidemiology

The twelve-month prevalence of clinical depression is 7,000 per 100,000 (7%) of the overall population. In some countries, such as Australia, one in four women and one in six men will suffer from depression. In Canada, major depression affects approximately 1.35 million people, and in the United States approximately 14 million adults per year. An estimated 121 million people worldwide currently suffer from depression. People who have had one episode of depression may be more than normally likely to have more episodes in the future, so the first time a young person becomes depressed is important both as a personal and public health concern. About twice as many females as males report or receive treatment for clinical depression, though this imbalance is shrinking over the course of recent history; this difference seems to completely disappear after the age of 50–55. Clinical depression is currently the leading cause of disability in North America, and is expected to become the second leading cause of disability worldwide (after heart disease) by the year 2020, according to the World Health Organization. Recent studies suggest that the diagnostic criteria for depression are far too broad, resulting in diagnosis of clinical depression in people who are not truly suffering from the disorder and who have shown normal responses to negative events.

Prognosis

Major depressive disorder has significant potential morbidity and mortality, contributing as it does to suicide, incidence and adverse outcomes of medical illness, disruption in interpersonal relationships, substance abuse, and lost work time. With appropriate treatment, 70-80% of individuals with major depressive disorder can achieve a significant reduction in symptoms, although as many as 50% of patients may not respond to the initial treatment trial. A study of first-episode psychotic depression by Tohen et al found that most patients achieved syndromal remission (86%) and recovery (84%); however, only 35% recovered functionally. Earlier syndromal recovery was associated with subacute onset, lower initial depression scores, and lack of mood-incongruent psychotic features. Within 2 years, almost half the patients experienced new episodes. In 41% of patients, the diagnosis was changed, usually to bipolar or schizoaffective disorders.

Natural Progression

Major depressive disorder is a serious health problem and will be the second leading cause of burden of disease worldwide by 2030. In any given 12-month period, 10–20% of adults will visit their general practitioner (GP) for mental complaints, of which the majority are related to depression. The prevalence of depression in primary care is estimated to be between 4 and 18%. People presenting with depressive symptoms are mainly seen in primary care; however, treatment guidelines are mainly based upon data from hospital settings or the general population. Few studies have examined the course and outcome of MDD in primary care over a greater period of time. In one study, 32% of the primary care patients who were depressed at baseline were not depressed after 12 months and 47% were not depressed after 3.5 years. A recent study showed that of the 79 primary care patients diagnosed with MDD at baseline, 25% persisted and 49% suffered from residual symptoms or recurrences after 18 months. These data suggest that the majority of adult patients with depression in primary care do not recover in the medium-term, but also that some patients do recover.

Pathophysiology

The underlying pathophysiology of major depressive disorder has not been clearly defined. Current evidence points to a complex interaction between neurotransmitter availability and receptor regulation and sensitivity underlying the affective symptoms. Clinical and preclinical trials suggest a disturbance in central nervous system serotonin (5-HT) activity as an important factor. Other neurotransmitters implicated include norepinephrine (NE), dopamine (DA), glutamate, and brain-derived neurotrophic factor (BDNF). However, drugs that produce only an acute rise in neurotransmitter availability, such as cocaine or amphetamines, do not have the efficacy over time that antidepressants do. The role of CNS 5-HT activity in the pathophysiology of major depressive disorder is suggested by the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs). In addition, studies have shown that an acute, transient relapse of depressive symptoms can be produced in research subjects in remission using tryptophan depletion, which causes a temporary reduction in CNS 5-HT levels. However, the effect of SSRIs on 5HT reuptake is immediate, but the antidepressant effect requires exposure of several weeks’ duration. Also, some antidepressants have no effect on 5HT (eg, desipramine), and the antidepressant tianeptine enhances 5HT uptake. All this, together with preclinical research findings, implies a role for neuronal receptor regulation, intracellular signaling, and gene expression over time, in addition to enhanced neurotransmitter availability. Seasonal affective disorder is a form of major depressive disorder that typically arises during the fall and winter and resolves during the spring and summer. Studies suggest that seasonal affective disorder is also mediated by alterations in CNS levels of 5-HT and appears to be triggered by alterations in circadian rhythm and sunlight exposure. Vascular lesions may contribute to depression by disrupting the neural networks involved in emotion regulation—in particular, frontostriatal pathways that link the dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate, and dorsal cingulate. Other components of limbic circuitry, in particular the hippocampus and amygdala, have been implicated in depression.

Brain structures

Functional neuroimaging studies support the hypothesis that the depressed state is associated with decreased metabolic activity in neocortical structures and increased metabolic activity in limbic structures. Serotonergic neurons implicated in affective disorders are found in the dorsal raphe nucleus, the limbic system, and the left prefrontal cortex. A meta-analysis comparing brain structures in patients with major depression, in healthy controls, and in patients with bipolar disorder demonstrated associations between depression and increased lateral ventricle size, larger cerebrospinal fluid volume, and smaller volumes of the basal ganglia, thalamus, hippocampus, frontal lobe, orbitofrontal cortex, and gyrus rectus. Patients experiencing a depressive episode had smaller hippocampal volume than those in remission. In one study, positron emission tomographic (PET) images showed abnormally diminished activity in an area of the prefrontal cortex in patients with unipolar depression and bipolar depression. This region is related to emotional response and has widespread connections with other areas of the brain, including the areas that appear to be responsible for the regulation of DA, noradrenaline (locus ceruleus), and 5-HT (raphe nuclei). Both functional and structural abnormalities were found in the same brain region during a major depressive episode. Sacher et al found increases in glucose metabolism in the right subgenual and pregenual anterior cingulate cortices and decreased gray matter volumes in the amygdala, dorsal frontomedian cortex, and right paracingulate cortex.

Aging

An integrative model of late-onset depression posits that age-related brain changes and disease-related changes (eg, cerebrovascular disease), coupled with physiologic vulnerabilities (eg, genetic risk factors, personal history of depression) and psychosocial adversity, lead to disruptions in the functional circuitry of emotion regulation—namely, hypometabolism of cortical structures and hypermetabolism of limbic structures. Endocrine changes in depression are evident across the life span, but some are unique to aging. Women with a previous history of depression are at higher risk of developing depression during menopause, although estrogen replacement does not relieve depression; low testosterone levels have been associated with depression in older men.

Possible Complications

Twenty percent of individuals with major depressive disorder untreated at 1 year will continue to meet criteria for the diagnosis, whereas an additional 40% will have a partial remission. Pretreatment irritability and psychotic symptoms may be associated with poorer outcomes. Partial remission and/or a history of prior chronic major depressive episodes are risk factors for recurrent episodes and treatment resistance.

Recurrence of early depression

According to the American Academy of Childand Adolescent Psychiatry (AACAP) practice parameters for depressive disorders in childhood and adolescence, a history of a previous depressive episode, subsyndromal symptoms of depression, dysthymia, and anxiety disorders increase the risk for future depression. In a study of an epidemiologic sample of 776 adolescents by Pine and associates, symptoms of majordepressioninadolescencestrongly predicted episodes of major depression in adulthood. 

Late-onset depression

The prognosis for patients with late-onset depression is felt to be poorer than that for younger patients, and it appears to be dependent on physical disability or illness and lack of social support. Of particular importance is the increasing risk of death by suicide, particularly among elderly men. The length of a depressive episode in the aging population is approximately 18 months, whereas in people 20–55 years of age, the length of an episode is 18 to 24 weeks. In older patients, depression is frequently comorbid with chronic medical conditions and can lead to worsening medical outcomes, including mortality. For example, coronary artery disease is a risk factor for the development of depression, and depression is an independent risk factor for the development of coronary disease. Patients with both conditions are more likely to die than those with coronary artery disease alone. Both behavioral and physiologic explanations are likely for these associations. 

Suicide

Depression plays a role in more than one half of all suicide attempts, whereas the lifetime risk of suicide among patients with untreated depressive disorder is nearly 20%. According to Centers for Disease Control and Prevention (CDC) data, suicide was the 10th leading cause of death in the United States in 2009, accounting for 36,909 deaths; it was the second leading cause of death in people 25-34 years of age, the third leading cause in people aged 10-24 years, and the fourth leading cause at ages 35-54.  However, despite these data and the fact that depression is more often diagnosed in women, the highest suicide rate is in men older than 75 years (see the graph below); more men than women die from suicide by a factor of 4.5:1. White men complete more than 78% of all suicides, and 56% of suicide deaths in males involve firearms. Poisoning is the predominant method among females. Attempted suicide is more frequent in women. In addition to older age and male sex, risk factors for suicide include the following:

• Diagnosis of major depression
• Previous history of suicide attempts
• Depressive symptoms with agitation or distress
• Burden of medical disease and the presence of a current serious medical condition (although this risk may be mediated by a diagnosis of depression)
• Recent stressful life events, especially family discord
• Lack of social support
• Being widowed or divorced
• The presence of a gun in the home
• Unexplained weight loss
• High levels of anxiety
• Lack of a reason not to commit suicide
• Presence of a specific plan that can be carried out
• Rehearsal of the plan

The relationship between use of antidepressants and risk of suicide varies with patient age. Treatment with antidepressants has been associated with increased suicidality in children, adolescents, and young adults 18 to 24 years of age. There is no evidence of increased risk for adults older than 24 years of age; for adults 65 years of age or older, the risk is actually decreased.

Possible Treatment

A wide range of effective treatments is available for major depressive disorder. Medication alone  and psychotherapy (e.g., cognitive-behavioral therapy, interpersonal therapy) alone can relieve depressive symptoms. There is also empirical support for the ability of psychotherapy (CBT) to prevent relapse. In children and adolescents, however, pharmacotherapy by itself is insufficient treatment. Moreover, in all patient populations, the combination of medication and psychotherapy generally provides the quickest and most sustained response. Combination therapy has also been associated with significantly higher rates of improvement in depressive symptoms; increased quality of life; and better treatment compliance, especially when treatment is needed for longer than 3 months.

Medications

Usually, 2–12 weeks at a therapeutic dose, with assumed adherence to the regimen, are needed for a clinical response to become evident. The choice of medication should be guided by anticipated safety and tolerability, which aid in compliance; physician familiarity, which aids in patient education and anticipation of adverse effects; and history of previous treatments. Often, treatment failures are caused by medication noncompliance, inadequate duration of therapy, or inadequate dosing. According to the 2008 American College of Physicians (ACP) guideline (the most recent release of the guideline) on using second-generation antidepressants to treat depressive disorders, patient preferences should be given serious consideration when choosing the best course of pharmacotherapy for patients with depressive disorders. The patient may want to avoid use of a particular antidepressant if he or she had a previous negative experience with the drug. The 2008 ACP guideline advises that treatment for major depressive disorder should be altered if the patient does not have an adequate response to pharmacotherapy within 6–8 weeks. Once satisfactory response is achieved, treatment should be continued for 4–9 months in patients with a first episode of major depression that was not associated with significant suicidality or catastrophic outcomes. In those who have had 2 or more episodes of depression, a longer course of maintenance treatment may prove beneficial. In 2011, the American Psychiatric Association (APA) updated its Practice Guideline for the Treatment of Patients with Major Depressive Disorder. The 2011 APA guideline emphasizes the need to customize a treatment plan for each patient based on a careful assessment of symptoms, including rating scale measurements administered by a clinician or the patient, as well as an analysis of therapeutic benefits and side effects. Treatment should maximize patient function within specific and realistic goals. The initial modality should be chosen on the basis of the following:

• Clinical assessment
• Presence of other disorders
• Stressors
• Patient preference
• Reactions to previous treatment

Psychotherapy

Psychotherapy is often conducted on an outpatient basis with weekly, 60-minute sessions. Although there is wide variation in practice, psychotherapy tends to be time-limited (e.g., 16 sessions). In the 1990s, The American Psychological Association’s Division 12 Task Force on Promotion and Dissemination of Psychological Procedures developed criteria for evaluating the empirical support for psychological treatments. Chambless and Hollon refined these guidelines such that a therapy is considered efficacious and specific if there is evidence from high-quality studies in two or more settings indicating that it is superior to a pill or psychological placebo or to another bonafide treatment. A treatment is considered efficacious if there is evidence from two or more settings that it is superior to no treatment. A therapy is considered to be possibly efficacious if there is research support from one or more studies in a single setting. It is recommended that individuals seeking psychotherapy for depression receive one with empirical support.

Primary Prevention

The following may help in preventing a depressed mood:

• Get more exercise
• Maintain good sleep habits
• Seek out activities that bring you pleasure
• Volunteer or get involved in group activities
• Talk to someone you trust about how you are feeling
• Try to be around people who are caring and positive
• Alcohol and illegal drugs should be avoided. These substances can make depression worse and might lead to thoughts of suicide.

Secondary Prevention

Healthy lifestyle habits can help prevent depression, and reduce the chances of it coming back. Talk therapy and antidepressant medication can also make you less likely to become depressed again. Talk therapy may help you through times of grief, stress, or low mood. Family therapy may help teens who feel sad. Keeping close contact with other people is important for preventing depression.

Risk factors

Depression often begins in the teens, 20s or 30s, but it can happen at any age. More women than men are diagnosed with depression, but this may be due in part because women are more likely to seek treatment. Factors that seem to increase the risk of developing or triggering depression include:

• Certain personality traits, such as low self-esteem and being too dependent, self-critical or pessimistic
• Traumatic or stressful events, such as physical or sexual abuse, the death or loss of a loved one, a difficult relationship, or financial problems
• Blood relatives with a history of depression, bipolar disorder, alcoholism or suicide
• Being lesbian, gay, bisexual or transgender, or having variations in the development of genital organs that aren’t clearly male or female (intersex) in an unsupportive situation
• History of other mental health disorders, such as anxiety disorder, eating disorders or post-traumatic stress disorder
• Abuse of alcohol or recreational drugs
• Serious or chronic illness, including cancer, stroke, chronic pain or heart disease
• Certain medications, such as some high blood pressure medications or sleeping pills (talk to your doctor before stopping any medication)

Signs or Symptoms

Although depression may occur only once during your life, people typically have multiple episodes. During these episodes, symptoms occur most of the day, nearly every day and may include:

• Feelings of sadness, tearfulness, emptiness or hopelessness
• Angry outbursts, irritability or frustration, even over small matters
• Loss of interest or pleasure in most or all normal activities, such as sex, hobbies or sports
• Sleep disturbances, including insomnia or sleeping too much
• Tiredness and lack of energy, so even small tasks take extra effort
• Reduced appetite and weight loss or increased cravings for food and weight gain
• Anxiety, agitation or restlessness
• Slowed thinking, speaking or body movements
• Feelings of worthlessness or guilt, fixating on past failures or self-blame
• Trouble thinking, concentrating, making decisions and remembering things
• Frequent or recurrent thoughts of death, suicidal thoughts, suicide attempts or suicide
• Unexplained physical problems, such as back pain or headaches

For many people with depression, symptoms usually are severe enough to cause noticeable problems in day-to-day activities, such as work, school, social activities or relationships with others. Some people may feel generally miserable or unhappy without really knowing why.

Studies

Active Not Recruiting

Number of studies: 258 Link

Completed

Number of studies: 3, 556 Link

Enrolling by Invitation

Number of studies: 85 Link

Not Yet Recruiting

Number of studies: 281 Link

Recruiting

Number of studies: 1, 033 Link

Results Available

Number of studies: 923 Link

Results Not available

Number of studies: 5, 366 Link

Suspended

Number of studies: 15 Link

Terminated

Number of studies: 325 Link

Withdrawn

Number of studies: 132 Link

Typical Test

Screening Tests

The U.S. Preventive Services Task Force (USPSTF) recommends screening for depression in the general adult population, including older adults and pregnant and postpartum women. It is important to understand that the results obtained from the use of any depression rating scales are imperfect in any population, especially the geriatric population. The simplest screening test is a single question: Are you depressed? A pooled analysis found that single-question screening had a specificity of 97% but an overall sensitivity of 32% and, thus, would identify only 3 of every 10 patients with depression in primary care. The following 2-question test addresses depressed mood and anhedonia:

• During the past month, have you been bothered by feeling down, depressed, or hopeless?
• During the past month, have you been bothered by little interest or pleasure in doing things?

In a cross-sectional study, these 2 screening questions showed a sensitivity of 97% and a specificity of 67%. Longer self-report screening instruments for depression include the following:

• PHQ-9 – The 9-item depression scale of the Patient Health Questionnaire; each item is scored 0 to 3, providing a 0 to 27 severity score
• Beck Depression Inventory (BDI) or Beck Depression Inventory-II (BDI-II) – 21-question symptom-rating scales
• BDI for primary care – A 7-question scale adapted from the BDI
• Zung Self-Rating Depression Scale – A 20-item survey
• Center for Epidemiologic Studies-Depression Scale (CES-D) – A 20-item instrument that allows patients to evaluate their feelings, behavior, and outlook from the previous week.

Given that the commonly atypical presentation of depression in the elderly population can challenge even the most experienced clinician, rating scales in the elderly should be used and interpreted only in the context of a more thorough examination for depression. Patients with major depressive disorder often complain of poor memory or concentration. This may be due to the depression itself or to an underlying dementia. In older patients with established dementia, the Cornell Scale for Depression in Dementia (see the image below) can be used to determine the category and severity of depression. The clinician completes the scale on the basis of prior observation and interviews with the patient and the patient’s caregiver.

Laboratory Studies to Rule Out Organic Causes

Depression is a clinical diagnosis, based on the history and physical findings. No diagnostic laboratory tests are available to diagnose major depressive disorder, but focused laboratory studies may be useful to exclude potential medical illnesses that may present as major depressive disorder. These laboratory studies might include the following:

• Complete blood cell (CBC) count
• Thyroid-stimulating hormone (TSH)
• Vitamin B-12
• Rapid plasma reagin (RPR)
• HIV test
• Electrolytes, including calcium, phosphate, and magnesium levels
• Blood urea nitrogen (BUN) and creatinine
• Liver function tests (LFTs)
• Blood alcohol level
• Blood and urine toxicology screen
• Arterial blood gas (ABG)
• Dexamethasone suppression test (Cushing disease, but also positive in depression)
• Cosyntropin (ACTH) stimulation test (Addison disease)

Neuroimaging

Neuroimaging can help clarify the nature of the neurologic illness that may produce psychiatric symptoms, but these studies are costly and may be of questionable value in patients without discrete neurologic deficits. Computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain should be considered if organic brain syndrome or hypopituitarism is included in the differential diagnosis. Positron emission tomography (PET) imaging provides the means for the study of receptor binding of certain ligands and the effect a compound may have on receptors. However, PET scanning is problematic for use with children and adolescents because it requires complex equipment and uses radiation. Using single-photon emission computed tomography (SPECT) scanning, Tutus et al reported significant differences between the perfusion index values of untreated adolescents with depression and those of control patients. The researchers found that adolescents with major depressive disorder may have regional blood flow deficits in the left anterofrontal and left temporal cortical regions, with greater right-left perfusion asymmetry than healthy control patients.

Reference/links:

https://emedicine.medscape.com/article/286759-overview
https://www.mayoclinic.org/diseases-conditions/depression/symptoms-causes/syc-20356007
https://medlineplus.gov/depression.html#cat_92
https://www.wikidoc.org/index.php/Clinical_depression
https://clinicaltrials.gov/ct2/results?cond=Depression&Search=Clear&age_v=&gndr=&type=&rslt=

 

Venlafaxine (Effexor XR)

Venlafaxine and its active metabolite inhibit neuronal serotonin and norepinephrine reuptake. They are weak inhibitors of dopamine reuptake. In addition, it causes beta-receptor down-regulation. Venlafaxine is sometimes prescribed for non–FDA-approved indications, such as obsessive-compulsive disorder, hot flashes, neuropathic pain, attention-deficit/hyperactivity disorder, and posttraumatic stress disorder.

Levomilnacipran (Fetzima)

Levomilnacipran is the active enantiomer milnacipran and should be administered once daily. It is a potent inhibitor of neuronal serotonin and norepinephrine reuptake, and inhibits norepinephrine uptake with approximately 3-fold higher potency in vitro than serotonin without directly affecting the uptake of dopamine or other neurotransmitters.

Antidepressants, TCAs

Amitriptyline (Elavil)

Amitriptyline inhibits the reuptake of norepinephrine and, more potently, serotonin at the presynaptic neuronal membrane, which increases concentration in the CNS. It has a high affinity for histamine H1 and muscarinic M1 receptors. Amitriptyline can cause weight gain, sedation, and anticholinergic side effects. It is often used for non–FDA-approved indications, such as chronic pain management, diabetic neuropathy, migraine prophylaxis, and posttraumatic stress disorder.

Desipramine (Norpramin)

Desipramine inhibits the reuptake of serotonin and, more potently, norepinephrine at the presynaptic neuronal membrane. It is a commonly used TCA that is relatively less sedating and tends to have fewer anticholinergic and antihistaminic adverse effects than other TCAs. It is sometimes used for off-label indications such as peripheral neuropathy and attention-deficit/hyperactivity disorder.

Imipramine (Tofranil)

Imipramine is one of the oldest agents available for the treatment of depression. It is demethylated in the liver to desipramine. Imipramine inhibits the reuptake of norepinephrine and, more potently, serotonin at the presynaptic neuronal membrane. It has a strong affinity for alpha-adrenergic, H1, and M1 receptors. Common side effects include orthostasis, sedation, weight gain, and anticholinergic effects. It is also used off-label in the treatment of panic disorder, posttraumatic stress disorder, and attention deficit/hyperactivity disorder.

Clomipramine (Anafranil)

Clomipramine potently inhibits the reuptake of serotonin at the presynaptic neuronal membrane. It has strong affinities to both H1 and M1 receptors, which results in sedation, weight gain, and anticholinergic side effects. Although clomipramine is FDA approved only for obsessive-compulsive disorder, it has also been prescribed for depression, panic attacks, and chronic pain.

Nortriptyline (Pamelor)

Nortriptyline blocks the reuptake of serotonin and, more potently, norepinephrine at the presynaptic neuronal membrane. It has less affinity for H1 and M1 receptors and, thus, is better tolerated than other TCAs. Although nortriptyline is FDA approved only for depression, it has also been prescribed for chronic pain, myofascial pain, anxiety disorders, and attention-deficit/hyperactivity disorder. As with desipramine, there is a therapeutic window for nortriptyline

Protriptyline (Vivactil)

Protriptyline increases the synaptic concentration of norepinephrine in the CNS by inhibiting reuptake at the presynaptic neuronal membrane. It has less affinity for H1 and M1 receptors and, thus, is better tolerated than tertiary amine TCAs.

Doxepin

Doxepin increases the concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake at the presynaptic neuronal membrane. These effects are associated with a decrease in the symptoms of depression. It has the highest affinity for H1 receptors of all TCAs and, thus, is very sedating and can cause weight gain.

Trimipramine (Surmontil)

Trimipramine inhibits reuptake of norepinephrine and serotonin at the presynaptic neuron and elicits strong anticholinergic effects. It has a high affinity for the H1 receptor and is thus very sedating, but it is useful for gastroesophageal reflux.

Amoxapine

Amoxapine inhibits reuptake of norepinephrine and, to a lesser extent, serotonin at the presynaptic neuron. It also blocks dopamine receptors, causing it to have antipsychotic activity, as well.

Antidepressants, MAO Inhibitors

Selegiline transdermal patch (Emsam)

Selegiline inhibits MAOb at lower doses and both forms at higher doses. Because it does not inhibit MAOa, it does not require dietary restrictions at lower doses. Lower doses of oral selegiline (Eldepryl) appear to lack antidepressant properties and are usually prescribed to treat Parkinson disease. Higher doses are used to treat major depressive disorder, and the selegiline transdermal patch is FDA approved for this indication. Selegiline is sometimes used off-label to treat attention-deficit/hyperactivity disorder. Dietary restrictions are not required for the 6 mg/24 hour patch because there is no risk of hypertensive crisis with this dose, given the lack of MAOa inhibition. Higher doses require dietary restrictions. The patch may be beneficial to those that cannot take oral medications. To avoid serotonin syndrome, initiating and stopping selegiline must be handled carefully.

Tranylcypromine (Parnate)

Tranylcypromine is used to treat major depression. It binds irreversibly to MAOa and to a lesser extent to MAOb, thereby reducing monoamine breakdown and enhancing synaptic availability. Clinical effects are not normally seen for 2-4 weeks. It has similar side effects as other MAOIs, but it is more likely to cause insomnia.

Phenelzine (Nardil)

Phenelzine is used to treat depression. It irreversibly inhibits both MOAa and MOAb. Side effects are similar to those of other MAOIs, but anticholinergic side effects are more common. Phenelzine causes less insomnia than tranylcypromine but is more likely to cause sedation, weight gain, and sexual dysfunction.

Isocarboxazid (Marplan)

Isocarboxazid is a nonselective hydrazine MAOI that is indicated for the treatment of depression. The mechanism by which MAOIs act as an antidepressant is not fully understood, but it is thought to be that these drugs increase the CNS concentrations of norepinephrine, dopamine, and serotonin.

Augmenting Agents

Lithium carbonate (Lithobid)

Lithium carbonate can be used as an effective augmenting agent in combination with an antidepressant in cases of treatment-resistant depression. It can also be used to treat or prevent episodes of depression. Lithium is contraindicated in patients with significant renal impairment. It is important to note that lithium interacts with many drugs. Use of lithium often requires monitoring of lithium levels and renal and thyroid function tests.

Buspirone

Buspirone is marketed as an antianxiety medication; however, it may have antidepressant effects at doses above 45 mg/day. The antidepressant effects may increase when buspirone is used in combination with SSRIs and TCAs in patients with treatment-resistant depression. Buspirone is a partial 5-HT1A agonist with serotonergic and some dopaminergic effects in the CNS. It has anxiolytic effects but may take up to 2-3 weeks for full efficacy.

Serotonin-Dopamine Activity Modulators

Brexpiprazole (Rexulti)

Serotonin-dopamine activity modulator (SDAM) indicated as an adjunct treatment for major depressive disorder. Dosage modifications are necessary with renal or hepatic impairment. Dosage modifications are also needed for individuals who are poor metabolizers of CYP2D6, or if coadministered drugs alter metabolism by CYP2D6 or CYP3A4.

Aripiprazole (Abilify, Abilify Discmelt)

Serotonin-dopamine activity modulator (SDAM) indicated as an adjunct treatment for major depressive disorder. Dosage modifications are also needed for individuals who are poor metabolizers of CYP2D6, or if coadministered drugs alter metabolism by CYP2D6 or CYP3A4. No dosage adjustment is required for renal or hepatic impairment.

Antidepressants, Other

Bupropion (Wellbutrin, Aplenzin, Forfivo XL)

Bupropion inhibits neuronal dopamine reuptake and decreases the rate of norepinephrine activity. In addition to major depressive disorder, the indications for bupropion include smoking cessation. Off-label indications include attention-deficit/hyperactivity disorder and depression associated with bipolar disorder. Common side effects include headache and mild weight loss. Unlike other antidepressants, bupropion does not cause sexual dysfunction.

Mirtazapine (Remeron, Remeron SolTab)

Mirtazapine blocks both presynaptic and postsynaptic alpha-2 receptors but has low affinity for alpha-1 receptors. It also blocks serotonin receptors 5HT2 and 5HT3. Common side effects include sedation, weight gain, and dry mouth.

Trazodone (Oleptro)

Trazodone is effective in the treatment of major depression. It inhibits reuptake of serotonin and modulates serotonergic neurotransmission. It also significantly blocks histamine (H1) receptors. Its most common side effect is sedation, and thus, it has an off-label indication as a hypnotic. It can be very rarely associated with priapism, a medical emergency and a dangerous side effect of this drug in men. It is often used at a low dosage (25 to 50 mg) as an adjunct to SSRIs to treat insomnia.

Esketamine intranasal (Spravato)

Esketamine, the S-enantiomer of racemic ketamine, is a nonselective, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist (NMDA is an ionotropic glutamate receptor). The mechanism by which esketamine exerts its antidepressant effect is unknown. It is indicated for treatment-resistant depression in conjunction with an oral antidepressant.

Stimulants

Dextroamphetamine (Dexedrine, ProCentra, Zenzedi)

This is an augmenting agent in resistant depression. It has been studied most for treating patients who are medically ill and depressed. It is available as a sustained-release preparation.

Methylphenidate (Ritalin, Aptensio XR, Concerta, Daytrana, Metadate ER, Quillivant ER)

Methylphenidate has been mostly studied for treating patients who are medically ill and depressed. It is available as a sustained-release preparation.

Thyroid Products

Liothyronine (Liothyronine T3, Cytomel, Triostat)

This synthetic salt of endogenous thyroid hormone may convert nonresponders (ie, nonresponders to antidepressants) to responders by increasing receptor sensitivity and enhancing the effects of TCAs.

Herbal products

Hypericum perforatum (St John’s Wort)

St John’s wort is believed to act as an antidepressant by increasing concentrations of CNS neurotransmitters, including serotonin. The common dosage is 300 mg 3 times a day with meals to prevent GI upset. If no clinical response occurs after 3-6 months, encouraging the use of another medication is essential.

Epidemiology

The twelve-month prevalence of clinical depression is 7,000 per 100,000 (7%) of the overall population. In some countries, such as Australia, one in four women and one in six men will suffer from depression. In Canada, major depression affects approximately 1.35 million people, and in the United States approximately 14 million adults per year. An estimated 121 million people worldwide currently suffer from depression. People who have had one episode of depression may be more than normally likely to have more episodes in the future, so the first time a young person becomes depressed is important both as a personal and public health concern. About twice as many females as males report or receive treatment for clinical depression, though this imbalance is shrinking over the course of recent history; this difference seems to completely disappear after the age of 50–55. Clinical depression is currently the leading cause of disability in North America, and is expected to become the second leading cause of disability worldwide (after heart disease) by the year 2020, according to the World Health Organization. Recent studies suggest that the diagnostic criteria for depression are far too broad, resulting in diagnosis of clinical depression in people who are not truly suffering from the disorder and who have shown normal responses to negative events.

Prognosis

Major depressive disorder has significant potential morbidity and mortality, contributing as it does to suicide, incidence and adverse outcomes of medical illness, disruption in interpersonal relationships, substance abuse, and lost work time. With appropriate treatment, 70-80% of individuals with major depressive disorder can achieve a significant reduction in symptoms, although as many as 50% of patients may not respond to the initial treatment trial. A study of first-episode psychotic depression by Tohen et al found that most patients achieved syndromal remission (86%) and recovery (84%); however, only 35% recovered functionally. Earlier syndromal recovery was associated with subacute onset, lower initial depression scores, and lack of mood-incongruent psychotic features. Within 2 years, almost half the patients experienced new episodes. In 41% of patients, the diagnosis was changed, usually to bipolar or schizoaffective disorders.

Natural Progression

Major depressive disorder is a serious health problem and will be the second leading cause of burden of disease worldwide by 2030. In any given 12-month period, 10–20% of adults will visit their general practitioner (GP) for mental complaints, of which the majority are related to depression. The prevalence of depression in primary care is estimated to be between 4 and 18%. People presenting with depressive symptoms are mainly seen in primary care; however, treatment guidelines are mainly based upon data from hospital settings or the general population. Few studies have examined the course and outcome of MDD in primary care over a greater period of time. In one study, 32% of the primary care patients who were depressed at baseline were not depressed after 12 months and 47% were not depressed after 3.5 years. A recent study showed that of the 79 primary care patients diagnosed with MDD at baseline, 25% persisted and 49% suffered from residual symptoms or recurrences after 18 months. These data suggest that the majority of adult patients with depression in primary care do not recover in the medium-term, but also that some patients do recover.

Pathophysiology

The underlying pathophysiology of major depressive disorder has not been clearly defined. Current evidence points to a complex interaction between neurotransmitter availability and receptor regulation and sensitivity underlying the affective symptoms. Clinical and preclinical trials suggest a disturbance in central nervous system serotonin (5-HT) activity as an important factor. Other neurotransmitters implicated include norepinephrine (NE), dopamine (DA), glutamate, and brain-derived neurotrophic factor (BDNF). However, drugs that produce only an acute rise in neurotransmitter availability, such as cocaine or amphetamines, do not have the efficacy over time that antidepressants do. The role of CNS 5-HT activity in the pathophysiology of major depressive disorder is suggested by the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs). In addition, studies have shown that an acute, transient relapse of depressive symptoms can be produced in research subjects in remission using tryptophan depletion, which causes a temporary reduction in CNS 5-HT levels. However, the effect of SSRIs on 5HT reuptake is immediate, but the antidepressant effect requires exposure of several weeks’ duration. Also, some antidepressants have no effect on 5HT (eg, desipramine), and the antidepressant tianeptine enhances 5HT uptake. All this, together with preclinical research findings, implies a role for neuronal receptor regulation, intracellular signaling, and gene expression over time, in addition to enhanced neurotransmitter availability. Seasonal affective disorder is a form of major depressive disorder that typically arises during the fall and winter and resolves during the spring and summer. Studies suggest that seasonal affective disorder is also mediated by alterations in CNS levels of 5-HT and appears to be triggered by alterations in circadian rhythm and sunlight exposure. Vascular lesions may contribute to depression by disrupting the neural networks involved in emotion regulation—in particular, frontostriatal pathways that link the dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate, and dorsal cingulate. Other components of limbic circuitry, in particular the hippocampus and amygdala, have been implicated in depression.

Brain structures

Functional neuroimaging studies support the hypothesis that the depressed state is associated with decreased metabolic activity in neocortical structures and increased metabolic activity in limbic structures. Serotonergic neurons implicated in affective disorders are found in the dorsal raphe nucleus, the limbic system, and the left prefrontal cortex. A meta-analysis comparing brain structures in patients with major depression, in healthy controls, and in patients with bipolar disorder demonstrated associations between depression and increased lateral ventricle size, larger cerebrospinal fluid volume, and smaller volumes of the basal ganglia, thalamus, hippocampus, frontal lobe, orbitofrontal cortex, and gyrus rectus. Patients experiencing a depressive episode had smaller hippocampal volume than those in remission. In one study, positron emission tomographic (PET) images showed abnormally diminished activity in an area of the prefrontal cortex in patients with unipolar depression and bipolar depression. This region is related to emotional response and has widespread connections with other areas of the brain, including the areas that appear to be responsible for the regulation of DA, noradrenaline (locus ceruleus), and 5-HT (raphe nuclei). Both functional and structural abnormalities were found in the same brain region during a major depressive episode. Sacher et al found increases in glucose metabolism in the right subgenual and pregenual anterior cingulate cortices and decreased gray matter volumes in the amygdala, dorsal frontomedian cortex, and right paracingulate cortex.

Aging

An integrative model of late-onset depression posits that age-related brain changes and disease-related changes (eg, cerebrovascular disease), coupled with physiologic vulnerabilities (eg, genetic risk factors, personal history of depression) and psychosocial adversity, lead to disruptions in the functional circuitry of emotion regulation—namely, hypometabolism of cortical structures and hypermetabolism of limbic structures. Endocrine changes in depression are evident across the life span, but some are unique to aging. Women with a previous history of depression are at higher risk of developing depression during menopause, although estrogen replacement does not relieve depression; low testosterone levels have been associated with depression in older men.

Possible Complications

Twenty percent of individuals with major depressive disorder untreated at 1 year will continue to meet criteria for the diagnosis, whereas an additional 40% will have a partial remission. Pretreatment irritability and psychotic symptoms may be associated with poorer outcomes. Partial remission and/or a history of prior chronic major depressive episodes are risk factors for recurrent episodes and treatment resistance.

Recurrence of early depression

According to the American Academy of Childand Adolescent Psychiatry (AACAP) practice parameters for depressive disorders in childhood and adolescence, a history of a previous depressive episode, subsyndromal symptoms of depression, dysthymia, and anxiety disorders increase the risk for future depression. In a study of an epidemiologic sample of 776 adolescents by Pine and associates, symptoms of majordepressioninadolescencestrongly predicted episodes of major depression in adulthood. 

Late-onset depression

The prognosis for patients with late-onset depression is felt to be poorer than that for younger patients, and it appears to be dependent on physical disability or illness and lack of social support. Of particular importance is the increasing risk of death by suicide, particularly among elderly men. The length of a depressive episode in the aging population is approximately 18 months, whereas in people 20–55 years of age, the length of an episode is 18 to 24 weeks. In older patients, depression is frequently comorbid with chronic medical conditions and can lead to worsening medical outcomes, including mortality. For example, coronary artery disease is a risk factor for the development of depression, and depression is an independent risk factor for the development of coronary disease. Patients with both conditions are more likely to die than those with coronary artery disease alone. Both behavioral and physiologic explanations are likely for these associations. 

Suicide

Depression plays a role in more than one half of all suicide attempts, whereas the lifetime risk of suicide among patients with untreated depressive disorder is nearly 20%. According to Centers for Disease Control and Prevention (CDC) data, suicide was the 10th leading cause of death in the United States in 2009, accounting for 36,909 deaths; it was the second leading cause of death in people 25-34 years of age, the third leading cause in people aged 10-24 years, and the fourth leading cause at ages 35-54.  However, despite these data and the fact that depression is more often diagnosed in women, the highest suicide rate is in men older than 75 years (see the graph below); more men than women die from suicide by a factor of 4.5:1. White men complete more than 78% of all suicides, and 56% of suicide deaths in males involve firearms. Poisoning is the predominant method among females. Attempted suicide is more frequent in women. In addition to older age and male sex, risk factors for suicide include the following:

• Diagnosis of major depression
• Previous history of suicide attempts
• Depressive symptoms with agitation or distress
• Burden of medical disease and the presence of a current serious medical condition (although this risk may be mediated by a diagnosis of depression)
• Recent stressful life events, especially family discord
• Lack of social support
• Being widowed or divorced
• The presence of a gun in the home
• Unexplained weight loss
• High levels of anxiety
• Lack of a reason not to commit suicide
• Presence of a specific plan that can be carried out
• Rehearsal of the plan

The relationship between use of antidepressants and risk of suicide varies with patient age. Treatment with antidepressants has been associated with increased suicidality in children, adolescents, and young adults 18 to 24 years of age. There is no evidence of increased risk for adults older than 24 years of age; for adults 65 years of age or older, the risk is actually decreased.

Possible Treatment

A wide range of effective treatments is available for major depressive disorder. Medication alone  and psychotherapy (e.g., cognitive-behavioral therapy, interpersonal therapy) alone can relieve depressive symptoms. There is also empirical support for the ability of psychotherapy (CBT) to prevent relapse. In children and adolescents, however, pharmacotherapy by itself is insufficient treatment. Moreover, in all patient populations, the combination of medication and psychotherapy generally provides the quickest and most sustained response. Combination therapy has also been associated with significantly higher rates of improvement in depressive symptoms; increased quality of life; and better treatment compliance, especially when treatment is needed for longer than 3 months.

Medications

Usually, 2–12 weeks at a therapeutic dose, with assumed adherence to the regimen, are needed for a clinical response to become evident. The choice of medication should be guided by anticipated safety and tolerability, which aid in compliance; physician familiarity, which aids in patient education and anticipation of adverse effects; and history of previous treatments. Often, treatment failures are caused by medication noncompliance, inadequate duration of therapy, or inadequate dosing. According to the 2008 American College of Physicians (ACP) guideline (the most recent release of the guideline) on using second-generation antidepressants to treat depressive disorders, patient preferences should be given serious consideration when choosing the best course of pharmacotherapy for patients with depressive disorders. The patient may want to avoid use of a particular antidepressant if he or she had a previous negative experience with the drug. The 2008 ACP guideline advises that treatment for major depressive disorder should be altered if the patient does not have an adequate response to pharmacotherapy within 6–8 weeks. Once satisfactory response is achieved, treatment should be continued for 4–9 months in patients with a first episode of major depression that was not associated with significant suicidality or catastrophic outcomes. In those who have had 2 or more episodes of depression, a longer course of maintenance treatment may prove beneficial. In 2011, the American Psychiatric Association (APA) updated its Practice Guideline for the Treatment of Patients with Major Depressive Disorder. The 2011 APA guideline emphasizes the need to customize a treatment plan for each patient based on a careful assessment of symptoms, including rating scale measurements administered by a clinician or the patient, as well as an analysis of therapeutic benefits and side effects. Treatment should maximize patient function within specific and realistic goals. The initial modality should be chosen on the basis of the following:

• Clinical assessment
• Presence of other disorders
• Stressors
• Patient preference
• Reactions to previous treatment

Psychotherapy

Psychotherapy is often conducted on an outpatient basis with weekly, 60-minute sessions. Although there is wide variation in practice, psychotherapy tends to be time-limited (e.g., 16 sessions). In the 1990s, The American Psychological Association’s Division 12 Task Force on Promotion and Dissemination of Psychological Procedures developed criteria for evaluating the empirical support for psychological treatments. Chambless and Hollon refined these guidelines such that a therapy is considered efficacious and specific if there is evidence from high-quality studies in two or more settings indicating that it is superior to a pill or psychological placebo or to another bonafide treatment. A treatment is considered efficacious if there is evidence from two or more settings that it is superior to no treatment. A therapy is considered to be possibly efficacious if there is research support from one or more studies in a single setting. It is recommended that individuals seeking psychotherapy for depression receive one with empirical support.

Primary Prevention

The following may help in preventing a depressed mood:

• Get more exercise
• Maintain good sleep habits
• Seek out activities that bring you pleasure
• Volunteer or get involved in group activities
• Talk to someone you trust about how you are feeling
• Try to be around people who are caring and positive
• Alcohol and illegal drugs should be avoided. These substances can make depression worse and might lead to thoughts of suicide.

Secondary Prevention

Healthy lifestyle habits can help prevent depression, and reduce the chances of it coming back. Talk therapy and antidepressant medication can also make you less likely to become depressed again. Talk therapy may help you through times of grief, stress, or low mood. Family therapy may help teens who feel sad. Keeping close contact with other people is important for preventing depression.

Risk factors

Depression often begins in the teens, 20s or 30s, but it can happen at any age. More women than men are diagnosed with depression, but this may be due in part because women are more likely to seek treatment. Factors that seem to increase the risk of developing or triggering depression include:

• Certain personality traits, such as low self-esteem and being too dependent, self-critical or pessimistic
• Traumatic or stressful events, such as physical or sexual abuse, the death or loss of a loved one, a difficult relationship, or financial problems
• Blood relatives with a history of depression, bipolar disorder, alcoholism or suicide
• Being lesbian, gay, bisexual or transgender, or having variations in the development of genital organs that aren’t clearly male or female (intersex) in an unsupportive situation
• History of other mental health disorders, such as anxiety disorder, eating disorders or post-traumatic stress disorder
• Abuse of alcohol or recreational drugs
• Serious or chronic illness, including cancer, stroke, chronic pain or heart disease
• Certain medications, such as some high blood pressure medications or sleeping pills (talk to your doctor before stopping any medication)

Signs or Symptoms

Although depression may occur only once during your life, people typically have multiple episodes. During these episodes, symptoms occur most of the day, nearly every day and may include:

• Feelings of sadness, tearfulness, emptiness or hopelessness
• Angry outbursts, irritability or frustration, even over small matters
• Loss of interest or pleasure in most or all normal activities, such as sex, hobbies or sports
• Sleep disturbances, including insomnia or sleeping too much
• Tiredness and lack of energy, so even small tasks take extra effort
• Reduced appetite and weight loss or increased cravings for food and weight gain
• Anxiety, agitation or restlessness
• Slowed thinking, speaking or body movements
• Feelings of worthlessness or guilt, fixating on past failures or self-blame
• Trouble thinking, concentrating, making decisions and remembering things
• Frequent or recurrent thoughts of death, suicidal thoughts, suicide attempts or suicide
• Unexplained physical problems, such as back pain or headaches

For many people with depression, symptoms usually are severe enough to cause noticeable problems in day-to-day activities, such as work, school, social activities or relationships with others. Some people may feel generally miserable or unhappy without really knowing why.

Studies

Active Not Recruiting

Number of studies: 258 Link

Completed

Number of studies: 3, 556 Link

Enrolling by Invitation

Number of studies: 85 Link

Not Yet Recruiting

Number of studies: 281 Link

Recruiting

Number of studies: 1, 033 Link

Results Available

Number of studies: 923 Link

Results Not available

Number of studies: 5, 366 Link

Suspended

Number of studies: 15 Link

Terminated

Number of studies: 325 Link

Withdrawn

Number of studies: 132 Link

Typical Test

Screening Tests

The U.S. Preventive Services Task Force (USPSTF) recommends screening for depression in the general adult population, including older adults and pregnant and postpartum women. It is important to understand that the results obtained from the use of any depression rating scales are imperfect in any population, especially the geriatric population. The simplest screening test is a single question: Are you depressed? A pooled analysis found that single-question screening had a specificity of 97% but an overall sensitivity of 32% and, thus, would identify only 3 of every 10 patients with depression in primary care. The following 2-question test addresses depressed mood and anhedonia:

• During the past month, have you been bothered by feeling down, depressed, or hopeless?
• During the past month, have you been bothered by little interest or pleasure in doing things?

In a cross-sectional study, these 2 screening questions showed a sensitivity of 97% and a specificity of 67%. Longer self-report screening instruments for depression include the following:

• PHQ-9 – The 9-item depression scale of the Patient Health Questionnaire; each item is scored 0 to 3, providing a 0 to 27 severity score
• Beck Depression Inventory (BDI) or Beck Depression Inventory-II (BDI-II) – 21-question symptom-rating scales
• BDI for primary care – A 7-question scale adapted from the BDI
• Zung Self-Rating Depression Scale – A 20-item survey
• Center for Epidemiologic Studies-Depression Scale (CES-D) – A 20-item instrument that allows patients to evaluate their feelings, behavior, and outlook from the previous week.

Given that the commonly atypical presentation of depression in the elderly population can challenge even the most experienced clinician, rating scales in the elderly should be used and interpreted only in the context of a more thorough examination for depression. Patients with major depressive disorder often complain of poor memory or concentration. This may be due to the depression itself or to an underlying dementia. In older patients with established dementia, the Cornell Scale for Depression in Dementia (see the image below) can be used to determine the category and severity of depression. The clinician completes the scale on the basis of prior observation and interviews with the patient and the patient’s caregiver.

Laboratory Studies to Rule Out Organic Causes

Depression is a clinical diagnosis, based on the history and physical findings. No diagnostic laboratory tests are available to diagnose major depressive disorder, but focused laboratory studies may be useful to exclude potential medical illnesses that may present as major depressive disorder. These laboratory studies might include the following:

• Complete blood cell (CBC) count
• Thyroid-stimulating hormone (TSH)
• Vitamin B-12
• Rapid plasma reagin (RPR)
• HIV test
• Electrolytes, including calcium, phosphate, and magnesium levels
• Blood urea nitrogen (BUN) and creatinine
• Liver function tests (LFTs)
• Blood alcohol level
• Blood and urine toxicology screen
• Arterial blood gas (ABG)
• Dexamethasone suppression test (Cushing disease, but also positive in depression)
• Cosyntropin (ACTH) stimulation test (Addison disease)

Neuroimaging

Neuroimaging can help clarify the nature of the neurologic illness that may produce psychiatric symptoms, but these studies are costly and may be of questionable value in patients without discrete neurologic deficits. Computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain should be considered if organic brain syndrome or hypopituitarism is included in the differential diagnosis. Positron emission tomography (PET) imaging provides the means for the study of receptor binding of certain ligands and the effect a compound may have on receptors. However, PET scanning is problematic for use with children and adolescents because it requires complex equipment and uses radiation. Using single-photon emission computed tomography (SPECT) scanning, Tutus et al reported significant differences between the perfusion index values of untreated adolescents with depression and those of control patients. The researchers found that adolescents with major depressive disorder may have regional blood flow deficits in the left anterofrontal and left temporal cortical regions, with greater right-left perfusion asymmetry than healthy control patients.

Reference/links:

https://emedicine.medscape.com/article/286759-overview
https://www.mayoclinic.org/diseases-conditions/depression/symptoms-causes/syc-20356007
https://medlineplus.gov/depression.html#cat_92
https://www.wikidoc.org/index.php/Clinical_depression
https://clinicaltrials.gov/ct2/results?cond=Depression&Search=Clear&age_v=&gndr=&type=&rslt=