Major depressive disorder

Major depressive disorder (MDD), is a mental disorder characterized by at least two weeks of low mood that is present in most situations.

MDD is a leading cause of disability worldwide and is estimated to affect 21 million adults in the United States.

MDD is defined as depressed mood or loss of interest or pleasure for at least two weeks, with primary symptom accompanied by at least 4 of the following additional symptoms: changes in sleep, changes in appetite or weight, poor concentration or indecision, fatigue or low energy, psychomotor slowing or agitation, feelings of worthlessness or inappropriate guilt, and  recurrent thoughts of death or suicide.

The pathophysiology of depression is not clear, but the currenes center around monoaminergic systems, the circadian rhythm, immunological dysfunction, HPA axis dysfunction and structural or functional abnormalities of emotional circuits.

Reduced GABA levels have been observed in plasma, CSF, and cortical brain tissues of patients with depression.

It is often accompanied by low self-esteem, loss of interest in normally enjoyable activities, low energy, and pain without a clear cause.

Anxiety often precedes and is a commonly present  with depression in adolescents.

Post-traumatic stress disorder and major depression often co-occur.

Associated with upregulation of the hypothalamic-pituitary-adrenal axis.

Depression and pain often co-occur.

Pain symptoms are present in 65% of depressed patients.

Majority depressive disorder affects approximately 3% of the global population.

Lifetime prevalence 17%.

The number of people who have depression in most countries,during their lives falls, within an 8-18% range.

The probability of having a major depressive episode within a year-long period is 3-5% for males and 8-10% for females.

Major depression to be about twice as common in women as in men.

Ranks second as leading contributor of years lived with disability.

1/3 of patients develop treatment resistance.

People are most likely to develop their first depressive episode onset between the ages of 30 and 40, and there is a second, smaller peak of incidence between ages 50 and 60.

Studies conflict on the prevalence of depression in the elderly.

Depression is especially common among those over 65 years of age and increases in frequency with age beyond this age.

It increases in relation to the age and frailty of the individual.

It is an important factor which negatively impacts quality of life in adults as well as the elderly.

It is common among the elderly not to present classical depressive symptoms.

Treatment is further complicated in that the elderly are often simultaneously treated with a number of other drugs, and often have comorbid diseases.

The effectiveness of anti-depressants is sub optimal, and more than a third of patients.

Studies of SSRI-drugs have shown lesser and often inadequate effect among the elderly, while other drugs with more clear effects have adverse effects which can be especially difficult to handle among the elderly.

More common in urban than in rural populations and the prevalence is higher in lower socioeconomic groups

At least 1/3 of patients receiving anti-depressive therapy do not have a response after two or more trials of such drugs, and are considered to have treatment resistant depression.

Reduced levels of allopregnanolone in the CSF normalizes after successful treatment of depression with antidepressants.

Patients with treatment resistant depression have an increased risk of suicide compared to non-resistant major depressive disorder patients, and at least 1/3 attempt suicide.

The first generation antidepressants-imipramine and amitriptyline were thought to work by increasing central noradrenergic and serotogeneric activity but were not uniformly effective.

Second generation anti-depressants target a single neurochemical system (norepinephrine, and dopamine, or serotonin), have not been successful in all patients with major depressive disorder.

The enhancement of various monoaminergic neurotransmitters such as norepinephrine, and dopamine, and serotonin can alleviate the symptoms of major depressive disorder, and this effect is typically seen about four weeks after the start of treatment.

The lifetime risk of suicide associated with a diagnosis of major depression in the US is estimated at 3.4%, which averages two highly disparate figures of almost 7% for men and 1% for women.

Depression is often associated with unemployment and poverty.

Depressed individuals have a shorter life expectancy because depressed patients risk of dying by suicide, a higher rate of dying from other causes, and being more susceptible to medical conditions such as heart disease.

Up to 60% of people who die by suicide have a mood disorder such as major depression, and the risk is especially high if a person has a marked sense of hopelessness or has both depression and borderline personality

For children, adolescents, and probably young adults between 18 and 24 years old, there is a higher risk of both suicidal ideations and suicidal behavior in those treated with SSRIs.

It is unclear whether SSRIs affect the risk of suicidality in adults.

Neurological conditions such as stroke, Parkinson’s disease, or multiple sclerosis associated with increased risk.

The first year after childbirth is associated with increased risk.

Major depression more common after cardiovascular illnesses, and is related more to a poor outcome.

Diagnosis requires a change of mood with sadness or irritability and accompanied by psychophysiological changes of sleep disturbances, impaired appetite, loss of libido, constipation, decreased pleasure associated with work, friends, suicide suicidal ideation, crying, slowing of speech and action.

Nearly 90% of people with major depressive disorder report disturbed sleep.

Before diagnosing a major depressive disorder, it is necessary to rule out other causes of symptoms including hypothyroidism, metabolic disturbances, systemic infection, chronic disease, adverse reactions to medications, alcohol misuse, hypogonadism, and low levels of vitamin D.

When depression is caused by a medication, drug abuse, or exposure to a toxin, it is then diagnosed as a specific mood disorder.

Excluded are a range of related diagnoses, including dysthymia, recurrent brief depression, and minor depressive disorder.

Melancholic depression is described as a loss of pleasure in most or all activities, a failure of reactivity to pleasurable stimuli, a quality of depressed mood more pronounced than that of grief or loss, a worsening of symptoms in the morning hours, early-morning waking, psychomotor retardation, excessive weight loss or excessive guilt.

Depression without mania is sometimes ref2241ed to as unipolar.

Diagnosis excludes cases where the symptoms are a result of bereavement.

It is possible for normal bereavement to evolve into a depressive episode if the mood persists and the characteristic features of a major depressive episode develop.

Adjustment disorder with depressed mood is a mood disturbance appearing as a response to an event or stressor, in which the resulting emotional or behavioral symptoms are significant but do not meet the criteria for a major depressive episode.

Bipolar disorder, also known as manic-depressive disorder, is a condition in which depressive phases alternate with periods of mania or hypomania.

Some individuals diagnosed with major depression often experience some hypomanic symptoms, indicating a mood disorder continuum.

Other disorders need to be ruled out before diagnosing major depressive disorder include: depressions due to physical illness, medications, and substance abuse.

Depression due to physical illness is a mood disorder due to a general medical condition.

Catatonic depression is a severe form of major depression involving disturbances of motor behavior and other symptoms.

In catatonic depression patients are mute, almost stuporous, and immobile or have purposeless or even bizarre movements.

Depressive symptoms defines three typical depressive symptoms: depressed mood, anhedonia, and reduced energy, two of which should be present to determine depressive disorder diagnosis.

A major depressive episode is characterized by a severely depressed mood that persists for at least two weeks.

Episodes may be isolated or recurrent and are categorized as mild, moderate, or severe.

An episode with psychotic feature is rated as severe.

If the patient has had an episode of mania or markedly elevated mood, a diagnosis of bipolar disorder is made instead.

Cognitive testing and brain imaging can help distinguish depression from dementia.

Meta-analyses of MRI neuroimaging studies in major depression reported that, compared to controls, depressed patients had increased volume of the lateral ventricles and adrenal gland and smaller volumes of the basal ganglia, thalamus, hippocampus, and frontal lobe.

In patients with rapid onset or atypical symptoms a CT scan can exclude brain abnormalities.

Presently, there are no biological tests to confirm the diagnosis of major depressive disorder.

Diagnosis of major depressive disorder is based on the reported experiences and a mental status examination.

Patients may be preoccupied with thoughts and feelings of worthlessness, inappropriate guilt or regret, helplessness, hopelessness, and self-hatred.

In severe cases people may have symptoms of psychosis: delusions or hallucinations.

DSM-5 diagnostic Criteria for Major Depressive Disorder:

Core symptoms-depressed mood most of the day, anhedonia or markedly decreased interest or pleasure in almost all activities.

In the elderly forgetfulness, and slowing of movement may manifest.

Depression often coexists with stroke, cardiovascular diseases, Parkinson’s disease, and chronic obstructive pulmonary disease.

The United States Preventive Services Task Force (USPSTF) recommended screening in the adult populations with evidence that it increases the detection of people with depression and with proper treatment improves outcomes.

They recommend screening in those between the age of 12 to 18 as well.

But a Cochrane review from 2005 found screening programs do not significantly improve detection rates, treatment, or outcome.

Efforts to prevent major depressive disorder may decrease rates of the condition of between 22 and 38%.

It has been suggested that eating large amounts of fish may also reduce the risk.

Interpersonal therapy and cognitive-behavioral therapy, are effective at preventing new onset depression.

Associated with a 1.5- to 2-fold increased risk of cardiovascular disease.

Depression results when a preexisting vulnerability, or diathesis, is activated by stressful life events.

The preexisting vulnerability can be either genetic, or schematic.

A genetic vulnerability implies an interaction between nature and nurture, while a schematic vulnerability results from views of the world learned in childhood.

The 5-HTTLPR, or serotonin transporter promoter gene’s short allele has been associated with increased risk of depression, but testing has not been consistent.

Genes that have been linked to a gene-environment interaction include CRHR1, FKBP5 and BDNF.

Childhood abuse, either physical, sexual or psychological are risk factors for depression.

May be secondary to:

A chronic or terminal medical condition, induced by drugs such as interferon therapy, beta-blockers, Isotretinoin, contraceptives, cardiac agents, anticonvulsants, antimigraine drugs, antipsychotics, hormonal agents agents such as gonadotropin-releasing hormone agonist, and interferon therapy

Early age drug abuse is also associated with increased risk of developing depression later in life.

Tends to relapse within twelve months.

Electroconvulsive therapy as treatment of the elderly is effective although less so than among the rest of the adult population.

The general physical risks of ECT are similar to those of brief general anesthesia, with the most common adverse effects are confusion and memory loss.

ECT is considered one of the least harmful treatment options available for severely depressed pregnant women.

ECT is administered under anesthetic with a muscle relaxant, and involves multiple administrations, typically given two or three times per week until the patient is no longer suffering symptoms.

After ECT, drug therapy is usually continued, and some patients receive maintenance ECT.

In the short term ECT has an anticonvulsant effect mostly in the frontal lobes.

Longer term effect of ECT is via neurotrophic effects primarily in the medial temporal lobe.

Hospitalization may be necessary in severe cases.

Many classes of antidepressants are efficacious including: selective serotonin reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, atypical or novel antidepressants as well as tricyclic antidepressants, or monoamine oxidase inhibitors.

In a randomized placebo-controlled trial of antidepressants in the treatment of major or minor depressive disorder, the magnitude of the superiority of medication over placebo increases in baseline depression severity and may be minimal or nonexistent in patients with mild to moderate symptoms: for patients with very severe depression: The benefits of medications over placebo is substantial (Fournier JC).

The goal of antidepressant therapy is to achieve full remission, but individuals who experience residual symptoms have a higher chance of experiencing one or more additional episodes of depression.

The optimal outcome for treatment is considered to be symptomatic remission.

Symptomatic remission is defined as minimal residual symptoms as measured by an 80% or greater reduction in symptoms using rating scales.

Treating to remission is key to recover full function and to prevent subsequent relapse.

Remitted patients experience residual symptoms still impair functioning.

Up to 70% of patients with major depressive disorder do not respond or achieve remission with the antidepressant therapy, and many experience long term persistent and disabling symptoms.

Antidepressant maintenance have concluded that maintenance treatment reduced the risk of relapse by 52% compared to placebo.

Guidelines recommend continuing antidepressants for four to six months after remission to prevent relapse.

Continuing antidepressant medications after recovery can reduce the chance of relapse by 70%, and the preventive effect probably lasts for at least the first 36 months of use.

In patients with repeated episodes of depression ongoing treatment in order to prevent more severe, long-term depression is required.

Antidepressant medication treatment is usually continued for 16 to 20 weeks after remission, to minimize recurrence,

As much as one year of continuation of antidepressants therapy may be recommended.

People with chronic depression may need to take medication indefinitely.

Matching treatment to symptoms targets fysfunctional brain networks and then neurotransmitters.

Multimodality treatment is often required to be able to target multiple neurotransmitters.

The use of multimodal antidepressants may cause fewer were adverse effects than the use of multiple single modality antidepressants.

Patients who do not respond or achieve only partial response to antidepressant treatment after 4-8 weeks require a change in anti-depressant dose, switch to another agent, or treat with augmenting therapies.

Medications are not recommended in children with mild disease.

There is also insufficient evidence to determine effectiveness of treatment in those with depression complicated by dementia.

Patients with MDD who do not respond to antidepressants are classified as having treatment resistant depressive disorder and require augmentation strategies.

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