Studies have shown a wide variability in the effectiveness of switching antidepressants, with anywhere from 25-70% of patients responding to a different antidepressant. There is support for the effectiveness of switching patients to a different SSRI; 50% of patients that were nonresponsive after taking one SSRI were responsive after taking a second type. Switching patients to a different class of antidepressants may also be effective. Patients who are nonresponsive after taking an SSRI may respond to bupropion or a MAOI.

Medications that have been shown to be effective in cases of treatment-resistant depression include lithium, triiodothyronine, benzodiazepines, atypical antipsychotics, and stimulants. Adding lithium may be effective for patients taking some types of antidepressants, I it does not appear to be effective in patients taking SSRI’s. Triiodothyroxine (T3) is a type of thyroid hormone and has been associated with improvement in mood and depression symptoms. Benzodiazepines may improve treatment-resistant depression by decreasing the adverse side effects caused by some antidepressants and therefore increasing patient compliance. Since the entry of olanzapine into psychopharmacology, many psychiatrists have been adding low dose olanzapine to antidepressants and other atypical antipsychotics such as aripiprazole and quetiapine.

Particularly, the combination of olanzapine and fluoxetine seems to be effective.

These have shown promise in treating refractory depression but come with serious side effects. Stimulants such as amphetamines and methylphenidate have also been tested with positive results but have a high potential for abuse. However, stimulants have been shown to be effective for the unyielding depressed combined lacking addictive personality traits or heart problems.

Ketamine has been tested as a rapid-acting antidepressant for treatment-resistant depression in bipolar disorder, and major depressive disorder.

There is some evidence that omega-3 fatty acids fish oil supplements containing high levels of eicosapentaenoic acid (EPA) to docosahexaenoic acid (DHA) are effective in the treatment of, but not the prevention of major depression. However, a Cochrane review determined there was insufficient high quality evidence to suggest Omega-3 fatty acids were effective in depression. There is limited evidence that vitamin D supplementation is of value in alleviating the symptoms of depression in individuals who are vitamin D deficient. There is some preliminary evidence that COX-2 inhibitors have a beneficial effect on major depression. Lithium appears effective at lowering the risk of suicide in those with bipolar disorder and unipolar depression to nearly the same levels as the general population. There is a narrow range of effective and safe dosages of lithium thus close monitoring may be needed. Low-dose thyroid hormone may be added to existing antidepressants to treat persistent depression symptoms in people who have tried multiple courses of medication. Limited evidence suggests stimulants such as amphetamine and modafinil may be effective in the short term, or as add on therapy.

Electroconvulsive therapy (ECT) is a standard psychiatric treatment in which seizures are electrically induced in patients to provide relief from psychiatric illnesses. ECT is used with informed consent as a last line of intervention for major depressive disorder.

A round of ECT is effective for about 50% of people with treatment-resistant major depressive disorder, whether it is unipolar or bipolar. Follow-up treatment is still poorly studied, but about half of people who respond relapse within twelve months.

Aside from effects in the brain, the general physical risks of ECT are similar to those of brief general anesthesia. Immediately following treatment, 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.

A usual course of ECT involves multiple administrations, typically given two or three times per week until the patient is no longer suffering symptoms. ECT is administered under anesthetic with a muscle relaxant. Electroconvulsive therapy can differ in its application in three ways: electrode placement, frequency of treatments, and the electrical waveform of the stimulus. These three forms of application have significant differences in both adverse side effects and symptom remission. After treatment, drug therapy is usually continued, and some patients receive maintenance ECT.

ECT appears to work in the short term via an anticonvulsant effect mostly in the frontal lobes, and longer term via neurotrophic effects primarily in the medial temporal lobe.

The first line of pharmacotherapy is usually SSRIs due to their more tolerable nature and reduced side effects compared to the irreversible monoamine oxidase inhibitors or tricyclic antidepressants. Studies have found that the mean response to antidepressant medications for people with dysthymia is 55%, compared with a 31% response rate to a placebo. The most commonly prescribed antidepressants/SSRIs for dysthymia are escitalopram, citalopram, sertraline, fluoxetine, paroxetine, and fluvoxamine. It often takes an average of 6–8 weeks before the patient begins to feel these medications' therapeutic effects. Additionally, STAR*D, a multi-clinic governmental study, found that people with overall depression will generally need to try different brands of medication before finding one that works specifically for them. Research shows that 1 in 4 of those who switch medications get better results regardless of whether the second medication is an SSRI or some other type of antidepressant.

In a meta-analytic study from 2005, it was found that SSRIs and TCAs are equally effective in treating dysthymia. They also found that MAOIs have a slight advantage over the use of other medication in treating this disorder. However, the author of this study cautions that MAOIs should not necessarily be the first line of defense in the treatment of dysthymia, as they are often less tolerable than their counterparts, such as SSRIs.

Tentative evidence supports the use of amisulpride to treat dysthymia but with increased side effects.

Pharmacotherapy for acute episodes of depression usually is effective and free of complications. Underuse or misuse of antidepressants and prescribing inadequate dosages are the most common mistakes physicians make when treating elderly patients for depression. Only 10 to 40 percent of depressed elderly patients are given medication. Antidepressants, in general, may also work by playing a neuroprotective role in how they relieve anxiety and depression. It's thought that antidepressants may increase the effects of brain receptors that help nerve cells keep sensitivity to glutamate which is an organic compound of a nonessential amino acid. This increased support of nerve cells lowers glutamate sensitivity, providing protection against the glutamate overwhelming and exciting key brain areas related to depression. Antidepressant medications are often the first treatment choice for adults with moderate or severe depression, sometimes along with psychotherapy. Although antidepressants may not cure depression, they can lead to remission, which is the disappearance or nearly complete reduction of depression symptoms.

A combination of antidepressant medication and psychotherapy has consistently been shown to be the most effective line of treatment for people diagnosed with dysthymia. Working with a psychotherapist to address the causes and effects of the disorder, in addition to taking antidepressants to help eliminate the symptoms, can be extremely beneficial. This combination is often the preferred method of treatment for those who have dysthymia. Looking at various studies involving treatment for dysthymia, 75% of people responded positively to a combination of cognitive behavioral therapy (CBT) and pharmacotherapy, whereas only 48% of people responded positively to just CBT or medication alone.

In a meta-analytic study from 2008, researchers found an effect size of -0.07 (Cohen's d) between pharmacologic treatments and psychological treatments for depressive disorders, suggesting pharmacologic treatments to be slightly more effective, though the results were not found to be statistically significant. This small effect is true only for SSRIs, with TCAs and other pharmacologic treatments showing no differences from psychological treatments. Additionally, there have been several studies yielding results that indicate that severe depression responds more favorably to psychotherapy than pharmacotherapy.

Treatment is effective in about 80% of identified cases, when treatment is provided. Effective management requires a biopsychosocial approach, combining pharmacotherapy and psychotherapy. Therapy generally results in improved quality of life, enhanced functional capacity, possible improvement in medical health status, increased longevity, and lower health care costs. Improvement should be evident as early as two weeks after the start of therapy, but full therapeutic effects may require several months of treatment. Psychotherapy and medication are the two primary treatment approaches.Therapy for older patients should be continued for longer periods than are typically used in younger patients.

There are multiple treatments that can be effective in treating children diagnosed with depression. Psychotherapy and medications are commonly used treatment options. In some research, adolescents showed a preference for psychotherapy rather than antidepressant medication for treatment. For adolescents, cognitive behavioral therapy and interpersonal therapy have been empirically supported as effective treatment options. The use of antidepressant medication in children is often seen as a last resort; however, studies have shown that a combination of psychotherapy and medication is the most effective treatment. Pediatric massage therapy may have an immediate effect on a child's emotional state at the time of the massage, but sustained effects on depression have not been identified.

Treatment programs have been developed that help reduce the symptoms of depression. These treatments focus on immediate symptom reduction by concentrating on teaching children skills pertaining to primary and secondary control. While much research is still needed to confirm this treatment program’s efficacy, one study showed it to be effective in children with mild or moderate depressive symptoms.

There have been a few studies of medications for treating PPD, however, the sample sizes were small, thus evidence is generally weak. Some evidence suggests that mothers with PPD will respond similarly to people with major depressive disorder. There is evidence which suggests that selective serotonin reuptake inhibitors (SSRIs) are effective treatment for PPD. However, a recent study has found that adding sertraline, an SSRI, to psychotherapy does not appear to confer any additional benefit. Therefore, it is not completely clear which antidepressants, if any, are most effective for treatment of PPD, and for whom antidepressants would be a better option than non-pharmacotherapy.

Some studies show that hormone therapy may be effective in women with PPD, supported by the idea that the drop in estrogen and progesterone levels post-delivery contribute to depressive symptoms. However, there is some controversy with this form of treatment because estrogen should not be given to people who are at higher risk of blood clots, which include women up to 12 weeks after delivery. Additionally, none of the existing studies included women who were breastfeeding.

There are currently no antidepressants that are FDA approved for use during lactation. Most antidepressants are excreted in breast milk. However, there are limited studies showing the effects and safety of these antidepressants on breastfed babies.

The most common treatment for reducing bipolar II disorder symptoms is medication, usually in the form of mood stabilizers. However, treatment with mood stabilizers may produce a flat affect in the patient, which is dose-dependent. Concurrent use of SSRI antidepressants may help some with bipolar II disorder, though these medications should be used with caution because it is believed that they may cause a hypomanic switch.

The pharmaceutical management of bipolar II disorder is not generally supported by strong evidence, with limited randomised controlled trials (RCTs) published in the literature. Some medications used are:

- Lithium - There is strong evidence that lithium is effective in treating both the depressive and hypomanic symptoms in bipolar II. In addition, its action as a mood stabilizer can be used to decrease the risk of hypomanic switch in patients treated with antidepressants.

- Anticonvulsants - there is evidence that lamotrigine decreases the risk of relapse in rapid cycling bipolar II. It appears to be more effective in bipolar II than bipolar I, suggesting that lamotrigine is more effective for the treatment of depressive rather than manic episodes. Doses ranging from 100–200 mg have been reported to have the most efficacy, while experimental doses of 400 mg have rendered little response. A large, multicentre trial comparing carbamazepine and lithium over two and a half years found that carbamazepine was superior in terms of preventing future episodes of bipolar II, although lithium was superior in individuals with bipolar I. There is also some evidence for the use of valproate and topiramate, although the results for the use of gabapentin have been disappointing.

- Antidepressants - there is evidence to support the use of SSRI and SNRI antidepressants in bipolar II. Indeed, some sources consider them to be one of the first line treatments. However, antidepressants also pose significant risks, including a switch to mania, rapid cycling, and dysphoria and so many psychiatrists advise against their use for bipolar. When used, antidepressants are typically combined with a mood stabilizer.

- Antipsychotics - there is good evidence for the use of quetiapine, and it has been approved by the FDA for this indication. There is also some evidence for the use of risperidone, although the relevant trial was not placebo controlled and was complicated by the use of other medications in some of the patients.

- Dopamine agonists - there is evidence for the efficacy of pramipexole from one RCT.

Antipsychotic medications are effective for short-term treatment of bipolar manic episodes and appear to be superior to lithium and anticonvulsants for this purpose. Atypical antipsychotics are also indicated for bipolar depression refractory to treatment with mood stabilizers. Olanzapine is effective in preventing relapses, although the supporting evidence is weaker than the evidence for lithium.

Antidepressants are not recommended for use alone in the treatment of bipolar disorder and have not been found to be of any benefit over that found with mood stabilizers. Atypical antipsychotic medications (e.g., aripiprazole) are preferred over antidepressants to augment the effects of mood stabilizers due to the lack of efficacy of antidepressants in bipolar disorder.

Treatment typically includes three things: the treatment of acute hypomania, the treatment of acute depression, and the prevention of the relapse of either hypomania or depression. The main goal is to make sure that patients do not harm themselves.

There are different types of treatments available for mood disorders, such as therapy and medications. Behaviour therapy, cognitive behaviour therapy and interpersonal therapy have all shown to be potentially beneficial in depression. Major depressive disorder medications usually include antidepressants, while bipolar disorder medications can consist of antipsychotics, mood stabilizers, anticonvulsants and/or lithium. Lithium specifically has been proven to reduce suicide and all causes of mortality in people with mood disorders. If mitochondrial dysfunction or mitochondrial diseases are the cause of mood disorders like bipolar disorder, then it has been hypothesized that N-acetyl-cysteine (NAC), acetyl-L-carnitine (ALCAR), S-adenosylmethionine (SAMe), coenzyme Q10 (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), and melatonin could be potential treatment options.

Treatment of minor depressive disorder has not been studied as extensively as major depressive disorder. Although there are often similarities in the treatments used, there are also differences in what may work better for the treatment of minor depressive disorder. Some third-party payers do not pay to cover treatment for minor depressive disorder.

The leading treatment techniques for minor depressive disorder are the use of antidepressants and therapy. Typically, patients with minor depression were treated by watchful waiting, prescribed antidepressants, and given brief supportive counseling, but Problem-Solving Treatment for Primary Care (PST-PC) is a Cognitive-Behavioral Therapy that has gained popularity. In one study, Problem-Solving Treatment for Primary Care (PST-PC) and Paroxetine, an antidepressant, were shown to be equally effective in significantly reducing symptoms. In another study, PST-PC was compared with the more typical care of the time and shown to reduce symptoms more quickly. Although the use of antidepressants has been widely used, not all agree that it is an appropriate treatment for some minor depression disorder settings.

Another alternative that has been researched is the use of St. John's wort ("Hypericum perforatum"). This herbal treatment has been studied by various groups with various results. Some studies show evidence of the treatment being helpful to treat minor depression, but others show that it does no better than the placebo.

Individuals suffering from endogenous depression require treatment plans that focus on the internal, cognitive thought processes since internal stressors are the root of somatic symptoms. Individual cognitive therapy (ICT) is therefore a common treatment used to gain insight to the individual's internal conflicts or thoughts that are motivating their distressing symptoms. Once the cause of the symptoms are identified, sessions are used to develop new coping skills, behavior modification, and changes in beliefs.

As preventative measures, pharmaceuticals such as SSRI's and antidepressants may also be utilized to avoid further development or progression to Major Depressive Disorder. There have been few treatments targeted specifically toward Endogenous Depression; therefore, symptoms are often managed similarly to Major Depressive Disorder. One such treatment is electroconvulsive therapy (ECT). ECT is used as a treatment option for endogenous depression in adults, however, practitioners avoid the use of ECT in young adolescents due to rates of injury.

There are three common types of talk therapy. These can assist people to live more fully and have a better life. Men are encouraged to open up more emotionally and communicate their personal distress, while women are encouraged to be assertive of their own strengths

Depressed mood may not require professional treatment, and may be a normal temporary reaction to life events, a symptom of some medical condition, or a side effect of some drugs or medical treatments. A prolonged depressed mood, especially in combination with other symptoms, may lead to a diagnosis of a psychiatric or medical condition which may benefit from treatment. Different sub-divisions of depression have different treatment approaches.

In the United States, it has been estimated that two thirds of people with depression do not actively seek treatment. The World Health Organisation (WHO) has predicted that by 2030, depression will account for the highest level of disability accorded any physical or mental disorder in the world (WHO, 2008).

The UK National Institute for Health and Care Excellence (NICE) 2009 guidelines indicate that antidepressants should not be routinely used for the initial treatment of mild depression, because the risk-benefit ratio is poor. A recent meta-analysis also indicated that most antidepressants, besides fluoxetine, do not seem to offer a clear advantage for children and adolescents in the acute treatment of major depressive disorder.

Pharmaceutical treatments for GAD include selective serotonin reuptake inhibitors (SSRIs). These are the preferred first line of treatment. SSRIs used for this purpose include escitalopram and paroxetine.

Common side effects include nausea, sexual dysfunction, headache, diarrhea, constipation, restlessness, increased risk of suicide in young adults and adolescents, among others. Overdose of an SSRI can result in serotonin syndrome.

For a number of years, scholars debated amongst themselves whether or not antipsychotic drugs had a tendency to increase depression or simply help the patient manage their mental illness. However, conclusive evidence points to antipsychotic drugs actually helping patients with their depression while simultaneously assisting in the suppression of schizophrenic episodes. Specifically risperidone, olanzapine, quetiapine, fluphenazine, haloperidol, and L-sulpiride have done the best in drug trials pertaining to people with schizophrenia. Along with antipsychotic drugs, post-schizophrenic patients may receive antidepressants to actively treat the depression. Drugs are certainly not the only answer, though. At the base of both depression and schizophrenia, social withdrawal is a shared symptom between the two. People suffering from schizophrenia require a strong support system to be healthy, just as is the case with the rest the human population. The opportunity to become a working citizen is another way to ward off depression in patients with schizophrenia, helping them create social ties and a feeling of accomplishment.

Benzodiazepines are most often prescribed to people with generalized anxiety disorder. Research suggests that these medications give some relief, at least in the short term. However, they carry some risks, mainly impairment of both cognitive and motor functioning, and psychological and physical dependence that makes it difficult for patients to stop taking them. It has been noted that people taking benzodiazepines are not as alert on their job or at school. Additionally, these medications may impair driving and they are often associated with falls in the elderly, resulting in hip fractures. These shortcomings make the use of benzodiazepines optimal only for short-term relief of anxiety. CBT and medication are of comparable efficacy in the short-term but CBT has advantages over medication in the longer term.

Benzodiazepines (or "benzos") are fast-acting hypnotic sedatives that are also used to treat GAD and other anxiety disorders. Benzodiazepines are prescribed for generalized anxiety disorder and show beneficial effects in the short term. Popular Benzodiazepines for GAD include alprazolam, lorazepam and clonazepam. The World Council of Anxiety does not recommend the long-term use of benzodiazepines because they are associated with the development of tolerance, psychomotor impairment, cognitive and memory impairments, physical dependence and a withdrawal syndrome. Side effects include drowsiness, reduced motor coordination and problems with equilibrioception.

In general, atypical depression tends to cause greater functional impairment than other forms of depression. Atypical depression is a chronic syndrome that tends to begin earlier in life than other forms of depression—usually beginning in the teenage years. Similarly, patients with atypical depression are more likely to suffer from personality disorders and anxiety disorders such as borderline personality disorder, avoidant personality disorder, generalized anxiety disorder, obsessive-compulsive disorder, and bipolar disorder.

Recent research suggests that young people are more likely to suffer from hypersomnia while older people are more likely to suffer from polyphagia.

Medication response differs between chronic atypical depression and acute melancholic depression. Some studies suggest that the older class of antidepressants, monoamine oxidase inhibitors (MAOIs), may be more effective at treating atypical depression. While the more modern SSRIs and SNRIs are usually quite effective in this illness, the tricyclic antidepressants typically are not. The wakefulness-promoting agent modafinil has shown considerable effect in combating atypical depression, maintaining this effect even after discontinuation of treatment. Antidepressant response can often be enhanced with supplemental medications, such as buspirone, bupropion, or aripiprazole. Psychotherapy, whether alone or in combination with medication, is also an effective treatment.

Involutional melancholia is classically treated with antidepressants and mood elevators.

Electroconvulsive therapy may also be used. Mid-century, there was a consensus that the technique indeed 'yields the best results in the long-lasting depressions of the change of life, the so-called "involutional melancholias", which before this form of treatment was introduced often required years of hospitalization'. The 21st century also records 'an excellent and rapid clinical response found in melancholia of recent onset...in older rather than younger patients' with ECT