Management of depression
This article addresses the management of the psychiatric syndrome known as major depressive disorder or often called simply "depression". This syndrome is being diagnosed more frequently in developed countries, where up to 20% of the population is affected at some stage of their lives. Over-diagnosis of depression may be common, because while the prevalence of major depressive disorder has remained unchanged, its diagnosis has doubled in 20 years. Depression is more likely over-diagnosed than under-diagnosed in primary care, resulting in patients without evidence of major depressive disorder being prescribed medications. The elderly may be at more risk of over-diagnosis. Patients are usually assessed and managed as outpatients, and only admitted to an inpatient mental health unit if they are considered a risk to themselves or others.
Though psychiatric medication is the most frequently prescribed therapy for major depression, psychotherapy may be effective, either alone or in combination with medication. Antidepressant medications fail to consistently demonstrate superiority over placebo pills, or their benefit is small. Likewise, psychotherapy has been unable to demonstrate substantial superiority over no-treatment. Combining psychotherapy and antidepressants may provide a "slight advantage", but antidepressants alone or psychotherapy alone are not significantly different from other treatments, or "active intervention controls". Given an accurate diagnosis of major depressive disorder, in general the type of treatment (psychotherapy and/or antidepressants, alternate or other treatments, or active intervention) is "less important than getting depressed patients involved in an active therapeutic program."
Psychotherapy is the treatment of choice in those under the age of 18, with medication offered only in conjunction with the former and generally not as a first line agent. The possibility of depression, substance misuse or other mental health problems in the parents should be considered and, if present and if it may help the child, the parent should be treated in parallel with the child.
- 1 Psychotherapy
- 2 Pharmaceutical drug treatment
- 3 Medical devices
- 4 Other treatments
- 5 References
There are a number of different psychotherapies for depression which are provided to individuals or groups by psychotherapists, psychiatrists, psychologists, clinical social workers, counselors or psychiatric nurses. With more chronic forms of depression, the most effective treatment is often considered to be a combination of medication and psychotherapy. Psychotherapy is the treatment of choice in people under 18.
The most studied form of psychotherapy for depression is cognitive behavioral therapy (CBT), thought to work by teaching clients to learn a set of cognitive and behavioral skills, which they can employ on their own. Earlier research suggested that cognitive behavioral therapy was not as effective as antidepressant medication in the treatment of depression; however, more recent research suggests that it can perform as well as antidepressants in treating patients with moderate to severe depression.
A systematic review of data comparing low-intensity CBT (such as guided self-help by means of written materials and limited professional support, and website-based interventions) with usual care found that patients who initially had more severe depression benefited from low-intensity interventions at least as much as less-depressed patients. One of the websites included in the study is MoodGym.
For the treatment of adolescent depression, one published study found that CBT without medication performed no better than a placebo, and significantly worse than the antidepressant fluoxetine. However, the same article reported that CBT and fluoxetine outperformed treatment with only fluoxetine. Combining fluoxetine with CBT appeared to bring no additional benefit in two different studies or, at the most, only marginal benefit, in a fourth study.
Behavior therapy for depression is sometimes referred to as behavioral activation. Studies exist showing behavioral activation to be superior to CBT. In addition, behavioral activation appears to take less time and lead to longer lasting change.
Acceptance and commitment therapy (ACT), a mindfulness form of CBT, which has its roots in behavior analysis, also demonstrates that it is effective in treating depression, and can be more helpful than traditional CBT, especially where depression is accompanied by anxiety and where it is resistant to traditional CBT.
A review of four studies on the effectiveness of mindfulness-based cognitive therapy (MBCT), a recently developed class-based program designed to prevent relapse, suggests that MBCT may have an additive effect when provided with the usual care in patients who have had three or more depressive episodes, although the usual care did not include antidepressant treatment or any psychotherapy, and the improvement observed may have reflected non-specific or placebo effects.
Interpersonal psychotherapy focuses on the social and interpersonal triggers that may cause depression. There is evidence that it is an effective treatment for depression. Here, the therapy takes a structured course with a set number of weekly sessions (often 12) as in the case of CBT; however, the focus is on relationships with others. Therapy can be used to help a person develop or improve interpersonal skills in order to allow him or her to communicate more effectively and reduce stress.
Psychoanalysis, a school of thought founded by Sigmund Freud that emphasizes the resolution of unconscious mental conflicts, is used by its practitioners to treat clients presenting with major depression. A more widely practiced technique, called psychodynamic psychotherapy, is loosely based on psychoanalysis and has an additional social and interpersonal focus. In a meta-analysis of three controlled trials, psychodynamic psychotherapy was found to be as effective as medication for mild to moderate depression.
Pharmaceutical drug treatment
To find the most effective pharmaceutical drug treatment, the dosages of medications must often be adjusted, different combinations of antidepressants tried, or antidepressants changed. Response rates to the first agent administered may be as low as 50%. It may take anywhere from three to eight weeks after the start of medication before its therapeutic effects can be fully discovered. Patients are generally advised not to stop taking an antidepressant suddenly and to continue its use for at least four months to prevent the chance of recurrence.
Selective serotonin reuptake inhibitors (SSRIs), such as sertraline (Zoloft, Lustral), escitalopram (Lexapro, Cipralex), fluoxetine (Prozac), paroxetine (Seroxat), and citalopram, are the primary medications considered, due to their relatively mild side effects and broad effect on the symptoms of depression and anxiety, as well as reduced risk in overdose, compared to their older tricyclic alternatives. Those who do not respond to the first SSRI tried can be switched to another. If sexual dysfunction is present prior to the onset of depression, SSRIs should be avoided. Another popular option is to switch to the atypical antidepressant bupropion (Wellbutrin) or to add bupropion to the existing therapy; this strategy is possibly more effective. It is not uncommon for SSRIs to cause or worsen insomnia; the sedating noradrenergic and specific serotonergic antidepressant (NaSSA) antidepressant mirtazapine (Zispin, Remeron) can be used in such cases. Cognitive Behavioral Therapy for Insomnia can also help to alleviate the insomnia without additional medication. Venlafaxine (Effexor) may be moderately more effective than SSRIs; however, it is not recommended as a first-line treatment because of the higher rate of side effects, and its use is specifically discouraged in children and adolescents. Fluoxetine is the only antidepressant recommended for people under the age of 18, though, if a child or adolescent patient is intolerant to fluoxetine, another SSRI may be considered. Evidence of effectiveness of SSRIs in those with depression complicated by dementia is lacking.
Tricyclic antidepressants have more side effects than SSRIs (but less sexual dysfunctions) and are usually reserved for the treatment of inpatients, for whom the tricyclic antidepressant amitriptyline, in particular, appears to be more effective. A different class of antidepressants, the monoamine oxidase inhibitors, have historically been plagued by questionable efficacy and life-threatening adverse effects. They are still used only rarely, although newer agents of this class (RIMA), with a better side effect profile, have been developed.
Stephen M. Stahl, renowned academician in psychopharmacology, has stated resorting to a dynamic psychostimulant, in particular, d-amphetamine is the "classical augmentation strategy for treatment-refractory depression" 
Physicians often add a medication with a different mode of action to bolster the effect of an antidepressant in cases of treatment resistance; a 2002 large community study of 244,859 depressed Veterans Administration patients found that 22% had received a second agent, most commonly a second antidepressant. Lithium has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone. Furthermore, lithium dramatically decreases the suicide risk in recurrent depression. Addition of atypical antipsychotics when the patient has not responded to an antidepressant is also known to increase the effectiveness of antidepressant drugs, albeit at the cost of more frequent and potentially serious side effects. There is some evidence for the addition of a thyroid hormone, triiodothyronine, in patients with normal thyroid function.
Table 1: Regulatory Status of, Efficacy and Tolerability of Adjunctive treatments in Major Depressive Disorder
|Drug||MHRA approved as an adjunct?||FDA approved as an adjunct?||TGA approved as an adjunct?||† for non-response over antidepressant monotherapy||‡ for MADRS||‡ for HAM-D||† for leaving the study early due to any reason||† for leaving the study early due to adverse effects||† for significant weight gain||‡ for weight gain (kg)||† for sedation|
|Aripiprazole||No||Yes||No||0.48 (0.37-0.63)||-3.04 (-4.09,0.00)||ND||1.21 (0.86, 1.71)||2.59 (1.18, 5.71)||5.93 (2.15, 16.36)||1.07 (0.30, 1.84)||3.42 (0.66, 17.81)|
|Lithium||No||No||No. But listed in the Australian Medicines Handbook as an accepted use of lithium treatment.||0.47 (0.27-0.81)||ND||ND||ND||ND||ND||ND||ND|
|Olanzapine||No||Yes (in combination with fluoxetine)||No||0.70 (0.48, 1.02)||-2.84 (-5.84,-0.20)||-7.90 (-16.63, 0.83)||1.22 (0.82, 1.83)||3.51 (1.58, 7.80)||12.14 (0.70, 208.95)||4.58 (4.06, 5.09)||3.53 (1.64, 7.60)|
|Quetiapine||Yes||Yes||Yes||0.66 (0.51, 0.87)||-2.67 (-4.00, -1.34)||-2.67 (-3.79, -1.55)||0.75 (0.26, 2.14)||5.59 (1.47, 21.26)||3.06 (1.22, 7.68)||1.11 (0.56, 1.66)||8.79 (4.90, 15.77)|
|Risperidone||No||No||No||0.57 (0.36, 0.89)||-1.85 (-9.17, 5.47)||-1.69 (-4.13, 0.74)||1.04 (0.59, 1.83)||2.11 (0.79, 5.68)||3.32 (0.99, 11.12)||1.80 (0.95, 2.65)||1.10 (0.31, 3.99)|
ND - No data available
An important note with the data in the above table is that most of the data for lithium is for when it is combined with tricyclic antidepressants.
† (Odds Ratio) and 95% CI (bracketed)
‡ (Mean difference) and 95% CI (bracketed)
Efficacy of medication and psychotherapy
Antidepressants are statistically superior to placebo but their overall effect is low-to-moderate. In that respect they often did not exceed the National Institute for Health and Clinical Excellence criteria for a "clinically significant" effect. In particular, the effect size was very small for moderate depression but increased with severity, reaching "clinical significance" for very severe depression. These results were consistent with the earlier clinical studies in which only patients with severe depression benefited from either psychotherapy or treatment with an antidepressant, imipramine, more than from the placebo treatment. Despite obtaining similar results, the authors argued about their interpretation. One author concluded that there "seems little evidence to support the prescription of antidepressant medication to any but the most severely depressed patients, unless alternative treatments have failed to provide benefit." The other author agreed that "antidepressant 'glass' is far from full" but disagreed "that it is completely empty". He pointed out that the first-line alternative to medication is psychotherapy, which does not have superior efficacy.
Antidepressants in general are as effective as psychotherapy for major depression, and this conclusion holds true for both severe and mild forms of MDD. In contrast, medication gives better results for dysthymia. The subgroup of SSRIs may be slightly more efficacious than psychotherapy. On the other hand, significantly more patients drop off from the antidepressant treatment than from psychotherapy, likely because of the side effects of antidepressants. Successful psychotherapy appears to prevent the recurrence of depression even after it has been terminated or replaced by occasional "booster" sessions. The same degree of prevention can be achieved by continuing antidepressant treatment.
Two studies suggest that the combination of psychotherapy and medication is the most effective way to treat depression in adolescents. Both TADS (Treatment of Adolescents with Depression Study) and TORDIA (Treatment of Resistant Depression in Adolescents) showed very similar results. TADS resulted in 71% of their teen subjects having "much" or "very much" improvement in mood over the 60.6% with medication alone and the 43.2% with CBT alone. Similarly, TORDIA showed a 54.8% improvement with CBT and drugs verses a 40.5% with drug therapy alone.
S-Adenosyl methionine (SAMe) is available as a prescription antidepressant in Europe and an over-the-counter dietary supplement in the US. Evidence from 16 clinical trials with a small number of subjects, reviewed in 1994 and 1996 suggested it to be more effective than placebo and as effective as standard antidepressant medication for the treatment of major depression.
Research on the antidepressant effects of ketamine infusions at subanaesthetic doses has consistently shown rapid (4 to 72 hours) responses from single doses, with substantial improvement in mood in the majority of patients and remission in some. However, these effects are often short-lived, and attempts to prolong the antidepressant effect with repeated doses and extended ("maintenance") treatment have resulted in only modest success.
The amino acid creatine, commonly used as a supplement to improve the performance of bodybuilders, has been studied for its potential antidepressant properties. In an open study of 8 volunteers taking several grams of creatine a day, six improved, and two bipolar patients developed hypomania or mania. More recently, a double-blinded, placebo-controlled trial focusing on women found that creatine, when used along with an antidepressant, exerted a powerful and rapid antidepressant effect. Studies on mice have found that the antidepressant effects of creatine can be blocked by drugs that act against dopamine receptors, suggesting that the drug acts on dopamine pathways.
The dietary supplement L-Acetylcarnitine has been shown to exert an antidepressant effect. The effect was very rapid- occurring within a few days- and persisted several weeks after the drug was withdrawn.
A variety of medical devices are in use or under consideration for treatment of depression including devices which offer electroconvulsive therapy, vagus nerve stimulation, repetitive transcranial magnetic stimulation, and cranial electrotherapy stimulation. Use of such devices in the United States requires approval by the U.S. Food and Drug Administration (FDA) after field trials. In 2010 a FDA advisory panel considered the question of how such field trials should be managed. Factors considered were whether drugs had been effective, how many different drugs had been tried, and what tolerance for suicides should be in field trials.
Electroconvulsive therapy (ECT), formerly known as electroshock, is a standard psychiatric treatment in which seizures are electrically induced in patients to provide relief from psychiatric illnesses. ECT is usually used as a last line of intervention for major depressive disorder, schizophrenia, mania and catatonia. A usual course of ECT involves multiple administrations across weeks, months and years. It was first introduced in 1938 by Italian neuropsychiatrists Ugo Cerletti and Lucio Bini, and gained widespread popularity among psychiatrists as a form of treatment in the 1940s and 1950s.
In western fiction, it is usually depicted as a painful procedure, but in western countries ECT is usually administered under anesthetic with a muscle relaxant.
About 70 percent of ECT patients are women, since they are at twice the risk of depression as men. Although a large amount of research has been carried out, the exact mechanism of action of ECT remains elusive, and ECT on its own does not usually have a sustained benefit. Administration is most commonly bilateral, in which the electrical current is passed across the whole brain, and which seems to have greater efficacy but greater risk of memory loss, or less commonly, unilateral, which has less efficacy but also reduced risk of memory loss. The World Health Organization (2005) advises that it should only be used with the informed consent of the patient or their proxy, only with adequate analgesia and muscle relaxants, and never on children. Psychiatrists and other mental health professionals differ on when and if ECT should be used as a first-line treatment or if it should be reserved for patients who have not responded to other interventions such as medication and psychotherapy. ECT is considered one of the least harmful treatment options available for severely depressed pregnant women.
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. In the United Kingdom and Ireland, drug therapy usually is continued during ECT.
Deep brain stimulation
The support for the use of deep brain stimulation in treatment-resistant depression comes from a handful of case studies, and this treatment is still in a very early investigational stage. In this technique electrodes are implanted in a specific region of the brain, which is then continuously stimulated. A March 2010 systematic review found that "about half the patients did show dramatic improvement" and that adverse events were "generally trivial" given the younger psychiatric patient population than with movements disorders. Deep brain stimulation is available on an experimental basis only; no systems are approved by the FDA for this use.
Repetitive transcranial magnetic stimulation
Repetitive transcranial magnetic stimulation (rTMS) use in treatment-resistant depression is supported by multiple controlled studies, and it has been approved for this indication in Europe, Canada, Australia, and the US. A 2008 meta-analysis based on 32 trials found a robust effect of this method on depression, and it appeared similarly effective for both uncomplicated depression and depression that is resistant to medication. However, it was inferior to ECT in a side-by-side randomized trial.
Vagus nerve stimulation
Vagus nerve stimulation (VNS) uses an implanted electrode and generator to deliver electrical pulses to the vagus nerve, one of the primary nerves emanating from the brain. It is an approved therapy for treatment-resistant depression in the EU and US and is sometimes used as an adjunct to existing antidepressant treatment. The support for this method comes mainly from open-label trials, which indicate that several months may be required to see a benefit. The only large double-blind trial conducted lasted only 10 weeks and yielded inconclusive results; VNS failed to show superiority over a sham treatment on the primary efficacy outcome, but the results were more favorable for one of the secondary outcomes. The authors concluded "This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression."
Cranial electrotherapy stimulation
Cranial electrotherapy stimulation (CES, electrosleep) devices currently on the market have been granted marketing authorization by the US Food and Drug Administration (FDA) because a sufficiently similar device had been marketed before 1976, when new regulations requiring controlled testing were introduced. The FDA considers them to be class III devices—"devices for which insufficient information exists to ... provide reasonable assurance of safety and effectiveness" The effects of CES on depression were inconclusive or negative in multiple double-blind studies of psychiatric patients. In one of them, four out of six clinically depressed patients dropped out of the study because of the massive worsening of depressive symptoms, with two of them becoming actively suicidal. One of the authors of the latter study cautioned that CES "should not be used as a treatment of choice" for patients with a primary diagnosis of depression, "and should be used with caution if this diagnosis is suspected."
Bright light therapy
A meta-analysis of bright light therapy commissioned by the American Psychiatric Association found a significant reduction in depression symptom severity associated with bright light treatment. Benefit was found for both seasonal affective disorder and for nonseasonal depression, with effect sizes similar to those for conventional antidepressants. For non-seasonal depression, adding light therapy to the standard antidepressant treatment was not effective. A meta-analysis of light therapy for non-seasonal depression conducted by Cochrane Collaboration, studied a different set of trials, where light was used mostly in combination with antidepressants or wake therapy. A moderate statistically significant effect of light therapy was found, with response significantly better than control treatment in high-quality studies, in studies that applied morning light treatment, and with patients who respond to total or partial sleep deprivation. Both analyses noted poor quality of most studies and their small size, and urged caution in the interpretation of their results. The short 1–2 weeks duration of most trials makes it unclear whether the effect of light therapy could be sustained in the longer term.
Clinical trials involving subjects with major depressive disorder suggest a modest short-term improvement in mood from exercise. Several studies have shown that exercise is equally effective as medication and more effective than a placebo, though medication provides more immediate relief from severe depression. The evidence for any long-term improvement in major depression is poor.
Mindfulness meditation programs may improve symptoms of depression.
A 2009 review by Gold and colleagues found a significant dose effect of music therapy on depressive symptoms, with small improvement after 3 to 10 sessions and greater improvement after 16 to 51 sessions.
St John's wort
A 2008 Cochrane Collaboration meta-analysis concluded that "The available evidence suggests that the hypericum extracts tested in the included trials a) are superior to placebo in patients with major depression; b) are similarly effective as standard antidepressants; c) and have fewer side effects than standard antidepressants. The association of country of origin and precision with effects sizes complicates the interpretation." The United States National Center for Complementary and Alternative Medicine advice is that "St. John’s wort may help some types of depression, similar to treatment with standard prescription antidepressants, but the evidence is not definitive." and warns that "Combining St. John’s wort with certain antidepressants can lead to a potentially life-threatening increase of serotonin, a brain chemical targeted by antidepressants. St. John’s wort can also limit the effectiveness of many prescription medicines."
Depression is sometimes associated with insomnia - (difficulty in falling asleep, early waking, and waking in the middle of the night). The combination of these two results, depression and insomnia will only worsen the situation. Hence, good sleep hygiene is important to help break this vicious circle. This would include measures such as regular sleep routines, avoidance of stimulants such as caffeine and management of sleeping disorders such as sleep apnea.
Stopping smoking cigarettes is associated with reduced depression and anxiety, with the effect "equal or larger than" those of antidepressant treatments.
Total/Partial Sleep Deprivation
Sleep deprivation (skipping a nights sleep) has been found to improve symptoms of depression in 40% - 60% of patients. Partial sleep deprivation in the second half of the night may be as effective as an all night sleep deprivation session. Improvement may last for weeks, though the majority (50-80%) relapse after recovery sleep. Shifting or reduction of sleep time, light therapy, antidepressant drugs, and lithium have been found to potentially stabilize sleep deprivation treatment effects.
Tryptophan and 5-HTP
The amino acid tryptophan is converted into 5-hydroxytryptophan (5-HTP) which is subsequently converted into the neurotransmitter serotonin. Since serotonin deficiency has been recognized as a possible cause of depression, it has been suggested that consumption of tryptophan or 5-HTP may therefore improve depression symptoms by increasing the level of serotonin in the brain. Both tryptophan and 5-HTP are sold over the counter in the United States, but requires prescription in Canada and Europe. Small studies have been performed using 5-HTP and tryptophan as adjunctive therapy in addition to standard treatment for depression. While some studies had positive results, they were criticized for having methodological flaws, and a more recent study did not find sustained benefit from their use. The safety of these medications has not been well studied. Due to the lack of high quality studies and preliminary nature of studies showing effectiveness and the lack of adequate study on their safety, the use of tryptophan and 5-HTP is not highly recommended or thought to be clinically useful.
- "Beyond Blue". Retrieved 2007-04-30.
- Dowrick, Christopher; Allen Frances (December 9, 2013). "Medicalising unhappiness: new classification of depression risks more patients being put on drug treatment from which they will not benefit". BMJ. doi:10.1136/bmj.f7140.
- Mojtabai, R (April 2013). "Clinician-Identified Depression in Community Settings: Concordance with Structured-Interview Diagnoses". Psychother Psychosom: 161–169. doi:10.1159/000345968.
- Carson VB (2000). Mental health nursing: the nurse-patient journey W.B. Saunders. ISBN 978-0-7216-8053-8. pp 423.
- The Merck Manual of Diagnosis and Therapy
- Khan, Arif; James Faucett; Pesach Lichtenberg; Irving Kirsch; Walter A. Brown (July 30, 2012). "A Systematic Review of Comparative Efficacy of Treatments and Controls for Depression". PLOS ONE 7 (7): e41778. doi:10.1371/journal.pone.0041778. PMC 3408478. PMID 22860015.
- NICE (2005). NICE Guidelines:depression in children and adolescents. London: NICE. p. 5. ISBN 1-84629-074-0. Retrieved 2008-08-16.
- Thase, ME (1999). "When are psychotherapy and pharmacotherapy combinations the treatment of choice for major depressive disorder?". Psychiatric Quarterly 70 (4): 333–46. doi:10.1023/A:1022042316895. PMID 10587988.
- Roth, Anthony; Fonagy, Peter (2006). "Cognitive-Behavioral Therapy Alone and in Combination with medication: University of Minnesota and University of Pennsylvania–Vanderbilt University Studies". What Works for Whom?: A Critical Review of Psychotherapy Research (2nd ed.). Guilford Press. pp. 76–8. ISBN 978-1-59385-272-6.
- Bower, Peter; Kontopantelis, Evangelos; Sutton, Alex; Kendrick, Tony; Richards, David A; Gilbody, Simon; Knowles, Sarah; Cuijpers, Pim; Andersson, Gerhard; Christensen, Helen; Meyer, Björn; Huibers, Marcus; Smit, Filip; van Straten, Annemieke; Warmerdam, Lisanne; Barkham, Michael; Bilich, Linda; Lovell, Karina; Liu, Emily Tung-Hsueh (2013). "Influence of initial severity of depression on effectiveness of low intensity interventions: Meta-analysis of individual patient data". BMJ 346: f540. doi:10.1136/bmj.f540. PMC 3582703. PMID 23444423.
- PubMed Health. "Featured review: Website for depression". NCBI. Retrieved 18 July 2013.
- March J, Silva S, Petrycki S, et al. (August 2004). "Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial". JAMA 292 (7): 807–20. doi:10.1001/jama.292.7.807. PMID 15315995.
- Goodyer I, Dubicka B, Wilkinson P, et al. (July 2007). "Selective serotonin reuptake inhibitors (SSRIs) and routine specialist care with and without cognitive behaviour therapy in adolescents with major depression: Randomised controlled trial". British Medical Journal 335 (7611): 142. doi:10.1136/bmj.39224.494340.55. PMC 1925185. PMID 17556431.
- Goodyer IM, Dubicka B, Wilkinson P, et al. (May 2008). "A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial". Health Technol Assess 12 (14): 1–80. PMID 18462573.
- Domino ME, Burns BJ, Silva SG, et al. (May 2008). "Cost-effectiveness of treatments for adolescent depression: results from TADS". American Journal of Psychiatry 165 (5): 588–96. doi:10.1176/appi.ajp.2008.07101610. PMID 18413703.
- Hopko, D. R., Lejuez, C. W., Lepage, J. P., Hopko, S. D., & McNeil, D. W. (2004). "A Brief Behavioral Activation Treatment for Depression". Behavior Modification 27 (4): 458–469. doi:10.1177/0145445503255489. PMID 12971122.
- Dimidjian, S., et al. (2006). "Randomized Trial of Behavioral Activation, Cognitive Therapy, and Antidepressant Medication in the Acute Treatment of Adults With Major Depression". Journal of Consulting and Clinical Psychology 74 (4): 658–670. doi:10.1037/0022-006X.74.4.658. PMID 16881773.
- Spates, C. R., Pagoto, S. and Kalata, A. (2006). A Qualitative And Quantitative Review of Behavioral Activation Treatment of Major Depressive Disorder. The Behavior Analyst Today, 7(4), 508-518 
- Ruiz, F. J. (2010). "A review of Acceptance and Commitment Therapy (ACT) empirical evidence: Correlational, experimental psychopathology, component and outcome studies". International Journal of Psychology and Psychological Therapy 10 (1): 125–62.
- "APA website on empirical treatments". Retrieved 2009-09-01.
- Hayes, Steven. "State of the ACT Evidence". ContextualPsychology.org.
- Coelho HF, Canter PH, Ernst E (December 2007). "Mindfulness-based cognitive therapy: Evaluating current evidence and informing future research". Journal of Consulting and Clinical Psychology 75 (6): 1000–05. doi:10.1037/0022-006X.75.6.1000. PMID 18085916.
- Weissman MM, Markowitz JC, Klerman GL (2000). Comprehensive Guide to Interpersonal Psychotherapy. New York: Basic Books. ISBN 0-465-09566-6.
- Dworetzky J (1997). Psychology. Pacific Grove, CA, USA: Brooks/Cole Pub. Co. p. 602. ISBN 0-314-20412-1.
- Doidge N, Simon B, Lancee WJ, et al. (2002). "Psychoanalytic patients in the US, Canada, and Australia: II. A DSM-III-R validation study". Journal of the American Psychoanalytic Association 50 (2): 615–27. doi:10.1177/00030651020500021101. PMID 12206545.
- Durand VM, Barlow D (1999). Abnormal psychology: An integrative approach. Pacific Grove, CA, USA: Brooks/Cole Pub. Co. ISBN 0-534-34742-8.
- de Maat S, Dekker J, Schoevers R, et al. (June 2007). "Short Psychodynamic Supportive Psychotherapy, antidepressants, and their combination in the treatment of major depression: A mega-analysis based on three Randomized Clinical Trials". Depression and Anxiety 25 (7): 565–74. doi:10.1002/da.20305. PMID 17557313.
- Depression Guideline Panel. Depression in primary care. Vol. 2. Treatment of major depression. Clinical practice guideline. No. 5. Rockville, MD: Agency for Health Care Policy and Research, 1999.
- Sutherland JE, Sutherland SJ, Hoehns JD (March 2003). "Achieving the best outcome in treatment of depression". Journal of Family Practice 52 (3): 201–09. PMID 12620174.
- Zisook S, Rush AJ, Haight BR, Clines DC, Rockett CB (2006). "Use of bupropion in combination with serotonin reuptake inhibitors". Biological Psychiatry 59 (3): 203–10. doi:10.1016/j.biopsych.2005.06.027. PMID 16165100.
- Rush AJ, Trivedi MH, Wisniewski SR, et al. (2006). "Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression". New England Journal of Medicine 354 (12): 1231–42. doi:10.1056/NEJMoa052963. PMID 16554525.
- Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA, Lebowitz BD, Biggs MM, Luther JF, Shores-Wilson K, Rush AJ (2006). "Medication augmentation after the failure of SSRIs for depression". New England Journal of Medicine 354 (12): 1243–52. doi:10.1056/NEJMoa052964. PMID 16554526.
- Mayers AG, Baldwin DS (December 2005). "Antidepressants and their effect on sleep". Human Psychopharmacology 20 (8): 533–59. doi:10.1002/hup.726. PMID 16229049.
- Winokur A, DeMartinis NA, McNally DP, Gary EM, Cormier JL, Gary KA (October 2003). "Comparative effects of mirtazapine and fluoxetine on sleep physiology measures in patients with major depression and insomnia". Journal of Clinical Psychiatry 64 (10): 1224–29. doi:10.4088/JCP.v64n1013. PMID 14658972.
- Lawrence RW (August 2004). "Effect of mirtazapine versus fluoxetine on "sleep quality"". Journal of Clinical Psychiatry 65 (8): 1149–50. doi:10.4088/JCP.v65n0818i. PMID 15323610.
- Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC (December 2007). "Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents". Biological Psychiatry 62 (11): 1217–27. doi:10.1016/j.biopsych.2007.03.027. PMID 17588546.
- Cipriani A, Geddes JR, Barbui C (2007). "Venlafaxine for major depression". British Medical Journal 334 (7587): 215 (editorial). doi:10.1136/bmj.39098.457720.BE. PMC 1790758. PMID 17272528. Retrieved 2008-09-13.
- "Depression in children and young people: identification and management in primary, community and secondary care". NHS National Institute for Health and Clinical Excellence. September 2005. Retrieved 2008-08-17.
- Nelson, JC; Devanand, DP (April 2011). "A systematic review and meta-analysis of placebo-controlled antidepressant studies in people with depression and dementia.". Journal of the American Geriatrics Society 59 (4): 577–85. doi:10.1111/j.1532-5415.2011.03355.x. PMID 21453380.
- Anderson IM (1998). "SSRIS versus tricyclic antidepressants in depressed inpatients: A meta-analysis of efficacy and tolerability". Depression and Anxiety. 7 Suppl 1: 11–17. doi:10.1002/(SICI)1520-6394(1998)7:1+<11::AID-DA4>3.0.CO;2-I. PMID 9597346.
- Anderson IM (April 2000). "Selective serotonin reuptake inhibitors versus tricyclic antidepressants: A meta-analysis of efficacy and tolerability". Journal of Affective Disorders 58 (1): 19–36. doi:10.1016/S0165-0327(99)00092-0. PMID 10760555.
- Krishnan KR (2007). "Revisiting monoamine oxidase inhibitors". Journal of Clinical Psychiatry. 68 Suppl 8: 35–41. PMID 17640156.
- Stahl, Stephen M. (2011). The Prescriber's Guide (Stahl's Essential Psychopharmacology). Cambridge University Press. p. 39.
- Valenstein M, McCarthy JF, Austin KL, Greden JF, Young EA, Blow FC (2006). "What happened to lithium? Antidepressant augmentation in clinical settings". American Journal of Psychiatry 163 (7): 1219–25. doi:10.1176/appi.ajp.163.7.1219. PMID 16816227.
- Bauer M, Dopfmer S (1999). "Lithium augmentation in treatment-resistant depression: Meta-analysis of placebo-controlled studies". Journal of Clinical Psychopharmacology 19 (5): 427–34. doi:10.1097/00004714-199910000-00006. PMID 10505584.
- Guzzetta F, Tondo L, Centorrino F, Baldessarini RJ (March 2007). "Lithium treatment reduces suicide risk in recurrent major depressive disorder". J Clin Psychiatry 68 (3): 380–83. doi:10.4088/JCP.v68n0304. PMID 17388706.
- Bender KJ (2008-02-01). "Evidence Grows for Value of Antipsychotics as Antidepressant Adjuncts - Psychiatric Times". Psychiatric Times. Retrieved 2008-08-06.
- Nierenberg AA, Fava M, Trivedi MH, Wisniewski SR, Thase ME, McGrath PJ, Alpert JE, Warden D, Luther JF, Niederehe G, Lebowitz B, Shores-Wilson K, Rush AJ (2006). "A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: A STAR*D report". American Journal of Psychiatry 163 (9): 1519–30. doi:10.1176/appi.ajp.163.9.1519. PMID 16946176.
- British National Formulary (BNF) 65. Pharmaceutical Pr; 2013.
- Drugs@FDA: FDA Approved Drug Products [Internet]. [cited 2013 Sep 13]. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
- Therapeutic Goods Administration. TGA eBusiness Services [Internet]. Australian Government Department of Health and Ageing.; [cited 2013 Sep 13]. Available from: https://www.ebs.tga.gov.au/
- Komossa, Katja; Depping, Anna M; Gaudchau, Andrea; Kissling, Werner; Leucht, Stefan (2010). "Second-generation antipsychotics for major depressive disorder and dysthymia". In Leucht, Stefan. Cochrane Database of Systematic Reviews (12): CD008121. doi:10.1002/14651858.CD008121.pub2. PMID 21154393.
- Bauer M, Dopfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies" J Clin Psychopharmacol 1999 Oct;19(5) 427–34.
- Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
- Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT (February 2008). "Initial severity and antidepressant benefits: A meta-analysis of data submitted to the Food and Drug Administration". PLoS Med. 5 (2): e45. doi:10.1371/journal.pmed.0050045. PMC 2253608. PMID 18303940.
- Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R (January 2008). "Selective publication of antidepressant trials and its influence on apparent efficacy". N. Engl. J. Med. 358 (3): 252–60. doi:10.1056/NEJMsa065779. PMID 18199864.
- Elkin I, Shea MT, Watkins JT, Imber SD, Sotsky SM, Collins JF, Glass DR, Pilkonis PA, Leber WR, Docherty JP (1989). "National Institute of Mental Health Treatment of Depression Collaborative Research Program. General effectiveness of treatments". Archives of General Psychiatry 46 (11): 971–82; discussion 983. doi:10.1001/archpsyc.1989.01810110013002. PMID 2684085.
- Elkin I, Gibbons RD, Shea MT, Sotsky SM, Watkins JT, Pilkonis PA, Hedeker D (1995). "Initial severity and differential treatment outcome in the National Institute of Mental Health Treatment of Depression Collaborative Research Program". Journal of Consulting and Clinical Psychology 63 (5): 841–47. doi:10.1037/0022-006X.63.5.841. PMID 7593878.
- Sotsky SM, Glass DR, Shea MT, Pilkonis PA, Collins JF, Elkin I, Watkins JT, Imber SD, Leber WR, Moyer J (1991). "Patient predictors of response to psychotherapy and pharmacotherapy: Findings in the NIMH Treatment of Depression Collaborative Research Program". American Journal of Psychiatry 148 (8): 997–1008. PMID 1853989.
- Turner EH, Rosenthal R (March 2008). "Efficacy of antidepressants". BMJ 336 (7643): 516–7. doi:10.1136/bmj.39510.531597.80. PMC 2265347. PMID 18319297.
- Cuijpers P, van Straten A, van Oppen P, Andersson G (August 2008). "Are Psychological and Pharmacologic Interventions Equally Effective in the Treatment of Adult Depressive Disorders? A Meta-Analysis of Comparative Studies". Journal of Clinical Psychiatry: e1–e11.
- Imel ZE, Malterer MB, McKay KM, Wampold BE (October 2008). "A meta-analysis of psychotherapy and medication in unipolar depression and dysthymia". J Affect Disord 110 (3): 197–206. doi:10.1016/j.jad.2008.03.018. PMID 18456340.
- Van Voorhees, Benjamin W.; Smith, Sandy; Ewigman, Bernard (2008). "Treat depressed teens with medication and psychotherapy". The Journal of Family Practice 57 (11): 735–9a. PMC 3183842. PMID 19006622.
- Mischoulon D, Fava M (November 2002). "Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence". Am. J. Clin. Nutr. 76 (5): 1158S–61S. PMID 12420702.
- Caddy C et al. Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Ther Adv Psychopharmacol. 2014 Apr;4(2):75-99. doi: 10.1177/2045125313507739. Review. PMID 24688759 PMC 3952483
- Roitman, S., Green, T., Osher, Y., Karni, N., & Levine, J. (2007). Creatine monohydrate in resistant depression: a preliminary study. Bipolar disorders, 9(7), 754-758.
- Lyoo, I. K., Yoon, S., Kim, T. S., Hwang, J., Kim, J. E., Won, W., ... & Renshaw, P. F. (2012). A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorder. American Journal of Psychiatry, 169(9), 937-945.
- Cunha, M. P., Machado, D. G., Capra, J. C., Jacinto, J., Bettio, L. E., & Rodrigues, A. L. S. (2012). Antidepressant-like effect of creatine in mice involves dopaminergic activation. Journal of Psychopharmacology, 26(11), 1489-1501.
- "FDA Panel Looks at Trials of Devices to Treat Depression" article by Emily P. Walker, Washington Correspondent, MedPage Today Published: October 08, 2010, accessed October 9, 2010
- Rudorfer, MV, Henry, ME, Sackeim, HA (2003). "Electroconvulsive therapy". In A Tasman, J Kay, JA Lieberman (eds) Psychiatry, Second Edition. Chichester: John Wiley & Sons Ltd, 1865–1901.
- Scott AIF (ed) et al. (2005). "The ECT Handbook Second Edition: The Third Report of the Royal College of Psychiatrists' Special Committee on ECT" (PDF). Royal College of Psychiatrists. Retrieved 2008-07-26.
- Shorter, Eward (2007). A History of Electroconvulsive Treatment in Mental Illness. New Brunswick, NJ: Rutgers University Press. pp. 46–47. ISBN 978-0-8135-4169-3.
- Psychology Frontiers and Applications – Second Canadian Edition (Passer, Smith, Atkinson, Mitchell, Muir)
- Reid WH, Keller S, Leatherman M, Mason M (January 1998). "ECT in Texas: 19 months of mandatory reporting". J Clin Psychiatry 59 (1): 8–13. doi:10.4088/JCP.v59n0103. PMID 9491059.
- Dr.Barnes, Richard. "Information on ECT". Royal College of Psychiatrists' Special Committee on ECT and related treatment. Retrieved 3 November 2013.
- Read, J; Bentall, R (Oct–Dec 2010). "The effectiveness of electroconvulsive therapy: a literature review.". Epidemiologia e psichiatria sociale 19 (4): 333–47. doi:10.1017/S1121189X00000671. PMID 21322506.
- World Health Organisation (2005). WHO Resource Book on Mental Health, Human Rights and Legislation. Geneva, 64.
- American Psychiatric Association, Committee on Electroconvulsive Therapy, Richard D. Weiner (chairperson) et al (2001). The practice of electroconvulsive therapy: recommendations for treatment, training, and privileging (2nd ed.). Washington, DC: American Psychiatric Publishing. ISBN 978-0-89042-206-9.
- Marangell LB, Martinez M, Jurdi RA, Zboyan H (September 2007). "Neurostimulation therapies in depression: a review of new modalities". Acta Psychiatr Scand 116 (3): 174–81. doi:10.1111/j.1600-0447.2007.01033.x. PMID 17655558.
- Emily Underwood (1 November 2013). "Short-Circuiting Depression". Science 342 (6158): 548. doi:10.1126/science.342.6158.548.
- Lakhan SE, Callaway H (2010). "Deep brain stimulation for obsessive-compulsive disorder and treatment-resistant depression: systematic review". BMC Research Notes 3: 60. doi:10.1186/1756-0500-3-60. PMC 2838907. PMID 20202203.
- National Institute of Mental Health. Brain Stimulation Therapies
- Schutter DJ (April 2008). "Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis". Psychol Med 39 (1): 1–11. doi:10.1017/S0033291708003462. PMID 18447962.
- Eranti S, Mogg A, Pluck G, et al. (January 2007). "A randomized, controlled trial with 6-month follow-up of repetitive transcranial magnetic stimulation and electroconvulsive therapy for severe depression". Am J Psychiatry 164 (1): 73–81. doi:10.1176/appi.ajp.164.1.73. PMID 17202547.
- Rush AJ, Marangell LB, Sackeim HA, et al. (September 2005). "Vagus nerve stimulation for treatment-resistant depression: A randomized, controlled acute phase trial". Biological Psychiatry 58 (5): 347–54. doi:10.1016/j.biopsych.2005.05.025. PMID 16139580.
- FDA > CDRH > CFR Title 21 Database Search
- FDA 515(i) Reclassification Letter to Manufacturers
- Levitt EA, James NM, Flavell P (December 1975). "A clinical trial of electrosleep therapy with a psychiatric inpatient sample". Aust N Z J Psychiatry 9 (4): 287–90. doi:10.3109/00048677509159864. PMID 769773.
- Passini FG, Watson CG, Herder J (October 1976). "The effects of cerebral electric therapy (electrosleep) on anxiety, depression, and hostility in psychiatric patients". J. Nerv. Ment. Dis. 163 (4): 263–66. doi:10.1097/00005053-197610000-00005. PMID 972328.
- Philip P, Demotes-Mainard J, Bourgeois M, Vincent JD (March 1991). "Efficiency of transcranial electrostimulation on anxiety and insomnia symptoms during a washout period in depressed patients. A double-blind study". Biol. Psychiatry 29 (5): 451–6. doi:10.1016/0006-3223(91)90267-P. PMID 2018818.
- Moore JA, Mellor CS, Standage KF, Strong H (1975). "A double-blind study of electrosleep for anxiety and insomnia". Biol. Psychiatry 10 (1): 59–63. PMID 1091305.
- Feighner JP, Brown SL, Olivier JE (1973). "Electrosleep therapy. A controlled double blind study". J. Nerv. Ment. Dis. 157 (2): 121–8. doi:10.1097/00005053-197308000-00004. PMID 4724809.
- Feighner JP (1 September 1971). "Electrosleep Therapy: Current Usage in Psychiatry". Calif. Med. 115 (3): 44. PMC 1518073. PMID 18730592. Retrieved 2007-12-02.
- Golden RN, Gaynes BN, Ekstrom RD, et al. (April 2005). "The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence". American Journal of Psychiatry 162 (4): 656–62. doi:10.1176/appi.ajp.162.4.656. PMID 15800134.
- Tuunainen A, Kripke DF, Endo T (2004). "Light therapy for non-seasonal depression". In Tuunainen, Arja. Cochrane Database Syst Rev (2): CD004050. doi:10.1002/14651858.CD004050.pub2. PMID 15106233.
- Blumenthal James A., Babyak Michael A., Moore Kathleen A., Craighead Edward W., Herman Steve, Khatri Parinda, Waugh Robert, Napolitano Melissa, Forman Leslie, Appelbaum Mark, Doraiswamy Murali, Krishnan K. Ranga (October 1999). "Effects of exercise training on older patients with major depression". Archives of Internal Medicine (JAMA) 159 (19): 2349–56. doi:10.1001/archinte.159.19.2349. PMID 10547175.
- Blumenthal James A., Babyak Michael A., Doraiswamy Murali, Watkins Lara, Hoffman Benson M., Barbour Krista A., Herman Steve, Craighead W. Edward, Brosse Alisha L., Waugh Robert, Hinderliter Alan, Sherwood Andrew (September 2007). "Exercise and pharmacotherapy in the treatment of major depressive disorder". Psychosomatic Medicine 69 (7): 587–596. doi:10.1097/PSY.0b013e318148c19a.
- Krogh J, Nordentoft M, Sterne JA, Lawlor DA (April 2011). "The effect of exercise in clinically depressed adults: systematic review and meta-analysis of randomized controlled trials". J Clin Psychiatry 72 (4): 529–38. doi:10.4088/JCP.08r04913blu. PMID 21034688.
- Madhav, Goyal; Sonal Singh, Erica M. S. Sibinga, Neda F. Gould, Anastasia Rowland-Seymour, Ritu Sharma, Zackary Berger, Dana Sleicher, David D. Maron, Hasan M. Shihab, Padmini D. Ranasinghe, Shauna Linn, Shonali Saha, Eric B. Bass, Jennifer A. Haythornthwaite (January 6, 2014). "Meditation Programs for Psychological Stress and Well-being". JAMA Intern Med 174 (3): 357–68. doi:10.1001/jamainternmed.2013.13018. PMID 24395196.
- Gold C, Solli HP, Krüger V, Lie SA (April 2009). "Dose-response relationship in music therapy for people with serious mental disorders: systematic review and meta-analysis". Clin Psychol Rev 29 (3): 193–207. doi:10.1016/j.cpr.2009.01.001. PMID 19269725.
- Linde K, Berner MM, Kriston L (2008). "St John's wort for major depression". Cochrane Database Syst Rev (4): CD000448. doi:10.1002/14651858.CD000448.pub3. PMID 18843608.
- "St John's Wort and depression". Retrieved January 25, 2014.
- Depression (PDF). NICE. December 2004.
- Wirz-Justice, A.; Benedetti, F.; Berger, M.; Lam, R.W.; Martiny, K.; Terman, M.; Wu, J.C. (July 2005). "Chronotherapeutics (light and wake therapy) in affective disorders". Psychological Medicine 35 (7): 939–44. doi:10.1017/S003329170500437X. PMID 16045060.
- Taylor, Gemma; Ann McNeill; Alan Girling; Amanda Farley; Nicola Lindson-Hawley; Paul Aveyard (February 13, 2014). "Change in mental health after smoking cessation: systematic review and meta-analysis". BMJ 348: g1151. doi:10.1136/bmj.g1151. PMC 3923980. PMID 24524926.
- Giedke, Henner; Schwärzler, Frank (2002). "Therapeutic use of sleep deprivation in depression". Sleep Medicine Reviews 6 (5): 361–77. doi:10.1053/smrv.2002.0235. PMID 12531127.
- Shaw, K; Turner, J; Del Mar, C (2002). "Tryptophan and 5-hydroxytryptophan for depression.". The Cochrane database of systematic reviews (1): CD003198. doi:10.1002/14651858.CD003198. PMID 11869656.
- Ravindran, AV; da Silva, TL (Sep 25, 2013). "Complementary and alternative therapies as add-on to pharmacotherapy for mood and anxiety disorders: a systematic review.". Journal of Affective Disorders 150 (3): 707–19. doi:10.1016/j.jad.2013.05.042. PMID 23769610.