Management of depression: Difference between revisions

[[Depression (mood)|Depression]] is a symptom of some physical diseases; a [[side effect]] of some drugs and medical treatments; and a symptom of some [[mood disorders]] such as [[major depressive disorder]] or [[dysthymia]].<ref name="DSM-5(2013)">{{cite book |title= Diagnostic and Statistical Manual of Mental Disorders | edition = Fifth Edition (DSM-5) |year= 2013 |publisher= American Psychiatric Association }}</ref> Physical causes are ruled out with a [[Major depressive disorder#Clinical assessment|clinical assessment of depression]] that measures vitamins, minerals, electrolytes, and hormones.<ref name="Parker_2017">{{cite journal | vauthors = Parker GB, Brotchie H, Graham RK | title = Vitamin D and depression | journal = Journal of Affective Disorders | volume = 208 | pages = 56–61 | date = January 2017 | pmid = 27750060 | doi = 10.1016/j.jad.2016.08.082 }}</ref><ref name="Orengo_2004">{{cite journal | vauthors = Orengo CA, Fullerton G, Tan R | title = Male depression: a review of gender concerns and testosterone therapy | journal = Geriatrics | volume = 59 | issue = 10 | pages = 24–30 | date = October 2004 | pmid = 15508552 }}</ref><ref name="Dale_2008">{{cite journal|vauthors=Dale J, Sorour E, Milner G|year=2008|title=Do psychiatrists perform appropriate physical investigations for their patients? A review of current practices in a general psychiatric inpatient and outpatient setting|journal=Journal of Mental Health|volume=17|issue=3|pages=293–98|doi=10.1080/09638230701498325|s2cid=72755878}}</ref>

Though [[psychiatric medication]] is the most frequently prescribed therapy for major depression,<ref name="Carson_2000">{{cite book | vauthors = Carson VB | date = 2000 | url = https://books.google.com/books?id=QM5rAAAAMAAJ | title = Mental health nursing: the nurse-patient journey | publisher = W.B. Saunders | isbn = 978-0-7216-8053-8 | page = 423 | access-date = 2016-09-24 | archive-date = 2023-01-11 | archive-url = https://web.archive.org/web/20230111101323/https://books.google.com/books?id=QM5rAAAAMAAJ | url-status = live }}</ref> [[psychotherapy]] may be effective, either alone or in combination with medication.<ref name="merckmanuals.com">{{cite book | chapter-url = http://www.merckmanuals.com/professional/psychiatric_disorders/mood_disorders/depressive_disorders.html#v1028131 | chapter = Psychotherapy | title = The Merck Manual of Diagnosis and Therapy | access-date = 2011-11-09 | archive-date = 2011-11-09 | archive-url = https://web.archive.org/web/20111109210617/http://www.merckmanuals.com/professional/psychiatric_disorders/mood_disorders/depressive_disorders.html#v1028131 | url-status = live }}</ref> Combining psychotherapy and antidepressants may provide a "slight advantage", but antidepressants alone or psychotherapy alone are not significantly different from other treatments, like "active intervention controls". ( e.g., sham acupuncture{{clarify inline|date=April 2023}}) 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."<ref name="Khan_2012">{{cite journal | vauthors = Khan A, Faucett J, Lichtenberg P, Kirsch I, Brown WA | title = A systematic review of comparative efficacy of treatments and controls for depression | journal = PLOS ONE | volume = 7 | issue = 7 | pages = e41778 | date = July 30, 2012 | pmid = 22860015 | pmc = 3408478 | doi = 10.1371/journal.pone.0041778 | doi-access = free | bibcode = 2012PLoSO...741778K }}</ref>

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.<ref name=NICEkids5>{{cite book |author=NICE |title=NICE Guidelines:depression in children and adolescents |publisher= NICE |location=London |year=2005 |pages=5 |isbn=978-1-84629-074-9 |url=http://www.nice.org.uk/Guidance/CG28/QuickRefGuide/pdf/English |access-date=2008-08-16 |archive-date=2008-09-24 |archive-url=https://web.archive.org/web/20080924152314/http://www.nice.org.uk/Guidance/CG28/QuickRefGuide/pdf/English |url-status=live }}</ref>

There are a number of different psychotherapies for depression which are provided to individuals or groups by psychotherapists, psychiatrists, psychologists, [[clinical social work]]ers, 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.<ref name="merckmanuals.com"/><ref name="Thase_1999">{{cite journal | vauthors = Thase ME | title = When are psychotherapy and pharmacotherapy combinations the treatment of choice for major depressive disorder? | journal = The Psychiatric Quarterly | volume = 70 | issue = 4 | pages = 333–346 | year = 1999 | pmid = 10587988 | doi = 10.1023/A:1022042316895 | s2cid = 45091134 }}</ref> Psychotherapy is the treatment of choice in people under 18.<ref name=NICEkids5/> A meta-analysis examined the effectiveness of psychotherapy for depression across ages from younger than 13 years to older than 75 years. It summarizes results from 366 trials included 36,702 patients. It found that the best results were for young adults, with an average [[effect size]] of ''g''=.98 ([[Confidence interval|95% ''CI'']], 0.79-179–1.16).<ref name="Cuijpers_2020">{{cite journal | vauthors = Cuijpers P, Karyotaki E, Eckshtain D, Ng MY, Corteselli KA, Noma H, Quero S, Weisz JR | display-authors = 6 | title = Psychotherapy for Depression Across Different Age Groups: A Systematic Review and Meta-analysis | journal = JAMA Psychiatry | volume = 77 | issue = 7 | pages = 694–702 | date = July 2020 | pmid = 32186668 | pmc = 7081149 | doi = 10.1001/jamapsychiatry.2020.0164 }}</ref> The effects were smallest for young children (<13 years), ''g'' = .35 (95% ''CI'', 0.15-015–0.55), and second largest in the oldest group, ''g'' = .97 (95% ''CI'', 0.42-142–1.52). The study was not able to compare the different types of therapy to each other. Most of the studies with children used therapies originally developed with adults, which may have reduced the effectiveness. The greater benefits with young adults might be due to a large number of studies including college students, who might have an easier time learning therapy skills and techniques.<ref name="Cuijpers_2020" /> Most of the studies in children were done in the US, whereas in older age groups, more balanced numbers of studies came from Europe and other parts of the world as well.<ref name="Cuijpers_2020" />

[[Behavior therapy]] for depression is sometimes referred to as [[behavioral activation]].<ref>{{cite journal | vauthors = Hopko DR, Lejuez CW, LePage JP, Hopko SD, McNeil DW | title = A brief behavioral activation treatment for depression. A randomized pilot trial within an inpatient psychiatric hospital | journal = Behavior Modification | volume = 27 | issue = 4 | pages = 458–469 | date = September 2003 | pmid = 12971122 | doi = 10.1177/0145445503255489 | url = http://web.utk.edu/~dhopko/BAinpatient.pdf | url-status = dead | s2cid = 30950124 | archive-url = https://web.archive.org/web/20150402162244/http://web.utk.edu/~dhopko/BAinpatient.pdf | archive-date = 2015-04-02 }}</ref> In addition, behavioral activation appears to take less time and lead to longer lasting change.<ref>{{cite journal | vauthors = Spates CR, Pagoto SL, Kalata A | year = 2006 | title = A Qualitative And Quantitative Review of Behavioral Activation Treatment of Major Depressive Disorder | journal = The Behavior Analyst Today | volume = 7 | issue = 4 | pages = 508–518 | doi = 10.1037/h0100089 | s2cid = 3337916 | url = https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1106&context=prevbeh_pp | access-date = 2019-07-14 | archive-date = 2022-02-21 | archive-url = https://web.archive.org/web/20220221073529/https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1106&context=prevbeh_pp | url-status = live }}</ref> Two well-researched treatment manuals include ''Social skills training for depression''<ref>{{cite journal | vauthors = Bellack AS, Hersen M, Himmelhoch J | title = Social skills training for depression: a treatment manual. | journal = J Select Ab Serv Cat Select Doc Psychol. | date = 1981 | volume = 10 | pages = 36–92 }}</ref> and ''Behavioral activation treatment for depression''.<ref>{{cite journal | vauthors = Jacobson NS, Martell CR, Dimidjian S | title = Behavioral activation treatment for depression: Returning to contextual roots. | journal = Clinical Psychology: Science and Practice | date = September 2001 | volume = 8 | issue = 3 | pages = 255–70 | doi = 10.1093/clipsy.8.3.255 }}</ref>

[[Emotionally focused therapy]], founded by Sue Johnson and Les Greenberg in 1985, treats depression by identifying and processing underlying emotions. The treatment manual, ''Facilitating emotional change'', outlines treatment techniques.<ref>{{cite book | vauthors = Greenberg LS, Rice LN, Elliott R | title = Facilitating emotional change: the moment-by-moment process. | location = New York | publisher = Guilford Press | date = 1993 }}</ref> This kind of therapy assumes that our emotions have a strong connection to our sense of identity. It believes that if we are able to foster and understand our emotions, our sense of identity will be healed as a result.

[[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.<ref>{{cite journal | vauthors = Ruiz FJ |year=2010 |title=A review of Acceptance and Commitment Therapy (ACT) empirical evidence: Correlational, experimental psychopathology, component and outcome studies |journal=International Journal of Psychology and Psychological Therapy |volume=10 |issue=1 |pages=125–62 |url=http://www.ijpsy.com/volumen10/num1/256.html |access-date=2013-04-30 |archive-date=2012-02-23 |archive-url=https://web.archive.org/web/20120223144433/http://www.ijpsy.com/volumen10/num1/256.html |url-status=live }}</ref><ref>{{cite web|title=APA website on empirical treatments |url=http://www.div12.org/PsychologicalTreatments/treatments.html |access-date=2009-09-01 |url-status=dead |archive-url=https://web.archive.org/web/20101005034058/http://www.div12.org/PsychologicalTreatments/treatments.html |archive-date=2010-10-05 }}</ref><ref name="evidence">{{cite web | vauthors = Hayes S |author-link=Steven C. Hayes |title=State of the ACT Evidence |publisher=ContextualPsychology.org |url=http://www.contextualpsychology.org/state_of_the_act_evidence/ |access-date=2013-04-30 |archive-date=2013-01-22 |archive-url=https://web.archive.org/web/20130122031152/http://contextualpsychology.org/state_of_the_act_evidence |url-status=live }}</ref>

Shared decision making is an approach whereby patients and clinicians freely share important evidence when tasked with decision making and where patients are guided to consider the best available options to make an informed decision.<ref>{{cite journal | vauthors = Sanda MG, Cadeddu JA, Kirkby E, Chen RC, Crispino T, Fontanarosa J, Freedland SJ, Greene K, Klotz LH, Makarov DV, Nelson JB, Rodrigues G, Sandler HM, Taplin ME, Treadwell JR | display-authors = 6 | title = Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline. Part I: Risk Stratification, Shared Decision Making, and Care Options | journal = The Journal of Urology | volume = 199 | issue = 3 | pages = 683–690 | date = March 2018 | pmid = 29203269 | doi = 10.1016/j.juro.2017.11.095 | publisher = Ovid Technologies (Wolters Kluwer Health) | s2cid = 21405694 }}</ref> The principles are well documented, but there is a gap in that it's hard to apply them in routine clinical practice. The steps have been simplified into five steps. The first step is seeking patient participation in that the health practitioner is tasked with communicating existing choices and therefore inviting them to the decision-making process. The next step involves assisting the patient to explore and compare the treatment options by a critical analysis of the risks and benefits. The third step involves the assessment of the patient's values and what they prefer taking to account what is of paramount urgency to the patient. Step 4 involves decision making where the patient and the practitioner make a conclusive decision on the best option and arrange for subsequent follow up meetings. Finally, the fifth step involves the analysis of the patient's decision'. Five steps for you and your patients to work together to make the best possible health care decisions. The step involves monitoring of the degree of implementation, overcoming of barriers of decision implantation consequently the decisions need to be revisited and optimized thus ensuring the decision has a positive impact on health outcomes. Its success relies on the ability of the health practitioner to create a good interpersonal relationship with the patient. (Stone, 2017){{Full citation needed|date=February 2019}}<!-- I found a Stone 2018, doi 10.7812/TPP/18-030 - it seems related but doesn't match up entirely with the statements here. The same author had two papers in 2017, however neither seem relevant -->

Depression is a major problem globally, affecting an estimated 4.4 percent of the world population in 2017, roughly equivalent to 300 million people.<ref>{{cite report |title=Depression and Other Common Mental Disorders: Global Health Estimates |date=2017 |publisher=World Health Organisation |location=Geneva |page=5 |url=https://apps.who.int/iris/bitstream/handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf |access-date=17 January 2022 |archive-date=20 January 2022 |archive-url=https://web.archive.org/web/20220120033754/https://apps.who.int/iris/bitstream/handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf |url-status=live }}</ref> The depression is multifactorial and has been on the increase due to societal pressure, genetic association and increase in use of drugs (Zhang et al. 2016){{Full citation needed|date=February 2019}}. incorporation of nursing in management of depression may seem important in that nursing hold a pivotal role in health care delivery where they are they are the health practitioners that have been trained to be versatile from clinical to psychological care Their incorporation shared decision making in treating depression may be important as nurses are known to have the best interpersonal relationship with the patients thus a better collaborative model can be achieved due to this fact (Williams et al. 2016){{Full citation needed|date=February 2019}}. With this in mind, the nurses may serve to administer drugs in management, prepare and maintain the patient's records, interaction with other care staff to achieve optimum care, and organizing therapy sessions (Lu et al. 2019){{Full citation needed|date=February 2019}}.

Kathleen Walsh, 2017, recognizes that Dr. Velligan{{who|date=January 2022|reason=There is no context for who Velligan is or why we should care what they said.}} stated that SDM is of importance in demonstrating patient preferences in decision making when there is no clear approach to treatment. In addition, numerous tools can be used to make the decision making the process easier these include the Controlled Preferences Scale that informs clinicians on how to actively involve patients. She further gives the suggestion that providers need to embrace shared decision making by making sure the patients participate actively in their management thus enabling the success of the model.<ref>{{cite journal | vauthors = Walsh K, Sandars J | title = Shared decision-making tools: do they really involve patients? | journal = British Journal of Hospital Medicine | volume = 78 | issue = 6 | pages = 304–305 | date = June 2017 | pmid = 28614022 | doi = 10.12968/hmed.2017.78.6.304 | publisher = Mark Allen Group | url = https://research.edgehill.ac.uk/en/publications/0d29f628-5514-4c7c-b49e-fc6effb40817 | access-date = 2022-06-11 | archive-date = 2024-02-24 | archive-url = https://web.archive.org/web/20240224184811/https://research.edgehill.ac.uk/en/publications/shared-decision-making-toolsdo-they-really-involve-patients-2 | url-status = live }}</ref>

To find the most effective [[pharmaceutical drug]] treatment, the dosages of medications must often be adjusted, different combinations of antidepressants tried, or antidepressants changed.{{citation needed|date=April 2023}} Some of the medications have side effects that affect certain people in different ways. The combinations of medication can change these side effects, so it is essential to monitor the changes that occur once we begin medication.

[[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.<ref>{{cite journal | vauthors = Sutherland JE, Sutherland SJ, Hoehns JD | title = Achieving the best outcome in treatment of depression | journal = The Journal of Family Practice | volume = 52 | issue = 3 | pages = 201–209 | date = March 2003 | pmid = 12620174 | url = http://www.jfponline.com/Pages.asp?AID=1406 | url-status = dead | archive-url = https://web.archive.org/web/20091002083433/http://www.jfponline.com/Pages.asp?AID=1406 | archive-date = 2009-10-02 }}</ref> Another popular option is to switch to the atypical antidepressant [[bupropion]] (Wellbutrin) or to add bupropion to the existing therapy;<ref>{{cite journal | vauthors = Zisook S, Rush AJ, Haight BR, Clines DC, Rockett CB | title = Use of bupropion in combination with serotonin reuptake inhibitors | journal = Biological Psychiatry | volume = 59 | issue = 3 | pages = 203–210 | date = February 2006 | pmid = 16165100 | doi = 10.1016/j.biopsych.2005.06.027 | s2cid = 20997303 }}</ref> this strategy is possibly more effective.<ref>{{cite journal | vauthors = Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, Ritz L, Biggs MM, Warden D, Luther JF, Shores-Wilson K, Niederehe G, Fava M | display-authors = 6 | title = Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression | journal = The New England Journal of Medicine | volume = 354 | issue = 12 | pages = 1231–1242 | date = March 2006 | pmid = 16554525 | doi = 10.1056/NEJMoa052963 | doi-access = free }}</ref><ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = Medication augmentation after the failure of SSRIs for depression | journal = The New England Journal of Medicine | volume = 354 | issue = 12 | pages = 1243–1252 | date = March 2006 | pmid = 16554526 | doi = 10.1056/NEJMoa052964 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Mayers AG, Baldwin DS | title = Antidepressants and their effect on sleep | journal = Human Psychopharmacology | volume = 20 | issue = 8 | pages = 533–559 | date = December 2005 | pmid = 16229049 | doi = 10.1002/hup.726 | s2cid = 17912673 }}</ref><ref>{{cite journal | vauthors = Winokur A, DeMartinis NA, McNally DP, Gary EM, Cormier JL, Gary KA | title = Comparative effects of mirtazapine and fluoxetine on sleep physiology measures in patients with major depression and insomnia | journal = The Journal of Clinical Psychiatry | volume = 64 | issue = 10 | pages = 1224–1229 | date = October 2003 | pmid = 14658972 | doi = 10.4088/JCP.v64n1013 }}</ref><ref>{{cite journal | vauthors = Lawrence RW | title = Effect of mirtazapine versus fluoxetine on "sleep quality" | journal = The Journal of Clinical Psychiatry | volume = 65 | issue = 8 | pages = 1149–1150 | date = August 2004 | pmid = 15323610 | doi = 10.4088/JCP.v65n0818i | doi-access = free }}</ref>

For children and adolescents with moderate-to-severe depressive disorder, fluoxetine seems to be the best treatment (either with or without [[Cognitive behavioral therapy|cognitive behavioural therapy]]) but more research is needed to be certain.<ref name="NIHR_Prozac">{{Cite journal |date=2020-10-12 |title=Prozac may be the best treatment for young people with depression – but more research is needed |url=https://evidence.nihr.ac.uk/alert/prozac-may-be-the-best-treatment-for-young-people-with-depression-but-more-research-is-needed/ |journal=NIHR Evidence |type=Plain English summary |language=en |publisher=National Institute for Health and Care Research |doi=10.3310/alert_41917 |s2cid=242952585 |access-date=2022-11-06 |archive-date=2022-11-06 |archive-url=https://web.archive.org/web/20221106195344/https://evidence.nihr.ac.uk/alert/prozac-may-be-the-best-treatment-for-young-people-with-depression-but-more-research-is-needed/ |url-status=live }}</ref><ref name="Zhou_2020">{{cite journal | vauthors = Zhou X, Teng T, Zhang Y, Del Giovane C, Furukawa TA, Weisz JR, Li X, Cuijpers P, Coghill D, Xiang Y, Hetrick SE, Leucht S, Qin M, Barth J, Ravindran AV, Yang L, Curry J, Fan L, Silva SG, Cipriani A, Xie P | display-authors = 6 | title = Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis | journal = The Lancet. Psychiatry | volume = 7 | issue = 7 | pages = 581–601 | date = July 2020 | pmid = 32563306 | pmc = 7303954 | doi = 10.1016/S2215-0366(20)30137-1 }}</ref><ref name="Boaden_2020">{{cite journal | vauthors = Boaden K, Tomlinson A, Cortese S, Cipriani A | title = Antidepressants in Children and Adolescents: Meta-Review of Efficacy, Tolerability and Suicidality in Acute Treatment | journal = Frontiers in Psychiatry | volume = 11 | pages = 717 | date = 2020-09-02 | pmid = 32982805 | pmc = 7493620 | doi = 10.3389/fpsyt.2020.00717 | doi-access = free }}</ref><ref name="Hetrick_2021">{{cite journal | vauthors = Hetrick SE, McKenzie JE, Bailey AP, Sharma V, Moller CI, Badcock PB, Cox GR, Merry SN, Meader N | display-authors = 6 | title = New generation antidepressants for depression in children and adolescents: a network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 5 | pages = CD013674 | date = May 2021 | pmid = 34029378 | pmc = 8143444 | doi = 10.1002/14651858.CD013674.pub2 | editor-last = Cochrane Common Mental Disorders Group }}</ref> Sertraline, escitalopram, [[duloxetine]] might also help in reducing symptoms.<ref name="Hetrick_2021" /> In the UK fluoxetine and escitalopram are the only antidepressants recommended for people under the age of 18, though, if a child or adolescent patient is intolerant to fluoxetine, another SSRI may be considered.<ref>{{Cite web |title=Overview {{!}} Depression in children and young people: identification and management {{!}} Guidance {{!}} NICE |url=https://www.nice.org.uk/guidance/ng134 |access-date=2022-11-06 |website=www.nice.org.uk |date=25 June 2019 |archive-date=2022-10-29 |archive-url=https://web.archive.org/web/20221029101150/https://www.nice.org.uk/guidance/ng134/ |url-status=live }}</ref>

[[Venlafaxine]] (Effexor) from the SNRI class may be moderately more effective than SSRIs;<ref>{{cite journal | vauthors = Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC | title = 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 | journal = Biological Psychiatry | volume = 62 | issue = 11 | pages = 1217–1227 | date = December 2007 | pmid = 17588546 | doi = 10.1016/j.biopsych.2007.03.027 | s2cid = 45621773 }}</ref> however, it is not recommended as a first-line treatment because of the higher rate of side effects,<ref>{{cite journal | vauthors = Cipriani A, Geddes JR, Barbui C | title = Venlafaxine for major depression | journal = BMJ | volume = 334 | issue = 7587 | pages = 215–216 | date = February 2007 | pmid = 17272528 | pmc = 1790758 | doi = 10.1136/bmj.39098.457720.BE }}</ref> and its use is specifically discouraged in children and adolescents.<ref name="nice.org.uk">{{cite web |url=http://www.nice.org.uk/Guidance/CG28 |title=Depression in children and young people: identification and management in primary, community and secondary care |date=September 2005 |publisher=NHS National Institute for Health and Clinical Excellence |access-date=2008-08-17 |archive-date=2022-10-17 |archive-url=https://web.archive.org/web/20221017025852/http://www.nice.org.uk/guidance/cg28 |url-status=live }}</ref>

[[Tricyclic antidepressant]]s (TCAs) have morea different side effectseffect profile than SSRIs. andIn area usually reserved for the treatmentstudy of inpatients, for whom the tricyclic antidepressant [[amitriptyline]], in particular, appears to be more effective.<ref>{{cite journal | vauthors = Anderson IM | title = SSRIS versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability | journal = Depression and Anxiety | volume = 7 | issue = S1 | pages = 11–17 | year = 1998 | pmid = 9597346 | doi = 10.1002/(SICI)1520-6394(1998)7:1+<11::AID-DA4>3.0.CO;2-I | s2cid = 25730459 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Anderson IM | title = Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability | journal = Journal of Affective Disorders | volume = 58 | issue = 1 | pages = 19–36 | date = April 2000 | pmid = 10760555 | doi = 10.1016/S0165-0327(99)00092-0 }}</ref>

[[Monoamine oxidase inhibitor]]s, have historically been plagued by questionable efficacy (although early studies used dosages now considered too low) and life-threatening adverse effects. They are still used only rarely, although newer agents of this class ([[Reversible inhibitor of monoamine oxidase A|RIMA]]), with a better side effect profile, have been developed.<ref>{{cite journal | vauthors = Krishnan KR | title = Revisiting monoamine oxidase inhibitors | journal = The Journal of Clinical Psychiatry | volume = 68 | issue = Suppl 8 | pages = 35–41 | year = 2007 | pmid = 17640156 | url = http://article.psychiatrist.com/?ContentType=START&ID=10003141 | access-date = 2008-08-27 | archive-date = 2012-07-07 | archive-url = https://archive.today/20120707213654/http://article.psychiatrist.com/?ContentType=START&ID=10003141 | url-status = live }}</ref>

{{blockquote|'funded by a pharmaceutical company (Servier) and two of its authors are employees of that company', which may bias the results. The study authors' note: "emotional blunting is reported by nearly half of depressed patients on antidepressants and that it appears to be common to all monoaminergic antidepressants not only SSRIs". Additionally, they note: "The OQuESA scores are highly correlated with the HAD depression score; emotional blunting cannot be described simply as a side-effect of antidepressant, but also as a symptom of depression. More emotional blunting is associated with a poorer quality of remission.<ref>{{Cite web | url=https://www.nationalelfservice.net/treatment/antidepressants/what-causes-emotional-blunting-in-people-taking-antidepressants-results-from-a-survey/ | title=What causes emotional blunting in people taking antidepressants?| date=2018-02-08| access-date=2018-04-25| archive-date=2019-04-09| archive-url=https://web.archive.org/web/20190409072842/https://www.nationalelfservice.net/treatment/antidepressants/what-causes-emotional-blunting-in-people-taking-antidepressants-results-from-a-survey/| url-status=live}}</ref>}}

Research on the antidepressant effects of [[Ketamine#Antidepressant use|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 (medicine)|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.<ref>{{cite journal | vauthors = Caddy C, Giaroli G, White TP, Shergill SS, Tracy DK | title = Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy | journal = Therapeutic Advances in Psychopharmacology | volume = 4 | issue = 2 | pages = 75–99 | date = April 2014 | pmid = 24688759 | pmc = 3952483 | doi = 10.1177/2045125313507739 }}</ref> A nasal spray formulation of [[esketamine]], sold under the brand name Spravato, gained FDA approval in 2019 for the treatment of treatment-resistant depression when combined with an oral antidepressant.<ref name="Gastaldon 2019">{{cite journal | vauthors = Gastaldon C, Papola D, Ostuzzi G, Barbui C | title = Esketamine for treatment resistant depression: a trick of smoke and mirrors? | journal = Epidemiology and Psychiatric Sciences | volume = 29 | pages = e79 | date = December 2019 | pmid = 31841104 | pmc = 8061126 | doi = 10.1017/s2045796019000751 | publisher = Cambridge University Press (CUP) }}</ref><ref name="U.S. FDA 2020">{{cite web | title=FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic | website=U.S. Food and Drug Administration | date=5 March 2019 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified | access-date=12 August 2022 | archive-date=23 July 2021 | archive-url=https://web.archive.org/web/20210723022112/https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified | url-status=live }}</ref>

Addition of [[atypical antipsychotic]]s 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.<ref>{{cite magazine |url= http://www.psychiatrictimes.com/display/article/10168/1147436 |title=Evidence Grows for Value of Antipsychotics as Antidepressant Adjuncts - Psychiatric Times |author=Bender KJ |date=2008-02-01 |magazine=Psychiatric Times |access-date=2008-08-06 |archive-date=2020-06-13 |archive-url=https://web.archive.org/web/20200613062630/https://www.psychiatrictimes.com/display/article/10168/1147436 |url-status=dead }}</ref>

Lithium has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone.<ref name="Bschor 2014 pp. 855–862">{{cite journal | vauthors = Bschor T | title = Lithium in the treatment of major depressive disorder | journal = Drugs | volume = 74 | issue = 8 | pages = 855–862 | date = June 2014 | pmid = 24825489 | doi = 10.1007/s40265-014-0220-x | publisher = Springer Science and Business Media LLC | s2cid = 12892550 }}</ref> Furthermore, lithium dramatically decreases the suicide risk in recurrent depression.<ref>{{cite journal | vauthors = Guzzetta F, Tondo L, Centorrino F, Baldessarini RJ | title = Lithium treatment reduces suicide risk in recurrent major depressive disorder | journal = The Journal of Clinical Psychiatry | volume = 68 | issue = 3 | pages = 380–383 | date = March 2007 | pmid = 17388706 | doi = 10.4088/JCP.v68n0304 }}</ref>

For TRD patients, T3T₃ has been studied in the STAR-D study with having a remission rate of 24.7%. T4T₄ is also being studied for this purpose and found remission rates of 21.5% - 64–64.7% for TRD patients.<ref name="de Sousa V. Zanetti R. Brunoni Machado-Vieira 2015 pp. 616–635">{{cite journal | vauthors = de Sousa RT, Zanetti MV, Brunoni AR, Machado-Vieira R | title = Challenging Treatment-Resistant Major Depressive Disorder: A Roadmap for Improved Therapeutics | journal = Current Neuropharmacology | volume = 13 | issue = 5 | pages = 616–635 | date = 2015-10-13 | pmid = 26467411 | pmc = 4761633 | doi = 10.2174/1570159x13666150630173522 | publisher = Bentham Science Publishers Ltd. }}</ref>

! Drug !! [[Medicines and Healthcare products Regulatory Agency|MHRA]] approved as an adjunct?<ref>British National Formulary (BNF) 65. Pharmaceutical Pr; 2013.</ref>!! [[Therapeutic Goods Administration|TGA]] approved as an adjunct?<ref>{{cite web | title = Therapeutic Goods Administration. TGA eBusiness Services [Internet]. | publisher = Australian Government Department of Health and Ageing. | access-date = 13 September 2013 | url = https://www.ebs.tga.gov.au/ | archive-date = 21 April 2013 | archive-url = https://web.archive.org/web/20130421054308/https://www.ebs.tga.gov.au/ | url-status = live }}</ref>!! [[Food and Drug Administration|FDA]] approved as an adjunct?<ref>{{cite web | author = Drugs@FDA | title = FDA Approved Drug Products | access-date = 13 September 2013 | url = http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm | archive-date = 14 August 2012 | archive-url = https://web.archive.org/web/20120814072104/http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/index.cfm | url-status = live }}</ref> !! [[Odds ratio|{{abbr|OR|odds ratio}}]] for non-response over antidepressant monotherapy<ref name="Cochrane">{{cite journal | vauthors = Komossa K, Depping AM, Gaudchau A, Kissling W, Leucht S | title = Second-generation antipsychotics for major depressive disorder and dysthymia | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD008121 | date = December 2010 | pmid = 21154393 | doi = 10.1002/14651858.CD008121.pub2 | veditors = Leucht S }}</ref> !! Mean difference for [[Montgomery–Åsberg Depression Rating Scale|{{abbr|MADRS|Montgomery–Åsberg Depression Rating Scale}}]]<ref name = "Cochrane" /> !! Mean difference for [[Hamilton Rating Scale for Depression|{{abbr|HAM-D|Hamilton Rating Scale for Depression}}]]<ref name = "Cochrane" /> !! [[Odds ratio|{{abbr|OR|odds ratio}}]] for leaving the study early due to any reason<ref name = "Cochrane" /> !! [[Odds ratio|{{abbr|OR|odds ratio}}]] for leaving the study early due to adverse effects<ref name = "Cochrane" /> !! [[Odds ratio|{{abbr|OR|odds ratio}}]] for significant weight gain<ref name = "Cochrane" /> !! Mean difference for weight gain (kg)<ref name = "Cochrane" /> !! [[Odds ratio|{{abbr|OR|odds ratio}}]] for sedation<ref name = "Cochrane" />

| [[Aripiprazole]] || No || No || Yes || 0.48 (0.37-037–0.63) || -3−3.04 (-4−4.09,0.00) || 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)

| [[Olanzapine]] || No || No || Yes (in combination with fluoxetine) || 0.70 (0.48, 1.02) || -2−2.84 (-5−5.84,-0−0.20) || -7−7.90 (-16−16.63, 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) || -2−2.67 (-4−4.00, -1−1.34) || -2−2.67 (-3−3.79, -1−1.55) || 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) || -1−1.85 (-9−9.17, 5.47) || -1−1.69 (-4−4.13, 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)

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.<ref name="Kirsch08">{{cite journal | vauthors = Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT | title = Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration | journal = PLOS Medicine | volume = 5 | issue = 2 | pages = e45 | date = February 2008 | pmid = 18303940 | pmc = 2253608 | doi = 10.1371/journal.pmed.0050045 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R | title = Selective publication of antidepressant trials and its influence on apparent efficacy | journal = The New England Journal of Medicine | volume = 358 | issue = 3 | pages = 252–260 | date = January 2008 | pmid = 18199864 | doi = 10.1056/NEJMsa065779 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Elkin I, Shea MT, Watkins JT, Imber SD, Sotsky SM, Collins JF, Glass DR, Pilkonis PA, Leber WR, Docherty JP | display-authors = 6 | title = National Institute of Mental Health Treatment of Depression Collaborative Research Program. General effectiveness of treatments | journal = Archives of General Psychiatry | volume = 46 | issue = 11 | pages = 971–82; discussion 983 | date = November 1989 | pmid = 2684085 | doi = 10.1001/archpsyc.1989.01810110013002 }}</ref><ref>{{cite journal | vauthors = Elkin I, Gibbons RD, Shea MT, Sotsky SM, Watkins JT, Pilkonis PA, Hedeker D | title = Initial severity and differential treatment outcome in the National Institute of Mental Health Treatment of Depression Collaborative Research Program | journal = Journal of Consulting and Clinical Psychology | volume = 63 | issue = 5 | pages = 841–847 | date = October 1995 | pmid = 7593878 | doi = 10.1037/0022-006X.63.5.841 }}</ref><ref>{{cite journal | vauthors = Sotsky SM, Glass DR, Shea MT, Pilkonis PA, Collins JF, Elkin I, Watkins JT, Imber SD, Leber WR, Moyer J | display-authors = 6 | title = Patient predictors of response to psychotherapy and pharmacotherapy: findings in the NIMH Treatment of Depression Collaborative Research Program | journal = The American Journal of Psychiatry | volume = 148 | issue = 8 | pages = 997–1008 | date = August 1991 | pmid = 1853989 | doi = 10.1176/ajp.148.8.997 }}</ref> 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."<ref name="Kirsch08"/> 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.<ref>{{cite journal | vauthors = Turner EH, Rosenthal R | title = Efficacy of antidepressants | journal = BMJ | volume = 336 | issue = 7643 | pages = 516–517 | date = March 2008 | pmid = 18319297 | pmc = 2265347 | doi = 10.1136/bmj.39510.531597.80 }}</ref>

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 61% with medication alone and 43% with CBT alone.<ref name="EBSCO">{{cite journal | vauthors = Van Voorhees BW, Smith S, Ewigman B | title = Treat depressed teens with medication and psychotherapy | journal = The Journal of Family Practice | volume = 57 | issue = 11 | pages = 735–79a | date = November 2008 | pmid = 19006622 | pmc = 3183842 }}</ref> Similarly, TORDIA showed a 55% improvement with CBT and drugs versus a 41% with drug therapy alone.<ref name="EBSCO"/> However, a more recent meta-analysis of 34 trials of 14 drugs used with children and adolescents found that only fluoxetine produced significant benefit compared to placebo, with a medium-sized effect (standardize mean difference = .5).<ref>{{cite journal | vauthors = Cipriani A, Zhou X, Del Giovane C, Hetrick SE, Qin B, Whittington C, Coghill D, Zhang Y, Hazell P, Leucht S, Cuijpers P, Pu J, Cohen D, Ravindran AV, Liu Y, Michael KD, Yang L, Liu L, Xie P | display-authors = 6 | title = Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis | journal = Lancet | volume = 388 | issue = 10047 | pages = 881–890 | date = August 2016 | pmid = 27289172 | doi = 10.1016/S0140-6736(16)30385-3 | s2cid = 19728203 | hdl = 11380/1279478 | url = https://ora.ox.ac.uk/objects/uuid:e0b5ae23-d562-4348-94b8-84f70b7812c5 | hdl-access = free | access-date = 2020-11-30 | archive-date = 2021-10-27 | archive-url = https://web.archive.org/web/20211027013100/https://ora.ox.ac.uk/objects/uuid:e0b5ae23-d562-4348-94b8-84f70b7812c5 | url-status = live }}</ref>

The risk factors <ref>{{cite journal | vauthors = Serretti A, Fabbri C | title = Factors that predispose patients to treatment-resistant depression. | journal = Psychiatric Times | date = September 2014 | volume = 31 | issue = 9 | url = http://www.psychiatrictimes.com/special-reports/factors-predispose-patients-treatment-resistant-depression | access-date = 2018-04-25 | archive-date = 2018-04-25 | archive-url = https://web.archive.org/web/20180425053343/http://www.psychiatrictimes.com/special-reports/factors-predispose-patients-treatment-resistant-depression | url-status = live }}</ref> for treatment resistant depression are: the duration of the episode of depression, severity of the episode, if bipolar, lack of improvement in symptoms within the first couple of treatment weeks, anxious or avoidant and borderline comorbidity and old age. Treatment resistant depression is best handled with a combination of conventional antidepressant together with atypical antipsychotics. Another approach is to try different antidepressants. It's inconclusive which approach is superior. Treatment resistant depression can be misdiagnosed if subtherapeutic doses of antidepressants is the case, patient nonadherence, intolerable adverse effects or their thyroid disease or other conditions is misdiagnosed as depression.

[[Inositol]], a sugar alcohol in fruits, beans, grains and nuts, was found to be significantly better than placebo in treating depression in a double-blind, controlled trial. <ref>{{cite journal | vauthors = Levine J, Barak Y, Gonzalves M, Szor H, Elizur A, Kofman O, Belmaker RH | title = Double-blind, controlled trial of inositol treatment of depression | journal = The American Journal of Psychiatry | volume = 152 | issue = 5 | pages = 792–4 | date = May 1995 | pmid = 7726322 | doi = 10.1176/ajp.152.5.792 }}</ref> It was also reported to be reduced in human CSF in depression and found to lead to “major"major improvement”improvement" in 9 of 11 depressed patients in an open label trial. <ref>{{cite journal | vauthors = Levine J, Gonsalves M, Babur I, Stier S, Elizur A, Kofman O, Belmaker RH | title = Inositol 6 g daily may be effective in depression but not in schizophrenia. | journal = Human Psychopharmacology: Clinical and Experimental | date = January 1993 | volume = 8 | issue = 1 | pages = 49–53 | doi = 10.1002/hup.470080109 | s2cid = 144478254 }}</ref>

A 2020 meta-analysis showed that a high dose of omega-3 polyunsaturated fatty acid (>2g2&nbsp;g/day) used as an adjuvent improved depressive symptoms.<ref name="Luo Feng Yang Huang p.">{{cite journal | vauthors = Luo XD, Feng JS, Yang Z, Huang QT, Lin JD, Yang B, Su KP, Pan JY | display-authors = 6 | title = High-dose omega-3 polyunsaturated fatty acid supplementation might be more superior than low-dose for major depressive disorder in early therapy period: a network meta-analysis | journal = BMC Psychiatry | volume = 20 | issue = 1 | pages = 248 | date = May 2020 | pmid = 32434488 | pmc = 7238659 | doi = 10.1186/s12888-020-02656-3 | publisher = Springer Science and Business Media LLC | doi-access = free }}</ref>

Some research suggests [[Dopamine agonist|dopamine receptor agonists]], most commonly [[pramipexole]], may be effective in treating depression. Studies are few and results are preliminary, however.<ref>{{cite journal | vauthors = Dunlop BW, Nemeroff CB | title = The role of dopamine in the pathophysiology of depression | journal = Archives of General Psychiatry | volume = 64 | issue = 3 | pages = 327–337 | date = March 2007 | pmid = 17339521 | doi = 10.1001/archpsyc.64.3.327 | s2cid = 26550661 }}</ref>

[[Psilocybin]] has been shown in several studies to improve symptoms in people with treatment-resistant depression.<ref name="Daws 2022">{{cite journal | vauthors = Daws RE, Timmermann C, Giribaldi B, Sexton JD, Wall MB, Erritzoe D, Roseman L, Nutt D, Carhart-Harris R | display-authors = 6 | title = Increased global integration in the brain after psilocybin therapy for depression | journal = Nature Medicine | volume = 28 | issue = 4 | pages = 844–851 | date = April 2022 | pmid = 35411074 | doi = 10.1038/s41591-022-01744-z | s2cid = 248099554 | doi-access = free | hdl = 10044/1/95521 | hdl-access = free }}</ref> In 2018 and 2019, the FDA designated psilocybin as a "[[breakthrough therapy]]" for drug-resistant depression and major depressive disorder.<ref name="Marks 2021">{{cite web | vauthors = Marks M | title=A Strategy for Rescheduling Psilocybin | website=Scientific American | date=11 October 2021 | url= https://www.scientificamerican.com/article/a-strategy-for-rescheduling-psilocybin/ | access-date=13 August 2022 | archive-date=13 August 2022 | archive-url=https://web.archive.org/web/20220813043840/https://www.scientificamerican.com/article/a-strategy-for-rescheduling-psilocybin/ | url-status=live }}</ref>

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 effect]]s than standard antidepressants. The association of country of origin and precision with effects sizes complicates the interpretation."<ref name = Linde2008>{{cite journal | vauthors = Linde K, Berner MM, Kriston L | title = St John's wort for major depression | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD000448 | date = October 2008 | volume = 2008 | pmid = 18843608 | pmc = 7032678 | doi = 10.1002/14651858.CD000448.pub3 }}</ref> The United States [[National Center for Complementary and Integrative Health]] 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 drug|prescription medicines]]."<ref name = NCCIH>{{cite web |url= http://nccih.nih.gov/health/stjohnswort/sjw-and-depression.htm |title= St John's Wort and depression|access-date= January 25, 2014|date= 2011-11-21|archive-date= 2015-02-05|archive-url= https://web.archive.org/web/20150205235301/https://nccih.nih.gov/health/stjohnswort/sjw-and-depression.htm|url-status= live}}</ref>

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.<ref name="Ravindran">{{cite journal | vauthors = Ravindran AV, da Silva TL | title = Complementary and alternative therapies as add-on to pharmacotherapy for mood and anxiety disorders: a systematic review | journal = Journal of Affective Disorders | volume = 150 | issue = 3 | pages = 707–719 | date = September 2013 | pmid = 23769610 | doi = 10.1016/j.jad.2013.05.042 }}</ref> The safety of these medications has not been well studied.<ref name="Shaw_2010" /> Due to the lack of high quality studies, preliminary nature of studies showing effectiveness, the lack of adequate study on their safety, and reports of [[Eosinophilia–myalgiaeosinophilia–myalgia syndrome]] from contaminated tryptophan in 1989 and 1990,<ref name="Iovieno_2011" /> the use of tryptophan and 5-HTP is not highly recommended or thought to be clinically useful.<ref name="Shaw_2010" /><ref name="Ravindran" />

A variety of medical devices are in use or under consideration for treatment of depression including devices that offer electroconvulsive therapy, [[vagus nerve stimulation]], [[repetitive transcranial magnetic stimulation]], and [[cranial electrotherapy stimulation]]. The use of such devices in the United States requires approval by the U.S. [[Food and Drug Administration]] (FDA) after field trials. In 2010 an 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.<ref>{{cite web | url = http://www.medpagetoday.com/Psychiatry/Depression/22648 | title = FDA Panel Looks at Trials of Devices to Treat Depression | vauthors = Walker EP | location = Washington | publisher = MedPage Today | date = 8 October 2010 | access-date = 9 October 2010 | archive-date = 12 October 2010 | archive-url = https://web.archive.org/web/20101012155129/http://www.medpagetoday.com/Psychiatry/Depression/22648 | url-status = live }}</ref>

[[Electroconvulsive therapy]] (ECT) is a standard [[psychiatry|psychiatric]] treatment in which [[seizure]]s are electrically induced in patients to provide relief from psychiatric illnesses.<ref name="Rudorfer">{{cite book | vauthors = Rudorfer MV, Henry ME, Sackeim HA | date = 2003 | chapter-url = http://media.wiley.com/assets/138/93/UK_Tasman_Chap92.pdf | chapter = Electroconvulsive therapy | veditors = Tasman A, Kay J, Lieberman JA | title = Psychiatry | edition = Second | location = Chichester | publisher = John Wiley & Sons Ltd | pages = 1865–1901 | access-date = 2013-11-03 | archive-date = 2007-08-10 | archive-url = https://web.archive.org/web/20070810172506/http://media.wiley.com/assets/138/93/UK_Tasman_Chap92.pdf | url-status = live }}</ref>{{rp|1880}} ECT is used with [[informed consent]]<ref name =Beloucif>{{cite journal | vauthors = Beloucif S | title = Informed consent for special procedures: electroconvulsive therapy and psychosurgery | journal = Current Opinion in Anesthesiology | volume = 26 | issue = 2 | pages = 182–5 | date = April 2013 | pmid = 23385317 | doi = 10.1097/ACO.0b013e32835e7380 | s2cid = 36643014 }}</ref> as a last line of intervention for major depressive disorder.<ref name=FDA2011rev>{{cite web | publisher = U.S. Food and Drug Administration | url = https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/NeurologicalDevicesPanel/UCM240933.pdf | title = FDA Executive Summary. | quote = Prepared for the January 27–28, 2011 meeting of the Neurological Devices Panel Meeting to Discuss the Classification of Electroconvulsive Therapy Devices (ECT). Quote, p38: "Three major practice guidelines have been published on ECT. These guidelines include: APA Task Force on ECT (2001); Third report of the Royal College of Psychiatrists' Special Committee on ECT (2004); National Institute for Health and Clinical Excellence (NICE 2003; NICE 2009). There is significant agreement between the three sets of recommendations." | access-date = 2019-12-16 | archive-date = 2015-09-24 | archive-url = https://web.archive.org/web/20150924161659/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/NeurologicalDevicesPanel/UCM240933.pdf | url-status = live }}</ref> Among the elderly, who often experience depression, the efficacy of ECT is difficult to determine due to the lack of trials comparing ECT to other treatments.<ref>{{cite journal | vauthors = Van der Wurff FB, Stek ML, Hoogendijk WL, Beekman AT | title = Electroconvulsive therapy for the depressed elderly | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD003593 | date = 2003 | volume = 2015 | pmid = 12804479 | doi = 10.1002/14651858.CD003593 | pmc = 8722425 }}</ref>

Aside from effects in the brain, the general physical risks of ECT are similar to those of brief [[general anesthesia]].<ref name="SG">{{cite book | author = Surgeon General | date = 1999 | url = http://www.surgeongeneral.gov/library/mentalhealth/home.html | title = Mental Health: A Report of the Surgeon General | chapter = Chapter 4 | access-date = 2015-01-07 | archive-date = 2007-01-12 | archive-url = https://web.archive.org/web/20070112012907/http://www.surgeongeneral.gov/library/mentalhealth/home.html | url-status = live }}</ref>{{rp|259}} Immediately following treatment, the most common adverse effects are confusion and memory loss.<ref name=FDA2011rev/><ref name="APA2001guideline">{{cite book | author = American Psychiatric Association |title=The practice of electroconvulsive therapy: recommendations for treatment, training, and privileging |edition=2nd |location=Washington, DC |publisher=American Psychiatric Publishing |year=2001 |url= https://books.google.com/books?id=iuuLJtmo_EYC |isbn=978-0-89042-206-9 |collaboration = Committee on Electroconvulsive Therapy | veditors = Weiner RD |access-date=2016-09-24 |archive-date=2024-02-24 |archive-url=https://web.archive.org/web/20240224184824/https://books.google.com/books?id=iuuLJtmo_EYC |url-status=live }}</ref> ECT is considered one of the least harmful treatment options available for severely depressed pregnant women.<ref name=Pompili2014Rev>{{cite journal | vauthors = Pompili M, Dominici G, Giordano G, Longo L, Serafini G, Lester D, Amore M, Girardi P | title = Electroconvulsive treatment during pregnancy: a systematic review | journal = Expert Review of Neurotherapeutics | volume = 14 | issue = 12 | pages = 1377–90 | date = December 2014 | pmid = 25346216 | doi = 10.1586/14737175.2014.972373 | s2cid = 31209001 }}</ref>

A usual course of ECT involves multiple administrations, typically given two or three times per week until the patient no longer has symptoms ECT is administered under anesthetic with a muscle relaxant.<ref>{{Cite web | url=http://psychcentral.com/lib/5-outdated-beliefs-about-ect/00011255 | title=5 Outdated Beliefs About ECT| date=2016-05-17| access-date=2013-11-03| archive-date=2013-08-08| archive-url=https://web.archive.org/web/20130808042410/http://psychcentral.com/lib/5-outdated-beliefs-about-ect/00011255| url-status=dead}}</ref>{{ums|date=November 2017}} 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.<ref name=FDA2011rev/>

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.<ref name="APS">{{cite journal | vauthors = Marangell LB, Martinez M, Jurdi RA, Zboyan H | title = Neurostimulation therapies in depression: a review of new modalities | journal = Acta Psychiatrica Scandinavica | volume = 116 | issue = 3 | pages = 174–81 | date = September 2007 | pmid = 17655558 | doi = 10.1111/j.1600-0447.2007.01033.x | s2cid = 38081703 }}</ref> In this technique electrodes are implanted in a specific region of the brain, which is then continuously stimulated.<ref>{{cite journal | vauthors = Underwood E | title = Short-circuiting depression | journal = Science | volume = 342 | issue = 6158 | pages = 548–51 | date = November 2013 | pmid = 24179199 | doi = 10.1126/science.342.6158.548 | bibcode = 2013Sci...342..548U }}</ref> 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.<ref>{{cite journal | vauthors = Lakhan SE, Callaway E | title = Deep brain stimulation for obsessive-compulsive disorder and treatment-resistant depression: systematic review | journal = BMC Research Notes | volume = 3 | pages = 60 | date = March 2010 | pmid = 20202203 | pmc = 2838907 | doi = 10.1186/1756-0500-3-60 | doi-access = free }}</ref> Deep brain stimulation is available on an experimental basis only in the United States; no systems are approved by the FDA for this use.<ref>{{cite web | work = National Institute of Mental Health | publisher = U.S. Department of Health and Human Services | url = http://www.nimh.nih.gov/health/topics/brain-stimulation-therapies/brain-stimulation-therapies.shtml | title = Brain Stimulation Therapies | access-date = 2013-11-21 | archive-date = 2013-11-13 | archive-url = https://web.archive.org/web/20131113181852/http://www.nimh.nih.gov/health/topics/brain-stimulation-therapies/brain-stimulation-therapies.shtml | url-status = live }}</ref>

[[Transcranial magnetic stimulation]] (TMS) or [[deep transcranial magnetic stimulation]] is a noninvasive method used to stimulate small regions of the brain. During a TMS procedure, a magnetic field generator, or "coil" is placed near the head of the person receiving the treatment.<ref name=NICE2014>{{cite web | work = NiCE | date = January 2014 | url = http://www.nice.org.uk/guidance/ipg477/resources/guidance-transcranial-magnetic-stimulation-for-treating-and-preventing-migraine-pdf | title = Transcranial magnetic stimulation for treating and preventing migraine | archive-url = https://web.archive.org/web/20151004194631/http://www.nice.org.uk/guidance/ipg477/resources/guidance-transcranial-magnetic-stimulation-for-treating-and-preventing-migraine-pdf |archive-date=2015-10-04 }}</ref>{{rp|3}} The coil produces small electric currents in the region of the brain just under the coil via [[electromagnetic induction]]. The coil is connected to a pulse generator, or stimulator, that delivers electric current to the coil.<ref name=Harvard>{{cite web | vauthors = Miller MC | work = Harvard Health Publications | date = 26 July 2012 | url = http://www.health.harvard.edu/blog/magnetic-stimulation-a-new-approach-to-treating-depression-201207265064 | title = Magnetic stimulation: a new approach to treating depression? | access-date = 2 January 2015 | archive-date = 29 October 2017 | archive-url = https://web.archive.org/web/20171029175601/https://www.health.harvard.edu/blog/magnetic-stimulation-a-new-approach-to-treating-depression-201207265064 | url-status = live }}</ref>

TMS was approved by the FDA for treatment-resistant [[major depressive disorder]] in 2008<ref name="Melkerson">{{cite web|url=http://www.accessdata.fda.gov/cdrh_docs/pdf8/K083538.pdf|date=2008-12-16|access-date=2010-07-16 |publisher=[[Food and Drug Administration]]| vauthors = Melkerson MN |title= Special Premarket 510(k) Notification for NeuroStar® TMS Therapy System for Major Depressive Disorder|archive-date=2010-03-31|archive-url=https://web.archive.org/web/20100331000421/http://www.accessdata.fda.gov/cdrh_docs/pdf8/K083538.pdf|url-status=live}}</ref> and as of 2014 clinical evidence supports this use.<ref name=Lefaucher1>{{cite journal | vauthors = Lefaucheur JP, André-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, Cantello RM, Cincotta M, de Carvalho M, De Ridder D, Devanne H, Di Lazzaro V, Filipović SR, Hummel FC, Jääskeläinen SK, Kimiskidis VK, Koch G, Langguth B, Nyffeler T, Oliviero A, Padberg F, Poulet E, Rossi S, Rossini PM, Rothwell JC, Schönfeldt-Lecuona C, Siebner HR, Slotema CW, Stagg CJ, Valls-Sole J, Ziemann U, Paulus W, Garcia-Larrea L | title = Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) | journal = Clinical Neurophysiology | volume = 125 | issue = 11 | pages = 2150–2206 | date = November 2014 | pmid = 25034472 | doi = 10.1016/j.clinph.2014.05.021 | s2cid = 206798663 | url = https://hal.archives-ouvertes.fr/hal-03183867/file/S1388245719312799.pdf | access-date = 2022-07-26 | archive-date = 2022-07-23 | archive-url = https://web.archive.org/web/20220723015843/https://hal.archives-ouvertes.fr/hal-03183867/file/S1388245719312799.pdf | url-status = live }}</ref><ref name=AHRQ>{{cite journal | vauthors = George MS, Post RM | title = Daily left prefrontal repetitive transcranial magnetic stimulation for acute treatment of medication-resistant depression | journal = The American Journal of Psychiatry | volume = 168 | issue = 4 | pages = 356–64 | date = April 2011 | pmid = 21474597 | doi = 10.1176/appi.ajp.2010.10060864 }}<br>(6) {{cite web| vauthors = Gaynes BN, Lux L, Lloyd S, Hansen RA, Gartlehner G, Thieda P, Brode S, Swinson Evans T, Jonas D, Crotty K, Viswanathan M, Lohr KN |archive-url = https://web.archive.org/web/20120516114514/http://www.effectivehealthcare.ahrq.gov/ehc/products/76/792/TRD_CER33_20111110.pdf |archive-date=2012-1005-1116 |url=http://www.effectivehealthcare.ahrq.gov/ehc/products/76/792/TRD_CER33_20111110.pdf |title=Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults. Comparative Effectiveness Review Number 33. (Prepared by RTI International-University of North Carolina (RTI-UNC) Evidence-based Practice Center) |work=AHRQ Publication No. 11-EHC056-EF |page=36 |location=[[Rockville, Maryland]] |publisher=[[Agency for Healthcare Research and Quality]] |date=September 2011 |access-date=2011-10-11 |url-status=dead }}</ref> The American Psychiatric Association,<ref>{{cite web | work = American Psychiatric Association | date = 2010 | veditors = Gelenberg AJ, Freeman MP, Markowitz JC, Rosenbaum JF, Thase ME, Trivedi MH, Van Rhoads RS | url = http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf | title = Practice Guidelines for the Treatment of Patients with Major Depressive Disorder | edition = 3rd | access-date = 2015-01-02 | archive-date = 2017-06-23 | archive-url = https://web.archive.org/web/20170623014506/http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf | url-status = live }}</ref>{{rp|46}} the Canadian Network for Mood and Anxiety Disorders,<ref>{{cite journal | vauthors = Kennedy SH, Lam RW, Parikh SV, Patten SB, Ravindran AV | title = Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. Introduction | journal = Journal of Affective Disorders | volume = 117 | issue = Suppl 1 | pages = S1-2 | date = October 2009 | pmid = 19682750 | doi = 10.1016/j.jad.2009.06.043 | url = http://www.canmat.org/resources/CANMAT%20Depression%20Guidelines%202009.pdf | archive-url = https://web.archive.org/web/20150823230409/http://www.canmat.org/resources/canmat%20depression%20guidelines%202009.pdf | url-status = dead | archive-date = 2015-08-23 }}</ref> and the Royal Australia and New Zealand College of Psychiatrists have endorsed rTMS for trMDD.<ref>{{cite web | publisher = The Royal Australian and New Zealand College of Psychiatrists. | date = 2013 | url = https://www.ranzcp.org/Files/Resources/College_Statements/Position_Statements/PS-79-PPC-Repetitive-Transcranial-Magnetic-Stimula.aspx | title = Position Statement 79. Repetitive Transcranial Magnetic Stimulation. | author = Practice and Partnerships Committee | access-date = 2015-01-02 | archive-date = 2017-08-29 | archive-url = https://web.archive.org/web/20170829114850/https://www.ranzcp.org/Files/Resources/College_Statements/Position_Statements/PS-79-PPC-Repetitive-Transcranial-Magnetic-Stimula.aspx | url-status = live }}</ref>

The response rate is about 29% for TRD patients.<ref name="Cheng Li Tsai 2021 pp. 333–349">{{cite book | vauthors = Cheng CM, Li CT, Tsai SJ | series=Advances in Experimental Medicine and Biology | title=Major Depressive Disorder | chapter=Current Updates on Newer Forms of Transcranial Magnetic Stimulation in Major Depression | journal=Advances in Experimental Medicine and Biology | publisher=Springer Singapore | publication-place=Singapore | volume=1305 | year=2021 | isbn=978-981-336-043-3 | issn=0065-2598 | pmid=33834408 | doi=10.1007/978-981-33-6044-0_18 | pages=333–349| s2cid=233194002 }}</ref> Remission rate is about 20%.<ref name="Psychiatry p.">{{cite book | veditors = Tasman A, Kay J, Lieberman JA, First MB, Riba MB | title=Psychiatry | publisher=John Wiley & Sons, Ltd | publication-place=Chichester, UK | date=2015-03-23 | isbn=978-1-118-75337-8 | doi=10.1002/9781118753378 | page=}}</ref>

[[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.<ref name="APS"/> 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."<ref>{{cite journal | vauthors = Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK, Davis SM, Howland R, Kling MA, Rittberg BR, Burke WJ, Rapaport MH, Zajecka J, Nierenberg AA, Husain MM, Ginsberg D, Cooke RG | title = Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial | journal = Biological Psychiatry | volume = 58 | issue = 5 | pages = 347–54 | date = September 2005 | pmid = 16139580 | doi = 10.1016/j.biopsych.2005.05.025 | s2cid = 22066326 | url = http://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1069&context=veterans | access-date = 2019-07-14 | archive-date = 2019-02-27 | archive-url = https://web.archive.org/web/20190227104329/http://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1069&context=veterans | url-status = live }}</ref>

A 2014 Cochrane review found insufficient evidence to determine whether or not [[Cranial electrotherapy stimulation]] with alternating current is safe and effective for treating depression.<ref name=Kavirajan>{{cite journal | vauthors = Kavirajan HC, Lueck K, Chuang K | title = Alternating current cranial electrotherapy stimulation (CES) for depression | journal = The Cochrane Database of Systematic Reviews | volume = 72014 | issue = 7 | pages = CD010521 | date = July 2014 | pmid = 25000907 | doi = 10.1002/14651858.CD010521.pub2 | doi-access = free | pmc = 10554095 }}</ref>

A 2016 meta-analysis of [[Transcranial direct-current stimulation|transcranial direct current stimulation]] (tDCS) reported some efficacy of tDCS in the treatment of acute depressive disorder with moderate effect size, and low efficacy in treatment-resistant depression, and that use of 2 &nbsp;mA current strength over 20 minminutes per day over a short time span can be considered safe.<ref>{{cite journal | vauthors = Palm U, Hasan A, Strube W, Padberg F | title = tDCS for the treatment of depression: a comprehensive review | journal = European Archives of Psychiatry and Clinical Neuroscience | volume = 266 | issue = 8 | pages = 681–694 | date = December 2016 | pmid = 26842422 | doi = 10.1007/s00406-016-0674-9 | s2cid = 1104287 }}</ref>

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.<ref>{{cite journal | vauthors = Golden RN, Gaynes BN, Ekstrom RD, Hamer RM, Jacobsen FM, [[Trisha Suppes|Suppes T]], Wisner KL, Nemeroff CB | display-authors = 6 | title = The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence | journal = The American Journal of Psychiatry | volume = 162 | issue = 4 | pages = 656–662 | date = April 2005 | pmid = 15800134 | doi = 10.1176/appi.ajp.162.4.656 }}</ref> 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.<ref>{{cite journal | vauthors = Tuunainen A, Kripke DF, Endo T | title = Light therapy for non-seasonal depression | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD004050 | year = 2004 | volume = 2004 | pmid = 15106233 | pmc = 6669243 | doi = 10.1002/14651858.CD004050.pub2 | editor1-last = Tuunainen | editor1-first = Arja }}</ref> 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.

The 2013 Cochrane Collaboration review on [[physical exercise]] for depression noted that, based upon limited evidence, it is moderately more effective than a control intervention and comparable to psychological or antidepressant drug therapies. Smaller effects were seen in more methodologically rigorous studies.<ref name="Cochrane exercise depression">{{cite journal | vauthors = Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE | display-authors = 6 | title = Exercise for depression | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 9 | pages = CD004366 | date = September 2013 | pmid = 24026850 | doi = 10.1002/14651858.CD004366.pub6 | pmc = 9721454 | quote = Exercise is moderately more effective than a control intervention for reducing symptoms of depression, but analysis of methodologically robust trials only shows a smaller effect in favour of exercise. When compared to psychological or pharmacological therapies, exercise appears to be no more effective, though this conclusion is based on a few small trials. }}</ref> Three subsequent 2014 systematic reviews that included the Cochrane review in their analysis concluded with similar findings: one indicated that physical exercise is effective as an [[wikt:adjunct treatment|adjunct treatment]] with antidepressant medication;<ref name="Exercise MDD antidepressant">{{cite journal | vauthors = Mura G, Moro MF, Patten SB, Carta MG | title = Exercise as an add-on strategy for the treatment of major depressive disorder: a systematic review | journal = CNS Spectrums | volume = 19 | issue = 6 | pages = 496–508 | date = December 2014 | pmid = 24589012 | doi = 10.1017/S1092852913000953 | quote = Considered overall, the studies included in the present review showed a strong effectiveness of exercise combined with antidepressants.&nbsp;... Conclusions<br /> This is the first review to have focused on exercise as an add-on strategy in the treatment of MDD. Our findings corroborate some previous observations that were based on few studies and which were difficult to generalize.^{41,51,73,92,93} Given the results of the present article, it seems that exercise might be an effective strategy to enhance the antidepressant effect of medication treatments. Moreover, we hypothesize that the main role of exercise on treatment-resistant depression is in inducing neurogenesis by increasing BDNF expression, as was demonstrated by several recent studies. | s2cid = 32304140 }}</ref> the other two indicated that physical exercise has marked antidepressant effects and recommended the inclusion of physical activity as an adjunct treatment for mild–moderate depression<ref name="Exercise depression intervention">{{cite journal | vauthors = Josefsson T, Lindwall M, Archer T | title = Physical exercise intervention in depressive disorders: meta-analysis and systematic review | journal = Scandinavian Journal of Medicine & Science in Sports | volume = 24 | issue = 2 | pages = 259–272 | date = April 2014 | pmid = 23362828 | doi = 10.1111/sms.12050 | quote = Physical activity has also become increasingly and firmly associated with improvements in mental health and psychological well-being (Mutrie, 2000; Landers & Arent, 2007). In particular, exercise is believed to be effective in preventing depression and also to significantly reduce depressive symptoms in clinical as well as in nonclinical populations (O'Neal et al., 2000; Landers & Arent, 2007). Several correlational studies show that exercise is negatively related to depressive symptoms (e.g., Galper et al., 2006; Hassmén et al., 2000). Moreover, a considerably large number of intervention studies have by now investigated the effect of various exercise programs on depression and the vast majority of them indicate that exercise significantly reduces depression (e.g., Blumenthal et al., 2007; Martinsen et al., 1985; Singh et al., 1997).&nbsp;... To date, it is not possible to determine exactly how effective exercise is in reducing depression symptoms in clinical and nonclinical depressed populations, respectively. However, the results from the present meta-analysis as well as from seven earlier meta-analyses (North et al., 1990; Craft & Landers, 1998; Lawlor & Hopker, 2001; Stathopoulou et al., 2006; Mead et al., 2009; Rethorst et al., 2009; Krogh et al., 2011) indicate that exercise has a moderate to large antidepressant effect. Some meta-analytic results (e.g., Rethorst et al., 2009) suggest that exercise may be even more efficacious for clinically depressed people.&nbsp;... In short, our final conclusion is that exercise may well be recommended for people with mild and moderate depression who are willing, motivated, and physically healthy enough to engage in such a program. | s2cid = 29351791 | doi-access = free }}</ref> and mental illness in general. These studies also found smaller effect sizes in more methodologically rigorous studies.<ref name="Physical activity intervention">{{cite journal | vauthors = Rosenbaum S, Tiedemann A, Sherrington C, Curtis J, Ward PB | title = Physical activity interventions for people with mental illness: a systematic review and meta-analysis | journal = The Journal of Clinical Psychiatry | volume = 75 | issue = 9 | pages = 964–974 | date = September 2014 | pmid = 24813261 | doi = 10.4088/JCP.13r08765 | quote = This systematic review and meta-analysis found that physical activity reduced depressive symptoms among people with a psychiatric illness. The current meta-analysis differs from previous studies, as it included participants with depressive symptoms with a variety of psychiatric diagnoses (except dysthymia and eating disorders).&nbsp;... This review provides strong evidence for the antidepressant effect of physical activity; however, the optimal exercise modality, volume, and intensity remain to be determined.&nbsp;... Conclusion<br /> Few interventions exist whereby patients can hope to achieve improvements in both psychiatric symptoms and physical health simultaneously without significant risks of adverse effects. Physical activity offers substantial promise for improving outcomes for people living with mental illness, and the inclusion of physical activity and exercise programs within treatment facilities is warranted given the results of this review. }}</ref> All four systematic reviews called for more research in order to determine the efficacy or optimal exercise intensity, duration, and modality.<ref name="Cochrane exercise depression" /><ref name="Exercise MDD antidepressant" /><ref name="Exercise depression intervention" /><ref name="Physical activity intervention" /> The evidence for [[brain-derived neurotrophic factor]] (BDNF) in mediating some of the [[neurobiological effects of physical exercise]]<ref name="epigenome">{{cite journal | vauthors = Denham J, Marques FZ, O'Brien BJ, Charchar FJ | title = Exercise: putting action into our epigenome | journal = Sports Medicine | volume = 44 | issue = 2 | pages = 189–209 | date = February 2014 | pmid = 24163284 | doi = 10.1007/s40279-013-0114-1 | quote = Aerobic physical exercise produces numerous health benefits in the brain. Regular engagement in physical exercise enhances cognitive functioning, increases brain neurotrophic proteins, such as brain-derived neurotrophic factor (BDNF), and prevents cognitive diseases [76–78]. Recent findings highlight a role for aerobic exercise in modulating chromatin remodelers [21, 79–82].&nbsp;... These results were the first to demonstrate that acute and relatively short aerobic exercise modulates epigenetic modifications. The transient epigenetic modifications observed due to chronic running training have also been associated with improved learning and stress-coping strategies, epigenetic changes and increased c-Fos-positive neurons&nbsp;... Nonetheless, these studies demonstrate the existence of epigenetic changes after acute and chronic exercise and show they are associated with improved cognitive function and elevated markers of neurotrophic factors and neuronal activity (BDNF and c-Fos).&nbsp;... The aerobic exercise training-induced changes to miRNA profile in the brain seem to be intensity-dependent [164]. These few studies provide a basis for further exploration into potential miRNAs involved in brain and neuronal development and recovery via aerobic exercise. | s2cid = 30210091 }}</ref><ref name="trophic factor signaling">{{cite journal | vauthors = Phillips C, Baktir MA, Srivatsan M, Salehi A | title = Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling | journal = Frontiers in Cellular Neuroscience | volume = 8 | pages = 170 | year = 2014 | pmid = 24999318 | pmc = 4064707 | doi = 10.3389/fncel.2014.00170 | quote = Moreover, recent evidence suggests that myokines released by exercising muscles affect the expression of brain-derived neurotrophic factor synthesis in the dentate gyrus of the hippocampus, a finding that could lead to the identification of new and therapeutically important mediating factors.&nbsp;... Studies have demonstrated the intensity of exercise training is positively correlated with BDNF plasma levels in young, healthy individuals (Ferris et al., 2007). Resistance exercise has also been shown to elevate serum BDNF levels in young individuals (Yarrow et al., 2010). Moreover, it has been shown that moderate levels of physical activity in people with AD significantly increased plasma levels of BDNF (Coelho et al., 2014).&nbsp;... In humans, it has been shown that 4 h of rowing activity leads to increased levels of plasma BDNF from the internal jugular (an indicator of central release from the brain) and radial artery (an indicator of peripheral release; Rasmussen et al., 2009). Seifert et al. (2010) reported that basal release of BDNF increases following 3 months endurance training in young and healthy individuals, as measured from the jugular vein. These trends are augmented by rodent studies showing that endurance training leads to increased synthesis of BDNF in the hippocampal formation (Neeper et al., 1995, 1996).&nbsp;... Both BDNF and IGF-1 play a significant role in cognition and motor function in humans.&nbsp;... Multiple large-scale studies in humans have shown that serum levels of IGF-1 are correlated with fitness and as well as body mass indices (Poehlman and Copeland, 1990). Furthermore, animal studies have shown that exercise in rats is associated with increased amounts of IGF-1 in the CSF. | doi-access = free }}</ref><ref name="Organ response">{{cite journal | vauthors = Heinonen I, Kalliokoski KK, Hannukainen JC, Duncker DJ, Nuutila P, Knuuti J | title = Organ-specific physiological responses to acute physical exercise and long-term training in humans | journal = Physiology | volume = 29 | issue = 6 | pages = 421–436 | date = November 2014 | pmid = 25362636 | doi = 10.1152/physiol.00067.2013 | quote = The Effects of Long-Term Exercise Training<br /> [A] physically active lifestyle has been shown to lead to higher cognitive performance and delayed or prevented neurological conditions in humans (71, 101, 143, 191).&nbsp;... The production of brain-derived neurotrophic factor (BDNF), a key protein regulating maintenance and growth of neurons, is known to be stimulated by acute exercise (145), which may contribute to learning and memory. BDNF is released from the brain already at rest but increases two- to threefold during exercise, which contributes 70–80% of circulating BDNF (145). }}</ref> was noted in one review which hypothesized that increased [[BDNF]] signaling is responsible for the antidepressant effect.<ref name="Exercise MDD antidepressant" /> A [[meta-analysis]] of 15 studies published in 2022 suggested a curvilinear dose-response relationship between exercise and depression risk, with low levels of exercise showing the best dose-response.<ref>{{cite journal | vauthors = Pearce M, Garcia L, Abbas A, Strain T, Schuch FB, Golubic R, Kelly P, Khan S, Utukuri M, Laird Y, Mok A, Smith A, Tainio M, Brage S, Woodcock J | display-authors = 6 | title = Association Between Physical Activity and Risk of Depression: A Systematic Review and Meta-analysis | journal = JAMA Psychiatry | volume = 79 | issue = 6 | pages = 550–559 | date = June 2022 | pmid = 35416941 | pmc = 9008579 | doi = 10.1001/jamapsychiatry.2022.0609 }}</ref>

Depression is sometimes associated with [[insomnia]] - (difficulty in falling asleep, early waking, or 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.<ref>{{cite web |url=http://www.nice.org.uk/nicemedia/pdf/CG023NICEguideline.pdf | archive-url = https://web.archive.org/web/20120210002212/http://www.nice.org.uk/nicemedia/pdf/CG023NICEguideline.pdf | archive-date = 10 February 2012 | work = National Collaborating Centre for Mental Health | location = London | publisher = National Institute for Clinical Excellence (NICE) |title=Depression: Management of depression in primary and secondary care, Clinical Guideline 23 | date = December 2004 }}</ref> It would include measures such as regular sleep routines, avoidance of [[stimulant]]s such as [[caffeine]] and management of sleeping disorders such as [[sleep apnea]].<ref>{{cite journal | vauthors = Wirz-Justice A, Benedetti F, Berger M, Lam RW, Martiny K, Terman M, Wu JC | title = Chronotherapeutics (light and wake therapy) in affective disorders | journal = Psychological Medicine | volume = 35 | issue = 7 | pages = 939–944 | date = July 2005 | pmid = 16045060 | doi = 10.1017/S003329170500437X | doi-access = free }}</ref>

[[Sleep deprivation]] (skipping a night's sleep) has been found to improve symptoms of depression in 40% - 6040–60% 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%-8050–80%) 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.<ref>{{cite journal | vauthors = Giedke H, Schwärzler F | title = Therapeutic use of sleep deprivation in depression | journal = Sleep Medicine Reviews | volume = 6 | issue = 5 | pages = 361–377 | date = October 2002 | pmid = 12531127 | doi = 10.1053/smrv.2002.0235 }}</ref>

[[Psilocybin]] may have a beneficial role in the treatment of depression.<ref>{{cite journal | vauthors = Goldberg SB, Pace BT, Nicholas CR, Raison CL, Hutson PR | title = The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis | journal = Psychiatry Research | volume = 284 | pages = 112749 | date = February 2020 | pmid = 31931272 | doi = 10.1016/j.psychres.2020.112749 | s2cid = 209527316 }}</ref><ref>{{cite journal | vauthors = Vargas AS, Luís Â, Barroso M, Gallardo E, Pereira L | title = Psilocybin as a New Approach to Treat Depression and Anxiety in the Context of Life-Threatening Diseases-A Systematic Review and Meta-Analysis of Clinical Trials | journal = Biomedicines | volume = 8 | issue = 9 | page = 331 | date = September 2020 | pmid = 32899469 | pmc = 7554922 | doi = 10.3390/biomedicines8090331 | doi-access = free }}</ref>

* {{Commons category-inline|Treatment of depression}}