Editing Major depressive disorder (section)

===Other medications and supplements===
The combined use of antidepressants plus [[benzodiazepine]]s demonstrates improved effectiveness when compared to antidepressants alone, but these effects may not endure. The addition of a benzodiazepine is balanced against possible harms and other alternative treatment strategies when antidepressant mono-therapy is considered inadequate.<ref name=Ogawa2019>{{cite journal | vauthors = Ogawa Y, Takeshima N, Hayasaka Y, et al| title = Antidepressants plus benzodiazepines for adults with major depression | journal = The Cochrane Database of Systematic Reviews | volume = 6 | pages = CD001026 | date = June 2019 | issue = 6 | pmid = 31158298 | pmc = 6546439 | doi = 10.1002/14651858.CD001026.pub2 }}</ref><!-- cites paragraph -->

For treatment-resistant depression, adding on the [[atypical antipsychotic]] [[brexpiprazole]] for short-term or acute management may be considered.<ref name=Ralovska2023>{{Cite journal |vauthors= Ralovska S, Koyvhev I, Marinov P, Furukawa TA, Mulsant B, Cipriani A |date=July 2023 | collaboration = Cochrane Common Mental Disorders Group |title= Brexpiprazole versus placebo or other antidepressive agents for treating depression  |journal=Cochrane Database of Systematic Reviews|volume=2023 |issue=7 |pages=CD013866 |doi=10.1002/14651858.CD013866.pub2 |pmc=10406422}}</ref> Brexpiprazole may be effective for some people, however, the evidence as of 2023 supporting its use is weak and this medication has potential adverse effects including weight gain and [[akathisia]].<ref name=Ralovska2023/> Brexpiprazole has not been sufficiently studied in older people or children and the use and effectiveness of this [[Adjunctive therapy|adjunctive]] therapy for longer term management is not clear.<ref name=Ralovska2023/>

[[Ketamine]] may have a rapid antidepressant effect lasting less than two weeks; there is limited evidence of any effect after that, common acute side effects, and longer-term studies of safety and adverse effects are needed.<ref>{{cite journal |vauthors=Corriger A, Pickering G |title=Ketamine and depression: a narrative review |journal=Drug Des Devel Ther |volume=13 |issue= |pages=3051–3067 |date=2019 |pmid=31695324 |pmc=6717708 |doi=10.2147/DDDT.S221437 |doi-access=free }}</ref><ref>{{cite journal |vauthors=Krystal JH, Abdallah CG, Sanacora G, Charney DS, Duman RS |title=Ketamine: A Paradigm Shift for Depression Research and Treatment |journal=Neuron |volume=101 |issue=5 |pages=774–778 |date=March 2019 |pmid=30844397 |pmc=6560624 |doi=10.1016/j.neuron.2019.02.005 }}</ref> A nasal spray form of [[esketamine]] was approved by the FDA in March 2019 for use in treatment-resistant depression when combined with an oral antidepressant; risk of substance use disorder and concerns about its safety, serious adverse effects, tolerability, effect on suicidality, lack of information about dosage, whether the studies on it adequately represent broad populations, and escalating use of the product have been raised by an international panel of experts.<ref>{{cite journal |vauthors=McIntyre RS, Rosenblat JD, Nemeroff CB, et al |title=Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation |journal=Am J Psychiatry |volume=178 |issue=5 |pages=383–399 |date=May 2021 |pmid=33726522 |doi=10.1176/appi.ajp.2020.20081251 |pmc=9635017 |s2cid=232262694 }}</ref><ref>{{cite journal |vauthors=Bahr R, Lopez A, Rey JA |title=Intranasal Esketamine (SpravatoTM) for Use in Treatment-Resistant Depression In Conjunction With an Oral Antidepressant |journal=P T |volume=44 |issue=6 |pages=340–375 |date=June 2019 |pmid=31160868 |pmc=6534172 }}</ref>

[[Nonsteroidal anti-inflammatory drug]]s (NSAIDs) and cytokine inhibitors may be effective in treating depression. For instance, [[celecoxib]], an NSAID, is a selective COX-2 inhibitor– which is an enzyme that helps in the production of pain and inflammation.<ref>{{Cite web |date=24 May 2022 |title=COX-2 Inhibitors |url=https://my.clevelandclinic.org/health/drugs/23119-cox-2-inhibitors |access-date= 23 June 2024 |website=Cleveland Clinic}}</ref> In recent clinical trials, this NSAID has been shown helpful with treatment-resistant depression as it helps inhibit proinflammatory signaling.<ref name="pmid37240605">{{cite journal |vauthors=Gędek A, Szular Z, Antosik AZ, Mierzejewski P, Dominiak M |title=Celecoxib for Mood Disorders: A Systematic Review and Meta-Analysis of Randomized Controlled Trials |journal=Journal of Clinical Medicine |volume=12 |issue=10 |date=May 2023 |page=3497 |pmid=37240605 |pmc=10218898 |doi=10.3390/jcm12103497|doi-access=free }}</ref><ref>{{cite journal | vauthors = Beckett CW, Niklison-Chirou MV | title = The role of immunomodulators in treatment-resistant depression: case studies | journal = Cell Death Discovery | volume = 8 | issue = 1 | pages = 367 | date = August 2022 | pmid = 35977923 | pmc = 9385739 | doi = 10.1038/s41420-022-01147-6 }}</ref>

[[Statin]]s, which are anti-inflammatory medications prescribed to lower cholesterol levels, have also been shown to have antidepressant effects. When prescribed for patients already taking SSRIs, this add-on treatment was shown to improve anti-depressant effects of SSRIs when compared to the placebo group. With this, statins have been shown to be effective in preventing depression in some cases too.<ref>{{cite journal | vauthors = Gutlapalli SD, Farhat H, Irfan H, Muthiah K, Pallipamu N, Taheri S, Thiagaraj SS, Shukla TS, Giva S, Penumetcha SS | title = The Anti-Depressant Effects of Statins in Patients With Major Depression Post-Myocardial Infarction: An Updated Review 2022 | journal = Cureus | volume = 14 | issue = 12 | pages = e32323 | date = December 2022 | pmid = 36628002 | pmc = 9825119 | doi = 10.7759/cureus.32323 | doi-access = free }}</ref>

There is insufficient high quality evidence to suggest [[omega-3 fatty acid]]s are effective in depression.<ref>{{cite journal | vauthors = Appleton KM, Voyias PD, Sallis HM, Dawson S, Ness AR, Churchill R, Perry R | title = Omega-3 fatty acids for depression in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 11 | pages = CD004692 | date = November 2021 | pmid = 34817851 | pmc = 8612309 | doi = 10.1002/14651858.CD004692.pub5 }}</ref> There is limited evidence that vitamin D supplementation is of value in alleviating the symptoms of depression in individuals who are vitamin D-deficient.<ref name=Parker2017>{{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> [[Lithium (medication)|Lithium]] appears effective at lowering the risk of suicide in those with bipolar disorder and unipolar depression by about 80%.<ref name="b789">{{cite journal | last1=Tondo | first1=Leonardo | last2=Baldessarini | first2=Ross J. | title=Prevention of suicidal behavior with lithium treatment in patients with recurrent mood disorders | journal=International Journal of Bipolar Disorders | volume=12 | issue=1 | date=9 March 2024 | issn=2194-7511 | pmid=38460088 | pmc=10924823 | doi=10.1186/s40345-024-00326-x | doi-access=free | page=6}}</ref> There is a narrow range of effective and safe dosages of lithium thus close monitoring may be needed.<ref name="x631">{{cite journal | last1=Nolen | first1=Willem A. | last2=Licht | first2=Rasmus W. | last3=Young | first3=Allan H. | last4=Malhi | first4=Gin S. | last5=Tohen | first5=Mauricio | last6=Vieta | first6=Eduard | last7=Kupka | first7=Ralph W. | last8=Zarate | first8=Carlos | last9=Nielsen | first9=René E. | last10=Baldessarini | first10=Ross J. | last11=Severus | first11=Emanuel | author12=the ISBD/IGSLI Task Force on the treatment with lithium | title=What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium | journal=Bipolar Disorders | volume=21 | issue=5 | date=2019 | issn=1398-5647 | pmid=31112628 | pmc=6688930 | doi=10.1111/bdi.12805 | doi-access=free | pages=394–409 }}</ref> Low-dose [[thyroid hormone]] may be added to existing antidepressants to treat persistent depression symptoms.<ref name="z385">{{cite journal | last1=Bauer | first1=M. | last2=Whybrow | first2=P. C. | title=Role of thyroid hormone therapy in depressive disorders | journal=Journal of Endocrinological Investigation | volume=44 | issue=11 | date=2021 | issn=1720-8386 | pmid=34129186 | pmc=8502157 | doi=10.1007/s40618-021-01600-w | doi-access=free | pages=2341–2347 | url=https://link.springer.com/content/pdf/10.1007/s40618-021-01600-w.pdf | access-date=17 March 2025}}</ref> Limited evidence suggests [[stimulants]], such as [[amphetamine]] and [[modafinil]], may be effective in the short term, or as [[adjuvant therapy]].<ref name="j433">{{cite journal | last1=Bahji | first1=Anees | last2=Mesbah-Oskui | first2=Lia | title=Comparative efficacy and safety of stimulant-type medications for depression: A systematic review and network meta-analysis | journal=Journal of Affective Disorders | volume=292 | date=2021 | doi=10.1016/j.jad.2021.05.119 | pages=416–423| pmid=34144366 }}</ref><ref>{{cite journal | vauthors = Malhi GS, Byrow Y, Bassett D, Boyce P, Hopwood M, Lyndon W, Mulder R, Porter R, Singh A, Murray G | title = Stimulants for depression: On the up and up? | journal = The Australian and New Zealand Journal of Psychiatry | volume = 50 | issue = 3 | pages = 203–207 | date = March 2016 | pmid = 26906078 | doi = 10.1177/0004867416634208 | s2cid = 45341424 }}</ref> Also, it is suggested that [[folate]] supplements may have a role in depression management.<ref>{{cite journal | vauthors = Taylor MJ, Carney S, Geddes J, Goodwin G | title = Folate for depressive disorders | journal = The Cochrane Database of Systematic Reviews | volume = 2003 | issue = 2 | pages = CD003390 | year = 2003 | pmid = 12804463 | pmc = 6991158 | doi = 10.1002/14651858.CD003390 }}</ref> There is tentative evidence for benefit from [[testosterone]] in males.<ref>{{cite journal | vauthors = Walther A, Breidenstein J, Miller R | title = Association of Testosterone Treatment With Alleviation of Depressive Symptoms in Men: A Systematic Review and Meta-analysis | journal = JAMA Psychiatry | volume = 76 | issue = 1 | pages = 31–40 | date = January 2019 | pmid = 30427999 | pmc = 6583468 | doi = 10.1001/jamapsychiatry.2018.2734 }}</ref>