{{Short description|Psychiatric medication used to treat mood disorders}} thumb|A bottle of lithium capsules. Lithium is the prototypical mood stabilizer. A '''mood stabilizer''' is a psychiatric medication used to treat mood disorders characterized by intense and sustained mood shifts, such as bipolar disorder and the bipolar type of schizoaffective disorder.
==Uses== Mood stabilizers are considered a cornerstone in the treatment of bipolar disorder, where they help prevent relapses into both manic and depressive episodes and maintain long-term mood stability.<ref name="Stahl">{{Cite book |last=Stahl |first=Stephen M. |title=Stahl's Essential Psychopharmacology |date=2021-07-29 |publisher=Cambridge University Press |doi=10.1017/9781108975292 |isbn=978-1-108-97529-2}}</ref>
They are also prescribed for the bipolar type of schizoaffective disorder, and in some cases are used as adjuncts for treatment-resistant major depressive disorder. In addition, certain mood stabilizers have been shown to reduce impulsivity and aggression in selected psychiatric and neurological conditions.<ref>{{Cite journal |last1=Miura |first1=Tomofumi |last2=Noma |first2=Hisashi |last3=Furukawa |first3=Toshi A |last4=Mitsuyasu |first4=Hiroshi |last5=Tanaka |first5=Shiro |last6=Stockton |first6=Sarah |last7=Salanti |first7=Georgia |last8=Motomura |first8=Keisuke |last9=Shimano-Katsuki |first9=Satomi |last10=Leucht |first10=Stefan |last11=Cipriani |first11=Andrea |last12=Geddes |first12=John R |last13=Kanba |first13=Shigenobu |date=October 2014 |title=Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a systematic review and network meta-analysis |url=https://linkinghub.elsevier.com/retrieve/pii/S2215036614703141 |journal=The Lancet Psychiatry |language=en |volume=1 |issue=5 |pages=351–359 |doi=10.1016/S2215-0366(14)70314-1 |pmid=26360999 |url-access=subscription }}</ref><ref>{{Cite journal |last1=Kishi |first1=Taro |last2=Ikuta |first2=Toshikazu |last3=Matsuda |first3=Yuki |last4=Sakuma |first4=Kenji |last5=Okuya |first5=Makoto |last6=Mishima |first6=Kazuo |last7=Iwata |first7=Nakao |date=2020-11-11 |title=Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: a systematic review and network meta-analysis of randomized controlled trials |journal=Molecular Psychiatry |volume=26 |issue=8 |pages=4146–4157 |doi=10.1038/s41380-020-00946-6 |pmid=33177610 |pmc=8550938 |issn=1359-4184}}</ref>
Evidence also suggests that lithium, in particular, reduces the risk of suicide in patients with mood disorders, making it a unique therapeutic option among mood stabilizers.<ref>{{Cite journal |last1=Cipriani |first1=A. |last2=Hawton |first2=K. |last3=Stockton |first3=S. |last4=Geddes |first4=J. R. |date=2013-06-27 |title=Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis |url=https://www.bmj.com/lookup/doi/10.1136/bmj.f3646 |journal=BMJ |language=en |volume=346 |issue=jun27 4 |article-number=f3646 |doi=10.1136/bmj.f3646 |pmid=23814104 |issn=1756-1833}}</ref>
==Examples== The term "mood stabilizer" does not describe a mechanism but an effect. More precise terminology based on pharmacology is used to further classify these agents. Drugs commonly classed as mood stabilizers include the drugs listed below.
=== Lithium === Lithium is the "classic" mood stabilizer, the first to be approved by the United States Food and Drug Administration (FDA), and still popular in treatment. Therapeutic drug monitoring is required to ensure lithium levels remain in the therapeutic range: 0.6 to 0.8 mmol/L for maintenance treatment or 0.8–1.0 mmol/L for acute mania.<ref>{{Cite book |last1=Taylor |first1=David M. |title=The Maudsley Prescribing Guidelines in Psychiatry |last2=Barnes |first2=Thomas R. E. |last3=Young |first3=Allan H. |date=2025 |publisher=Wiley-Blackwell |isbn=9781394238767 |edition=15th |location=Hoboken, NJ |pages=279–280}}</ref><ref>{{Cite book |last=Ghaemi |first=S. Nassir |title=Clinical Psychopharmacology: Principles and Practice |date=2019 |publisher=Oxford University Press |isbn=9780199995486 |edition=1st |location=New York, NY |pages=128}}</ref><ref>{{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 |last12=ISBD/IGSLI Task Force on the treatment with lithium |date=Aug 2019 |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 |pages=394–409 |doi=10.1111/bdi.12805 |issn=1399-5618 |pmc=6688930 |pmid=31112628}}</ref> Signs and symptoms of toxicity include nausea, vomiting, diarrhea, and ataxia.<ref name="pmid_18789369">{{Cite journal | last1 = Marmol | first1 = F. | title = Lithium: Bipolar disorder and neurodegenerative diseases Possible cellular mechanisms of the therapeutic effects of lithium | doi = 10.1016/j.pnpbp.2008.08.012 | journal = Progress in Neuro-Psychopharmacology and Biological Psychiatry | volume = 32 | issue = 8 | pages = 1761–1771 | year = 2008 | pmid = 18789369 | s2cid = 25861243 }}</ref> The most common side effects are lethargy and weight gain (up to {{convert|2|kg|lb}}).<ref name="Malhi_2013b">{{cite journal |title=Safe and effective use of lithium |journal=Australian Prescriber |volume=36 |pages=18–21 |doi=10.18773/austprescr.2013.008 |year=2013 | vauthors = Malhi GS, Tanious M, Bargh D, Das P, Berk M |doi-access=free}}</ref> The less common side effects of using lithium are blurred vision, a slight tremble in the hands, and a feeling of being mildly ill (malaise).
In general, these side effects occur in the first few weeks after commencing lithium treatment. These symptoms can often be improved by lowering the dose.<ref>Kozier, B et al. (2008). Fundamentals Of Nursing: Concepts, Process, and Practice. London: Pearson Education. p. 189.</ref> Long-term lithium therapy also carries risks such as hypothyroidism and chronic kidney disease, requiring periodic monitoring of thyroid and renal function.<ref>{{Cite journal |last=Gitlin |first=Michael |date=December 2016 |title=Lithium side effects and toxicity: prevalence and management strategies |journal=International Journal of Bipolar Disorders |language=en |volume=4 |issue=1 |article-number=27 |doi=10.1186/s40345-016-0068-y |pmid=27900734 |doi-access=free |issn=2194-7511|pmc=5164879 }}</ref>
It is also one of the few drugs with proven anti-suicidal properties, making it unique among psychiatric medications.<ref name="Stahl" /> In addition to its effects on suicide, lithium also decreases all-cause mortality in people with mood disorders.<ref>{{Cite journal |last1=Cipriani |first1=Andrea |last2=Pretty |first2=Heather |last3=Hawton |first3=Keith |last4=Geddes |first4=John R. |date=October 2005 |title=Lithium in the Prevention of Suicidal Behavior and All-Cause Mortality in Patients With Mood Disorders: A Systematic Review of Randomized Trials |url=https://psychiatryonline.org/doi/full/10.1176/appi.ajp.162.10.1805 |journal=American Journal of Psychiatry |volume=162 |issue=10 |pages=1805–1819 |doi=10.1176/appi.ajp.162.10.1805|pmid=16199826 |url-access=subscription }}</ref>
===Anticonvulsants=== Anticonvulsants, also known as antiseizure medications, are agents originally developed for treating epilepsy and seizure disorders. In the 1970s, clinical trials demonstrated that certain anticonvulsants were effective in mood stabilization, subsequently, these medications were adopted in psychiatry for treating mood disorders.<ref>{{Cite journal |last=Rybakowski |first=Janusz K. |date=2023-04-29 |title=Mood Stabilizers of First and Second Generation |journal=Brain Sciences |language=en |volume=13 |issue=5 |page=741 |doi=10.3390/brainsci13050741 |doi-access=free |issn=2076-3425 |pmc=10216063 |pmid=37239213}}</ref>
This class of medication is divided into first generation and second generation agents based on the time of their development, with the second generation agents having lesser adverse effects and better tolerability compared to the first generation.<ref name=":7">{{Cite journal |last=Hakami |first=Tahir |date=September 2021 |title=Neuropharmacology of Antiseizure Drugs |journal=Neuropsychopharmacology Reports |language=en |volume=41 |issue=3 |pages=336–351 |doi=10.1002/npr2.12196 |issn=2574-173X |pmc=8411307 |pmid=34296824}}</ref>
==== Valproate ==== Valproate is a first generation anticonvulsant agent. This drug is considered as the first line treatment for both acute mania and maintenance of bipolar disorder.<ref>{{Cite journal |last1=Crapanzano |first1=Calogero |last2=Casolaro |first2=Ilaria |last3=Amendola |first3=Chiara |last4=Damiani |first4=Stefano |date=2022-08-31 |title=Lithium and Valproate in Bipolar Disorder: From International Evidence-based Guidelines to Clinical Predictors |journal=Clinical Psychopharmacology and Neuroscience |language=en |volume=20 |issue=3 |pages=403–414 |doi=10.9758/cpn.2022.20.3.403 |issn=1738-1088 |pmc=9329114 |pmid=35879025}}</ref> It primarily acts by inhibiting GABA transaminase and increasing GABAergic activity, thereby decreasing neuronal excitability. It can also inactivate sodium and calcium channels.<ref name=":7" />
This drug can be very irritating to the stomach, especially when taken as a free acid. Requires regular hepatic panels and full blood count monitoring. Common side effects include sleepiness, nausea, and dry mouth. More serious side effects include liver dysfunction, pancreatitis, and polycystic ovary syndrome.<ref name="eMC">{{cite web|title=Depakote 500mg Tablets|url=https://www.medicines.org.uk/emc/medicine/25947|website=electronic Medicine Compendium|publisher=Dataphram Communications Limited|access-date=28 September 2016}}</ref><ref name="Depakote FDA label">{{cite web|title=Depakote- divalproex sodium tablet, delayed release|url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08a65cf4-7749-4ceb-6895-8f4805e2b01f |access-date=10 November 2015|url-status=live|archive-url=https://web.archive.org/web/20160305202922/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08a65cf4-7749-4ceb-6895-8f4805e2b01f|archive-date=5 March 2016}}</ref> Weight gain is possible.<ref>{{cite journal | vauthors = Chukwu J, Delanty N, Webb D, Cavalleri GL | title = Weight change, genetics and antiepileptic drugs | journal = Expert Review of Clinical Pharmacology | volume = 7 | issue = 1 | pages = 43–51 | date = January 2014 | pmid = 24308788 | doi = 10.1586/17512433.2014.857599 | s2cid = 33444886 }}</ref>
It is recommended that women of childbearing age should avoid using valproate due its teratogenic potential, including the increased risk of neural tube defects, even with folic acid supplementation.<ref name=":6">{{Cite journal |last1=Yatham |first1=Lakshmi N |last2=Kennedy |first2=Sidney H |last3=Parikh |first3=Sagar V |last4=Schaffer |first4=Ayal |last5=Bond |first5=David J |last6=Frey |first6=Benicio N |last7=Sharma |first7=Verinder |last8=Goldstein |first8=Benjamin I |last9=Rej |first9=Soham |last10=Beaulieu |first10=Serge |last11=Alda |first11=Martin |last12=MacQueen |first12=Glenda |last13=Milev |first13=Roumen V |last14=Ravindran |first14=Arun |last15=O'Donovan |first15=Claire |date=March 2018 |title=Canadian Network for Mood and Anxiety Treatments ( CANMAT ) and International Society for Bipolar Disorders ( ISBD ) 2018 guidelines for the management of patients with bipolar disorder |journal=Bipolar Disorders |language=en |volume=20 |issue=2 |pages=97–170 |doi=10.1111/bdi.12609 |issn=1398-5647 |pmc=5947163 |pmid=29536616}}</ref> In the United Kingdom and European Union, valproate has been restricted for women and men under age 55 due to pregnancy and fertility concerns.<ref>{{Cite web |date=2024-10-01 |title=Sodium valproate {{!}} Epilepsy Society |url=https://epilepsysociety.org.uk/about-epilepsy/sodium-valproate |access-date=2026-01-19 |website=epilepsysociety.org.uk |language=en}}</ref><ref>{{Cite web |date=2013-10-11 |title=Valproate and related substances - referral {{!}} European Medicines Agency (EMA) |url=https://www.ema.europa.eu/en/medicines/human/referrals/valproate-related-substances |access-date=2026-01-19 |website=www.ema.europa.eu |language=en}}</ref>
==== Carbamazepine ==== Carbamazepine is also a first generation anticonvulsant. It is considered second-line for bipolar disorder due to its side effects,<ref>{{cite journal | vauthors = Nevitt SJ, Marson AG, Weston J, Tudur Smith C | title = Sodium valproate versus phenytoin monotherapy for epilepsy: an individual participant data review | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | article-number = CD001769 | date = August 2018 | issue = 8 | pmid = 30091458 | pmc = 6513104 | doi = 10.1002/14651858.CD001769.pub4 }}</ref> including gastrointestinal symptoms, Stevens‐Johnson syndrome, toxic epidermal necrolysis, and weight gain.<ref name=":6" /> It primarily acts by inhibiting sodium channels.<ref name=":7" /> Carbamazepine can rarely cause a dangerous decrease in neutrophils, a type of white blood cell, called agranulocytosis.<ref name="CBZ PI">{{cite web |title=EQUETRO(carbamazepine) Package Insert |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021710s11s012lbl.pdf |archive-url=https://web.archive.org/web/20170217043753/http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021710s11s012lbl.pdf |archive-date=February 17, 2017 |access-date=10 July 2020 |publisher=Validus Pharmaceuticals LLC}}</ref> It interacts with many medications, including other mood stabilizers (e.g., lamotrigine) and antipsychotics (e.g., quetiapine).<ref name="CBZ PI" />
While using carbamazepine, the effectiveness of oral contraceptive is significantly decreased, and it also has teratogenic potential.<ref name=":6" />
==== Lamotrigine ==== Lamotrigine (brand name Lamictal) is FDA-approved for bipolar disorder maintenance therapy, but not for acute mood problems like acute depression or mania, including hypomania.<ref name="FDA Prescribing Information at drugs.com" /> The usual target dose is 100–200 mg daily, titrated to by 25 mg increments every 2 weeks.<ref>Healy D. 2005 Psychiatric Drugs explained 4th ed. Churchill Liviingstone: London p.110</ref> Lamotrigine can cause Stevens–Johnson syndrome, a very rare but potentially fatal skin condition.<ref name="FDA Prescribing Information at drugs.com">{{cite web | url = https://www.drugs.com/pro/lamictal.html | title = Lamictal – FDA Prescribing Information}}</ref>
There is insufficient evidence to support the use of various other anticonvulsants, such as gabapentin and topiramate, as mood stabilizers.<ref name="Ketter2007">{{cite book | author = Terence A. Ketter | title = Advances in Treatment of Bipolar Disorder | url = https://books.google.com/books?id=aSh-GEQfbhAC&pg=PA42 | date = 3 May 2007 | publisher = American Psychiatric Pub | isbn = 978-1-58562-666-3 | page = 42}}</ref>
===Antipsychotics=== Some atypical antipsychotics (aripiprazole, asenapine, cariprazine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) also have mood-stabilizing effects and are thus commonly prescribed even when psychotic symptoms are absent.<ref name=pmid15762830>{{cite journal |author=Bowden CL |title=Atypical antipsychotic augmentation of mood stabilizer therapy in bipolar disorder |journal=J Clin Psychiatry |volume=Suppl 3 |series=66|pages=12–9 |year=2005 |pmid=15762830 |url=http://article.psychiatrist.com/?ContentType=START&ID=10001256}}</ref>
===Other===
==== Omega-3 fatty acids ==== It is also conjectured that omega-3 fatty acids may have mood-stabilizing effects.<ref name="pmid11152679">{{cite journal |vauthors=Mirnikjoo B, Brown SE, Kim HF, Marangell LB, Sweatt JD, Weeber EJ |title=Protein kinase inhibition by omega-3 fatty acids |journal=J. Biol. Chem. |volume=276 |issue=14 |pages=10888–96 |date=April 2001 |pmid=11152679 |doi=10.1074/jbc.M008150200 |doi-access=free }}</ref> Compared with placebo, omega-3 fatty acids appear better able to augment known mood stabilizers in reducing depressive—but perhaps not manic—symptoms of bipolar disorder; additional trials would be needed to establish the effects of omega-3 fatty acids alone.''<ref>{{Cite journal | doi = 10.1111/j.1399-5618.2005.00250.x | pmid = 16225556 | title = Newer treatment studies for bipolar depression | year = 2005 | last1 = Gao | first1 = K. | last2 = Calabrese | first2 = J. R. | journal = Bipolar Disorders | volume = 7 | issue = s5 | pages = 13–23 }}</ref>'' Recent studies suggest that preparations with a higher ratio of eicosapentaenoic acid (EPA) to docosahexaenoic acid (DHA) -types of omega-3 fatty acids- are more effective in improving depressive symptoms, while effects on mania remain inconsistent.<ref>{{Cite journal |last1=Kraguljac |first1=Nina V. |last2=Montori |first2=Victor M. |last3=Pavuluri |first3=Mani |last4=Chai |first4=High S. |last5=Wilson |first5=Brian S. |last6=Unal |first6=Sencan S. |date=2009 |title=Efficacy of omega-3 fatty acids in mood disorders - a systematic review and metaanalysis |journal=Psychopharmacology Bulletin |volume=42 |issue=3 |pages=39–54 |issn=0048-5764 |pmid=19752840}}</ref><ref>{{Cite journal |last1=Grosso |first1=Giuseppe |last2=Pajak |first2=Andrzej |last3=Marventano |first3=Stefano |last4=Castellano |first4=Sabrina |last5=Galvano |first5=Fabio |last6=Bucolo |first6=Claudio |last7=Drago |first7=Filippo |last8=Caraci |first8=Filippo |date=2014-05-07 |title=Role of Omega-3 Fatty Acids in the Treatment of Depressive Disorders: A Comprehensive Meta-Analysis of Randomized Clinical Trials |journal=PLOS ONE |language=en |volume=9 |issue=5 |article-number=e96905 |doi=10.1371/journal.pone.0096905 |pmid=24805797 |pmc=4013121 |bibcode=2014PLoSO...996905G |doi-access=free |issn=1932-6203}}</ref>
==== Levothyroxine ==== It is known that even subclinical hypothyroidism can blunt a patient's response to both mood stabilizers and antidepressants. Furthermore, preliminary research into the use of thyroid augmentation in patients with refractory and rapid-cycling bipolar disorder has been positive, showing a slowing in cycle frequency and reduction in symptoms.
Most studies have been conducted on an open-label basis. One large, controlled study of a 300 mcg daily dose of levothyroxine (T<sub>4</sub>) found it superior to placebo in the setting of bipolar disorder. In general, studies have shown T4 to be well tolerated and to show effectiveness even in patients without overt hypothyroidism.<ref>{{Cite journal |last=Chakrabarti |first=Subho |date=2011 |title=Thyroid Functions and Bipolar Affective Disorder |journal=Journal of Thyroid Research |language=en |volume=2011 |pages=1–13 |doi=10.4061/2011/306367 |doi-access=free |issn=2042-0072 |pmc=3144691 |pmid=21808723}}</ref> It is reported that supraphysiological doses of levothyroxine may be particularly beneficial in women with treatment-resistant bipolar depression, although long-term safety still needs further evaluation.<ref>{{Cite journal |last1=Seshadri |first1=Ashok |last2=Sundaresh |first2=Vishnu |last3=Prokop |first3=Larry J. |last4=Singh |first4=Balwinder |date=2022-11-14 |title=Thyroid Hormone Augmentation for Bipolar Disorder: A Systematic Review |journal=Brain Sciences |volume=12 |issue=11 |page=1540 |doi=10.3390/brainsci12111540 |doi-access=free |issn=2076-3425 |pmc=9688441 |pmid=36421864}}</ref> Hypothyroidism is common among patients with bipolar disorder regardless of the mood stabilizer used.<ref>{{cite journal | vauthors = Lambert CG, Mazurie AJ, Lauve NR, Hurwitz NG, Young SS, Obenchain RL, Hengartner NW, Perkins DJ, Tohen M, Kerner B | title = Hypothyroidism risk compared among nine common bipolar disorder therapies in a large US cohort | journal = Bipolar Disorders | volume = 18 | issue = 3 | pages = 247–260 | date = May 2016 | pmid = 27226264 | pmc = 5089566 | doi = 10.1111/bdi.12391 }}</ref>
===Combination therapy=== In routine practice, monotherapy is often insufficiently effective for acute and/or maintenance therapy. Thus, most patients are placed on combination therapy.<ref name=Geoffroy-2012/> Combination therapy (e.g., an atypical antipsychotic with lithium or valproate) has demonstrated better effectiveness over monotherapy in the control of manic episodes, as well as the prevention of relapse.<ref name=Geoffroy-2012/> However, side effects are more frequent and discontinuation rates are higher due to adverse events with combination therapy than with monotherapy.<ref name=Geoffroy-2012>{{Cite journal | last1 = Geoffroy | first1 = P. A. | last2 = Etain | first2 = B. | last3 = Henry | first3 = C. | last4 = Bellivier | first4 = F. | title = Combination Therapy for Manic Phases: A Critical Review of a Common Practice | doi = 10.1111/cns.12017 | journal = CNS Neuroscience & Therapeutics | volume = 18 | issue = 12 | pages = 957–964 | year = 2012 | pmid = 23095277 | pmc = 6493634| url = http://www.hal.inserm.fr/inserm-00786653/document }}</ref>
==Relationship to antidepressants== {{See also|SSRI#Bipolar switch}} Most mood stabilizers are primarily antimanic agents, meaning that they are effective at treating mania and mood cycling and shifting, but are not effective at treating acute depression. The principal exceptions to that rule, because they treat both manic and depressive symptoms, are lamotrigine, lithium carbonate, olanzapine and quetiapine. There is a need for caution when treating bipolar patients with antidepressant medication due to the risks that they pose.<ref>Chris Aiken: [https://www.psychiatrictimes.com/view/antidepressants-bipolar-ii-disorder ''Antidepressants in Bipolar II Disorder''], May 14, 2019. In: psychiatrictimes.com</ref><ref name="Gitlin">{{cite journal | vauthors = Gitlin MJ | title = Antidepressants in bipolar depression: an enduring controversy | journal = International Journal of Bipolar Disorders | volume = 6 | issue = 1 | article-number = 25 | date = December 2018 | pmid = 30506151 | pmc = 6269438 | doi = 10.1186/s40345-018-0133-9 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Viktorin A, Lichtenstein P, Thase ME, Larsson H, Lundholm C, Magnusson PK, Landén M | title = The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer | journal = The American Journal of Psychiatry | volume = 171 | issue = 10 | pages = 1067–1073 | date = October 2014 | pmid = 24935197 | doi = 10.1176/appi.ajp.2014.13111501 | s2cid = 25152608 | hdl = 10616/42159 | hdl-access = free }}</ref>
Nevertheless, antidepressants are still often prescribed in addition to mood stabilizers during depressive phases. This brings some risks, however, as antidepressants can induce mania (increases risk by 34%),<ref>{{cite journal |last1=Patel |first1=Rashmi |title=Do antidepressants increase the risk of mania and bipolar disorder in people with depression? A retrospective electronic case register cohort study |journal=BMJ Open |date=2015 |volume=5 |issue=12 |article-number=e008341 |doi=10.1136/bmjopen-2015-008341 |doi-access=free|pmid=26667012 |pmc=4679886}}</ref> psychosis (relative risk not reported),<ref>{{cite journal |last1=Preda |first1=A |last2=MacLean |first2=RW |last3=Mazure |first3=CM |last4=Bowers MB |first4=Jr |title=Antidepressant-associated mania and psychosis resulting in psychiatric admissions. |journal=The Journal of Clinical Psychiatry |date=January 2001 |volume=62 |issue=1 |pages=30–3 |doi=10.4088/jcp.v62n0107 |pmid=11235925 }}</ref> cycle acceleration,<ref name="Gitlin" /> and other disturbing problems in people with bipolar disorder—in particular, when taken alone. The risk of antidepressant-induced mania when given to patients concomitantly on antimanic agents is not known for certain but may still exist.<ref name=":0">Amit BH, Weizman A. Antidepressant Treatment for Acute Bipolar Depression: An Update. Depression Research and Treatment [Internet]. 2012 [cited 2013 Jul 18];2012:1–10. Available from: http://www.hindawi.com/journals/drt/2012/684725/</ref>
SSRIs and bupropion appear to have lower chances of switching, while SNRIs and tricyclics are more likely to cause switching. A single large, population based study reports that the manic "switch" risk is not increased over regular mood stabilizer treatment when an antidepressant is combined with a mood stabilizer. When an antidepressant is used alone, the risk is about 3 times the regular value.<ref name="Gitlin" /> Gitlin (2018) notes that "the potential issue of worsening suicidality in adolescents and young adults treated with antidepressants [...] both controversial and infrequently seen."<ref name="Gitlin" />
Equally critical is the question of whether adding antidepressant has any effect on bipolar depression. High-quality data is lacking in this field, and simply using different analytical approaches can lead to different conclusions. It's also possible that the effect depends on the mood stabilizer used: one study finds no effect when antidepressant is added to lithium or valporate, but some efficacy when it's added to atypical antipsychotics.<ref name=Gitlin/>
==Pharmacodynamics==
{{see also|Atypical antipsychotic#Pharmacodynamics}}
Pharmacodynamics refers to the study of the biochemical and cellular effects of medications, as well as their mechanisms of action.<ref>{{Cite web |title=Pharmacodynamics: Molecular Mechanisms of Drug Action |url=https://accesspharmacy.mhmedical.com/content.aspx?bookid=1810§ionid=124489721 |access-date=2025-08-25 |website=McGraw Hill Medical |language=en}}</ref> As noted, "mood stabilizers" do not share a single way of working; the term simply indicates how these drugs are used in treatment. However, some research shows that Lithium, Valproate, and Carbamazepine may share a common mechanism of action, but not tricyclic antidepressants.<ref name=":2">{{Cite journal |last1=Lubrich |first1=Beate |last2=van Calker |first2=Dietrich |date=October 1999 |title=Inhibition of the High Affinity Myo-Inositol Transport System: A Common Mechanism of Action of Antibipolar Drugs? |url=https://www.nature.com/articles/1395361 |journal=Neuropsychopharmacology |language=en |volume=21 |issue=4 |pages=519–529 |doi=10.1016/S0893-133X(99)00037-8 |pmid=10481836 |issn=1740-634X}}</ref> This mechanism includes the reduction of inositol, a compound involved in many pathways that lead to increased cell signaling in the brain.<ref>{{Cite journal |last1=Concerto |first1=Carmen |last2=Chiarenza |first2=Cecilia |last3=Di Francesco |first3=Antonio |last4=Natale |first4=Antimo |last5=Privitera |first5=Ivan |last6=Rodolico |first6=Alessandro |last7=Trovato |first7=Antonio |last8=Aguglia |first8=Andrea |last9=Fisicaro |first9=Francesco |last10=Pennisi |first10=Manuela |last11=Bella |first11=Rita |last12=Petralia |first12=Antonino |last13=Signorelli |first13=Maria Salvina |last14=Lanza |first14=Giuseppe |date=2023-02-20 |title=Neurobiology and Applications of Inositol in Psychiatry: A Narrative Review |journal=Current Issues in Molecular Biology |volume=45 |issue=2 |pages=1762–1778 |doi=10.3390/cimb45020113 |doi-access=free |issn=1467-3045 |pmc=9955821 |pmid=36826058}}</ref> When these pathways are inhibited or blocked, the mood stabilizing effect is accomplished.<ref name=":2" /> Another possible target of several mood stabilizers is the arachidonic acid cascade.<ref name="pmid18347600">{{cite journal |vauthors=Rao JS, Lee HJ, Rapoport SI, Bazinet RP |date=June 2008 |title=Mode of action of mood stabilizers: is the arachidonic acid cascade a common target? |journal=Mol. Psychiatry |volume=13 |issue=6 |pages=585–96 |doi=10.1038/mp.2008.31 |pmid=18347600 |s2cid=21273538 |doi-access=}}</ref>
Lithium's exact mechanism of action remains unknown; it likely affects several sites within the neuron including the nucleus and the synapse. As mentioned, lithium is thought to cause inositol reduction. It does this by being an uncompetitive inhibitor to the enzymes inositol monophosphatase 1 and inositol polyphosphate 1-phosphatase.<ref name=":4">{{Citation |last1=Nath |first1=Mala |title=Mood Stabilizers |date=2025 |work=StatPearls |url=http://www.ncbi.nlm.nih.gov/books/NBK556141/ |access-date=2025-08-25 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32310601 |last2=Gupta |first2=Vikas}}</ref> Lithium is also known to inhibit the enzyme GSK-3B,<ref>{{Cite journal |last1=Rohr |first1=Kayla E. |last2=McCarthy |first2=Michael J. |date=2022-08-24 |title=The impact of lithium on circadian rhythms and implications for bipolar disorder pharmacotherapy |journal=Neuroscience Letters |volume=786 |article-number=136772 |doi=10.1016/j.neulet.2022.136772 |issn=1872-7972 |pmc=11801369 |pmid=35798199}}</ref> which helps regulate the circadian rhythm. If the circadian rhythm is disrupted, it may lead to key traits of bipolar disorder, like mood episodes.<ref>{{Cite journal |last1=McCarthy |first1=Michael J. |last2=Gottlieb |first2=John F. |last3=Gonzalez |first3=Robert |last4=McClung |first4=Colleen A. |last5=Alloy |first5=Lauren B. |last6=Cain |first6=Sean |last7=Dulcis |first7=Davide |last8=Etain |first8=Bruno |last9=Frey |first9=Benicio N. |last10=Garbazza |first10=Corrado |last11=Ketchesin |first11=Kyle D. |last12=Landgraf |first12=Dominic |last13=Lee |first13=Heon-Jeong |last14=Marie-Claire |first14=Cynthia |last15=Nusslock |first15=Robin |date=May 2022 |title=Neurobiological and behavioral mechanisms of circadian rhythm disruption in bipolar disorder: A critical multi-disciplinary literature review and agenda for future research from the ISBD task force on chronobiology |journal=Bipolar Disorders |volume=24 |issue=3 |pages=232–263 |doi=10.1111/bdi.13165 |issn=1399-5618 |pmc=9149148 |pmid=34850507}}</ref>
Chronic use of lithium helps regulate gene transcription of brain-derived neurotrophic factor (BDNF).<ref>{{Cite journal |last1=Deliyannides |first1=Deborah A. |last2=Graff |first2=Jamie A. |last3=Niño |first3=Izael |last4=Lee |first4=Seonjoo |last5=Husain |first5=Mustafa M. |last6=Forester |first6=Brent P. |last7=Crocco |first7=Elizabeth |last8=Vahia |first8=Ipsit V. |last9=Devanand |first9=Davangere P. |date=September 2023 |title=Effects of lithium on serum Brain-Derived Neurotrophic Factor in Alzheimer's patients with agitation |journal=International Journal of Geriatric Psychiatry |volume=38 |issue=9 |article-number=e6002 |doi=10.1002/gps.6002 |issn=1099-1166 |pmid=37732619}}</ref> This boosts neural plasticity; which may be key to lithium's therapeutic effects. Lithium's role in the human body isn't fully clear. However, its benefits likely connect to its impact on electrolytes like potassium, sodium, calcium, and magnesium.<ref>Raber, Jack H. "Lithium carbonate." The Gale Encyclopedia of Mental Disorders, edited by Madeline Harris and Ellen Thackerey, vol. 1, Gale, 2003, pp. 571-573. Gale eBooks, link.gale.com/apps/doc/CX3405700220/GVRL?u=tamp44898&sid=GVRL&xid=9ef84e18. Accessed 20 Jan. 2021.</ref> Lithium is generally neuroprotective.<ref name="Quiroz">{{cite journal |vauthors=Quiroz JA, Machado-Vieira R, Zarate CA, Manji HK |title=Novel insights into lithium's mechanism of action: neurotrophic and neuroprotective effects |journal=Neuropsychobiology |volume=62 |issue=1 |pages=50–60 |date=2010 |pmid=20453535 |doi=10.1159/000314310 |pmc=2889681}}</ref>
Valproate, also known as Valproic Acid, is an anticonvulsant. It affects brain activity in several ways. Valproate's main effect is the indirect inhibition of the breakdown of GABA, which is an inhibitory neurotransmitter. It works by reducing the activity of enzymes that break down GABA. This includes GABA transaminase and succinate semialdehyde dehydrogenase.<ref name=":3">{{Cite journal |last1=Mishra |first1=Manish Kumar |last2=Kukal |first2=Samiksha |last3=Paul |first3=Priyanka Rani |last4=Bora |first4=Shivangi |last5=Singh |first5=Anju |last6=Kukreti |first6=Shrikant |last7=Saso |first7=Luciano |last8=Muthusamy |first8=Karthikeyan |last9=Hasija |first9=Yasha |last10=Kukreti |first10=Ritushree |date=2021-12-24 |title=Insights into Structural Modifications of Valproic Acid and Their Pharmacological Profile |journal=Molecules (Basel, Switzerland) |volume=27 |issue=1 |page=104 |doi=10.3390/molecules27010104 |doi-access=free |issn=1420-3049 |pmc=8746633 |pmid=35011339}}</ref> It also decreases the expression of glutamate receptors; thus decreasing neuronal excitability.<ref name=":3" />
In addition, valproate blocks sodium, potassium and calcium voltage-gated channels, and this reduces how often neurons fire.<ref name="Gh2013">{{cite journal | vauthors = Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, Altman RB, Klein TE | title = Valproic acid pathway: pharmacokinetics and pharmacodynamics | journal = Pharmacogenetics and Genomics | volume = 23 | issue = 4 | pages = 236–241 | date = April 2013 | pmid = 23407051 | pmc = 3696515 | doi = 10.1097/FPC.0b013e32835ea0b2 }}</ref><ref>{{Cite journal |last1=Van den Berg |first1=R. J. |last2=Kok |first2=P. |last3=Voskuyl |first3=R. A. |date=January 1993 |title=Valproate and sodium currents in cultured hippocampal neurons |url=http://link.springer.com/10.1007/BF00228395 |journal=Experimental Brain Research |language=en |volume=93 |issue=2 |pages=279–287 |doi=10.1007/BF00228395 |pmid=8387930 |issn=0014-4819|url-access=subscription }}</ref> Research has since shown valproate to have several cellular effects. These include the inhibition of histone deacetylases and upregulation of LEF1. These mechanisms hint at possible uses in cancer therapy.<ref>{{cite journal | vauthors = Santos R, Linker SB, Stern S, Mendes AP, Shokhirev MN, Erikson G, Randolph-Moore L, Racha V, Kim Y, Kelsoe JR, Bang AG, Alda M, Marchetto MC, Gage FH | title = Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients | journal = Molecular Psychiatry | volume = 26 | issue = 6 | pages = 2440–2456 | date = June 2021 | pmid = 33398088 | pmc = 9129103 | doi = 10.1038/s41380-020-00981-3 }}</ref><ref>{{Cite journal |last=Gottlicher |first=M. |date=2001-12-17 |title=Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells |url=http://emboj.embopress.org/cgi/doi/10.1093/emboj/20.24.6969 |journal=The EMBO Journal |volume=20 |issue=24 |pages=6969–6978 |doi=10.1093/emboj/20.24.6969 |pmc=125788 |pmid=11742974}}</ref> It is also neuroprotective.<ref name="Quiroz" />
Carbamazepine is another anticonvulsant that functions mainly as a sodium channel blocker.<ref>{{cite journal | vauthors = Rogawski MA, Löscher W, Rho JM | title = Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet | journal = Cold Spring Harbor Perspectives in Medicine | volume = 6 | issue = 5 | article-number = a022780 | date = May 2016 | pmid = 26801895 | pmc = 4852797 | doi = 10.1101/cshperspect.a022780 }}</ref> Voltage-gated sodium channels are found on the cell membrane of neurons and help create action potentials.<ref>{{Cite journal |last1=Pal |first1=Rohit |last2=Kumar |first2=Bhupinder |last3=Akhtar |first3=Md Jawaid |last4=Chawla |first4=Pooja A. |date=October 2021 |title=Voltage gated sodium channel inhibitors as anticonvulsant drugs: A systematic review on recent developments and structure activity relationship studies |journal=Bioorganic Chemistry |volume=115 |article-number=105230 |doi=10.1016/j.bioorg.2021.105230 |issn=1090-2120 |pmid=34416507}}</ref> Carbamazepine keeps these channels inactivated, which stops continuous action potential firing.<ref name=":1">{{Citation |last=Dean |first=Laura |title=Carbamazepine Therapy and HLA Genotype |date=2012 |work=Medical Genetics Summaries |editor-last=Pratt |editor-first=Victoria M. |url=http://www.ncbi.nlm.nih.gov/books/NBK321445/ |access-date=2025-08-25 |place=Bethesda (MD) |publisher=National Center for Biotechnology Information (US) |pmid=28520367 |editor2-last=Scott |editor2-first=Stuart A. |editor3-last=Pirmohamed |editor3-first=Munir |editor4-last=Esquivel |editor4-first=Bernard}}</ref> The liver breaks down carbamazepine through the liver enzyme CYP3A4. Many drugs can change how CYP3A4 works. They can either boost or reduce its activity. This is why carbamazepine needs careful monitoring when other medications are used with it, with a possible need for dosage adjustment.<ref name=":1" />
Lamotrigine lowers excitatory nerve signaling in the central nervous system by lowering glutamate release.<ref name=":5">{{Cite journal |last1=Cunningham |first1=M. O. |last2=Jones |first2=R. S. |date=2000-08-23 |title=The anticonvulsant, lamotrigine decreases spontaneous glutamate release but increases spontaneous GABA release in the rat entorhinal cortex in vitro |journal=Neuropharmacology |volume=39 |issue=11 |pages=2139–2146 |doi=10.1016/s0028-3908(00)00051-4 |issn=0028-3908 |pmid=10963757}}</ref><ref>{{Cite web |title=Prescribing Information for LAMICTAL (lamotrigine) |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020241s10s21s25s26s27,020764s3s14s18s19s20lbl.pdf |archive-url=https://web.archive.org/web/20200112201226/https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020241s10s21s25s26s27,020764s3s14s18s19s20lbl.pdf |archive-date=12 January 2020 |access-date=12 January 2020 |website=FDA}}</ref> In addition, it increases inhibitory nerve signaling by boosting GABA release.<ref name=":4" /><ref name=":5" /> Recent studies suggest the lamotrigine is relatively safe during pregnancy, but does need close monitoring by a specialist. This is important because researchers have linked it to neonatal malformations, such as oral clefts.<ref>{{Cite journal |last1=Kaplan |first1=Yusuf Cem |last2=Demir |first2=Omer |date=2021 |title=Use of Phenytoin, Phenobarbital Carbamazepine, Levetiracetam Lamotrigine and Valproate in Pregnancy and Breastfeeding: Risk of Major Malformations, Dose-dependency, Monotherapy vs Polytherapy, Pharmacokinetics and Clinical Implications |journal=Current Neuropharmacology |volume=19 |issue=11 |pages=1805–1824 |doi=10.2174/1570159X19666210211150856 |issn=1875-6190 |pmc=9185784 |pmid=33573557}}</ref>
==See also== * Treatment of bipolar disorder
===Categories=== {{See also for drug classes defined by psychological effects|Mood stabilizers}}
==References== {{reflist|30em}}
==External links== *{{Commons category-inline|Mood stabilizers}}
{{Mood stabilizers}} {{Major Drug Groups}} {{Chemical classes of psychoactive drugs}}
{{DEFAULTSORT:Mood Stabilizer}} Category:Mood stabilizers