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Mood stabilizer

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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

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Mood stabilizers are best known for the treatment of bipolar disorder,[1] preventing mood shifts to mania (or hypomania) and depression. Mood stabilizers are also used in schizoaffective disorder when it is the bipolar type.[2]

Examples

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The term "mood stabilizer" does not describe a mechanism, but rather an effect. More precise terminology based on pharmacology is used to further classify these agents. Drugs commonly classed as mood stabilizers include:

Mineral

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Lithium
Lithium is the "classic" mood stabilizer, the first to be approved by the US 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 or 0.8–1.2 mEq/L (or millimolar). Signs and symptoms of toxicity include nausea, vomiting, diarrhea, and ataxia.[3] The most common side effects are lethargy and weight gain (up to 2 kilograms (4.4 lb)).[4] The less common side effects of using lithium are blurred vision, a slight tremble in the hands, and a feeling of being mildly ill. 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.[5]

Anticonvulsants

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Many agents described as "mood stabilizers" are also categorized as anticonvulsants. The term "anticonvulsant mood stabilizers" is sometimes used to describe these as a class.[6] Although this group is also defined by effect rather than mechanism, there is at least a preliminary understanding of the mechanism of most of the anticonvulsants used in the treatment of mood disorders.[citation needed]

Valproate
Available in extended release form. This drug can be very irritating to the stomach, especially when taken as a free acid. Liver function and CBC should be monitored. Common side effects include sleepiness, nausea, dry mouth. More serious side effects include liver dysfunction, pancreatitis and polycystic ovary syndrome.[7][8] Weight gain is possible.[9]
Lamotrigine (aka Lamictal)
FDA approved for bipolar disorder maintenance therapy, not for acute mood problems like depression or mania/hypomania.[10] The usual target dose is 100–200 mg daily, titrated to by 25 mg increments every 2 weeks.[11] Lamotrigine can cause Stevens–Johnson syndrome, a very rare but potentially fatal skin condition.[10]
Carbamazepine
FDA approved for the treatment of acute manic or mixed (i.e., both depressed and manic mood features) episodes in people with bipolar disorder type I.[12] Carbamazepine can rarely cause a dangerous decrease in neutrophils, a type of white blood cell, called agranulocytosis.[12] It interacts with many medications, including other mood stabilizers (e.g. lamotrigine) and antipsychotics (e.g. quetiapine).[12] It is considered second-line for bipolar disorder due to its side effects.[13]

There is insufficient evidence to support the use of various other anticonvulsants, such as gabapentin and topiramate, as mood stabilizers.[14]

Antipsychotics

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Some atypical antipsychotics (aripiprazole, asenapine, cariprazine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) also have mood stabilizing effects[15] and are thus commonly prescribed even when psychotic symptoms are absent.[15]

Other

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Omega-3 fatty acids
It is also conjectured that omega-3 fatty acids may have a mood stabilizing effect.[16] 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.[17]
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 300 mcg daily dose of levothyroxine (T4) found it superior to placebo for this purpose. In general, studies have shown T4 to be well tolerated and to show efficacy even in patients without overt hypothyroidism.[18] Hypothyrodism is common among bipolar patients regardless of the mood stabilizer used.[19]

Combination therapy

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In routine practice, monotherapy is often not sufficiently effective for acute and/or maintenance therapy and thus most patients are given combination therapies.[20] Combination therapy (atypical antipsychotic with lithium or valproate) shows better efficacy over monotherapy in the manic phase in terms of efficacy and prevention of relapse.[20] However, side effects are more frequent and discontinuation rates due to adverse events are higher with combination therapy than with monotherapy.[20]

Relationship to antidepressants

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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.[21][22][23]

See also: SSRI § Bipolar switch

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%),[24] psychosis (relative risk not reported),[25] cycle acceleration,[22] 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.[26] 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.[22] Gitlin (2018) notes that "the potential issue of worsening suicidality in adolescents and young adults treated with antidepressants [...] both controversial and infrequently seen."[22]

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.[22]

Pharmacodynamics

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As mentioned above, "mood stabilizers" do not have a unified mechanism of action; the term simply describes how these drugs can be used.

The precise mechanism of action of lithium is still unknown, and it is suspected that it acts at various points of the neuron between the nucleus and the synapse. Lithium is known to inhibit the enzyme GSK-3B. This improves the functioning of the circadian clock—which is thought to be often malfunctioning in people with bipolar disorder—and positively modulates gene transcription of brain-derived neurotrophic factor (BDNF). The resulting increase in neural plasticity may be central to lithium's therapeutic effects. How lithium works in the human body is not completely understood, but its benefits are most likely related to its effects on electrolytes such as potassium, sodium, calcium and magnesium.[27] Lithium is, broadly speaking, neuroprotective.[28]

The classical theory of valporate's action involves affecting GABA levels and blocking voltage-gated sodium channels (which would affect the brain's glutamate system).[29] It has since been found to have many other cellular effects, such as inhibiting histone deacetylases and increasing LEF1.[30] It is also neuroprotective.[28]

Carbamazepine is mainly a sodium channel blocker, though it too has other activities.[31] Lamotrigine is a similar case.[32]

See also: Atypical antipsychotic § Pharmacodynamics

One possible downstream target of several mood stabilizers such as lithium, valproate, and carbamazepine is the arachidonic acid cascade.[33]

See also

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Categories

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Mood stabilizers
Drug classes defined by psychological effects
Drugs by psychological effects
Psychoactive drugs

References

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  1. ^ "Texas State - Student Health Center". Archived from the original on 2008-08-28.
  2. ^ "Schizoaffective disorder - Diagnosis and treatment - Mayo Clinic". www.mayoclinic.org. Mayo Foundation for Medical Education and Research. Retrieved 10 July 2020.
  3. ^ Marmol, F. (2008). "Lithium: Bipolar disorder and neurodegenerative diseases Possible cellular mechanisms of the therapeutic effects of lithium". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 32 (8): 1761–1771. doi:10.1016/j.pnpbp.2008.08.012. PMID 18789369. S2CID 25861243.
  4. ^ Malhi GS, Tanious M, Bargh D, Das P, Berk M (2013). "Safe and effective use of lithium". Australian Prescriber. 36: 18–21. doi:10.18773/austprescr.2013.008.
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  10. ^ a b "Lamictal – FDA Prescibing Information".
  11. ^ Healy D. 2005 Psychiatric Drugs explained 4th ed. Churchill Liviingstone: London p.110
  12. ^ a b c "EQUETRO(carbamazepine) Package Insert" (PDF). Validus Pharmaceuticals LLC. Retrieved 10 July 2020.
  13. ^ Nevitt SJ, Marson AG, Weston J, Tudur Smith C (August 2018). "Sodium valproate versus phenytoin monotherapy for epilepsy: an individual participant data review". The Cochrane Database of Systematic Reviews. 2018 (8): CD001769. doi:10.1002/14651858.CD001769.pub4. PMC 6513104. PMID 30091458.
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  16. ^ Mirnikjoo B, Brown SE, Kim HF, Marangell LB, Sweatt JD, Weeber EJ (April 2001). "Protein kinase inhibition by omega-3 fatty acids". J. Biol. Chem. 276 (14): 10888–96. doi:10.1074/jbc.M008150200. PMID 11152679.
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  18. ^ AMA Chakrabarti S. Thyroid Functions and Bipolar Affective Disorder. Journal of Thyroid Research. 2011;2011:306367. doi:10.4061/2011/306367. MLA Chakrabarti, Subho. "Thyroid Functions and Bipolar Affective Disorder". Journal of Thyroid Research 2011 (2011): 306367. PMC. Web. 19 May 2017. APA Chakrabarti, S. (2011). Thyroid Functions and Bipolar Affective Disorder. Journal of Thyroid Research, 2011, 306367. http://doi.org/10.4061/2011/306367
  19. ^ Lambert CG, Mazurie AJ, Lauve NR, Hurwitz NG, Young SS, Obenchain RL, Hengartner NW, Perkins DJ, Tohen M, Kerner B (May 2016). "Hypothyroidism risk compared among nine common bipolar disorder therapies in a large US cohort". Bipolar Disorders. 18 (3): 247–260. doi:10.1111/bdi.12391. PMC 5089566. PMID 27226264.
  20. ^ a b c Geoffroy, P. A.; Etain, B.; Henry, C.; Bellivier, F. (2012). "Combination Therapy for Manic Phases: A Critical Review of a Common Practice". CNS Neuroscience & Therapeutics. 18 (12): 957–964. doi:10.1111/cns.12017. PMC 6493634. PMID 23095277.
  21. ^ Chris Aiken: Antidepressants in Bipolar II Disorder, May 14, 2019. In: psychiatrictimes.com
  22. ^ a b c d e Gitlin MJ (December 2018). "Antidepressants in bipolar depression: an enduring controversy". International Journal of Bipolar Disorders. 6 (1): 25. doi:10.1186/s40345-018-0133-9. PMC 6269438. PMID 30506151.
  23. ^ Viktorin A, Lichtenstein P, Thase ME, Larsson H, Lundholm C, Magnusson PK, Landén M (October 2014). "The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer". The American Journal of Psychiatry. 171 (10): 1067–1073. doi:10.1176/appi.ajp.2014.13111501. hdl:10616/42159. PMID 24935197. S2CID 25152608.
  24. ^ Patel, Rashmi (2015). "Do antidepressants increase the risk of mania and bipolar disorder in people with depression? A retrospective electronic case register cohort study". BMJ Open. 5 (12): e008341. doi:10.1136/bmjopen-2015-008341. PMC 4679886. PMID 26667012.
  25. ^ Preda, A; MacLean, RW; Mazure, CM; Bowers MB, Jr (January 2001). "Antidepressant-associated mania and psychosis resulting in psychiatric admissions". The Journal of Clinical Psychiatry. 62 (1): 30–3. doi:10.4088/jcp.v62n0107. PMID 11235925.
  26. ^ 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/
  27. ^ 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.
  28. ^ a b Quiroz JA, Machado-Vieira R, Zarate CA, Manji HK (2010). "Novel insights into lithium's mechanism of action: neurotrophic and neuroprotective effects". Neuropsychobiology. 62 (1): 50–60. doi:10.1159/000314310. PMC 2889681. PMID 20453535.
  29. ^ Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, Altman RB, Klein TE (April 2013). "Valproic acid pathway: pharmacokinetics and pharmacodynamics". Pharmacogenetics and Genomics. 23 (4): 236–241. doi:10.1097/FPC.0b013e32835ea0b2. PMC 3696515. PMID 23407051.
  30. ^ 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 (June 2021). "Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients". Molecular Psychiatry. 26 (6): 2440–2456. doi:10.1038/s41380-020-00981-3. PMC 9129103. PMID 33398088.
  31. ^ Rogawski MA, Löscher W, Rho JM (May 2016). "Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet". Cold Spring Harbor Perspectives in Medicine. 6 (5): a022780. doi:10.1101/cshperspect.a022780. PMC 4852797. PMID 26801895.
  32. ^ "Prescribing Information for LAMICTAL (lamotrigine)" (PDF). FDA. Archived (PDF) from the original on 12 January 2020. Retrieved 12 January 2020.
  33. ^ Rao JS, Lee HJ, Rapoport SI, Bazinet RP (June 2008). "Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?". Mol. Psychiatry. 13 (6): 585–96. doi:10.1038/mp.2008.31. PMID 18347600. S2CID 21273538.
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