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.

A bottle of lithium capsules. Lithium is the prototypical mood stabilizer.

Uses

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

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
  • 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 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. 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.[4]

Anticonvulsants

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.[5] 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.

  • 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.[6]
  • Lamotrigine – FDA approved for bipolar disorder maintenance therapy, not for acute mood problems like depression or mania/hypomania.[7] The usual target dose is 100–200 mg daily, titrated to by 25 mg increments every 2 weeks.[8] Lamotrigine can cause Stevens–Johnson syndrome, a very rare but potentially fatal skin condition.[7]
  • 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.[9] Carbamazepine can rarely cause a dangerous decrease in neutrophils, a type of white blood cell, called agranulocytosis.[9] It interacts with many medications, including other mood stabilizers (e.g. lamotrigine) and antipsychotics (e.g. quetiapine).[9]

There is insufficient evidence to support the use of various other anticonvulsants, such as gabapentin and topiramate, as mood stabilizers.[10]

Antipsychotics

Other
  • It is also conjectured that omega-3 fatty acids may have a mood stabilizing effect.[12] 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.[13]
  • 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.[14]

Combination therapy

In routine practice, monotherapy is often not sufficiently effective for acute and/or maintenance therapy and thus most patients are given combination therapies.[15] 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.[15] However, side effects are more frequent and discontinuation rates due to adverse events are higher with combination therapy than with monotherapy.[15]

Relationship to antidepressants

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.

Nevertheless, antidepressants are still often prescribed in addition to mood stabilizers during depressive phases. This brings some risks, however, as antidepressants can induce mania,[16] psychosis,[17] 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.[18] The majority of antidepressants appear ineffective in treating bipolar depression.[18]

Antidepressants cause several risks when given to bipolar patients. They are ineffective in treating acute bipolar depression, preventing relapse, and can cause rapid cycling. Studies have shown that antidepressants have no benefit versus a placebo or other treatment. Antidepressants can also lead to a higher rate of non-lethal suicidal behavior. Relapse can also be related to treatment with antidepressants. This is less likely to occur if a mood stabilizer is combined with an antidepressant, rather than an antidepressant being used alone. Evidence from previous studies shows that rapid cycling is linked to use of antidepressants. Rapid cycling is defined as the presence of four or more mood episodes within a year's time. Evidence suggests that rapid cycling and mixed symptoms have become more common since antidepressant medication has come into widespread use. There is a need for caution when treating bipolar patients with antidepressant medication due to the risks that they pose.

Use of mood stabilizers and anticonvulsants such as lamotrigine, carbamazapine, valproate and others may lead to chronic folate deficiency, potentiating depression. Also, "Folate deficiency may increase the risk of depression and reduce the action of antidepressants."[19] L-methylfolate (also formally known as 5-MTHF or levomefolic acid), a centrally acting trimonoamine modulator, boosts the synthesis of three CNS neurotransmitters: dopamine, norepinephrine and serotonin. Mood stabilizers and anticonvulsants may interfere with folic acid absorption and L-methylfolate formation. Augmentation with the medical food L-methylfolate may improve antidepressant effects of these medicines, including lithium and antidepressants themselves, by boosting the synthesis of antidepressant neurotransmitters. However, the U.S. National Institutes of Health issued a warning caution about the use of L-methylfolate for patients with bipolar disease.[20]

Pharmacodynamics

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.[21]

All of the anticonvulsants routinely used to treat bipolar disorder are blockers of voltage-gated sodium channels, affecting the brain's glutamate system. For valproic acid, carbamazepine and oxcarbazepine, however, their mood-stabilizing effects may be more related to effects on the GABAergic system. Lamotrigine is known to decrease the patient's cortisol response to stress.

One possible downstream target of several mood stabilizers such as lithium, valproate, and carbamazepine is the arachidonic acid cascade.[22]

See also

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

References
  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.
  4. Kozier, B et al. (2008). Fundamentals Of Nursing, Concepts, Process, and Practice. London: Pearson Education. p. 189.
  5. Ichikawa J, Dai J, Meltzer HY (July 2005). "Lithium differs from anticonvulsant mood stabilizers in prefrontal cortical and accumbal dopamine release: role of 5-HT(1A) receptor agonism". Brain Res. 1049 (2): 182–90. doi:10.1016/j.brainres.2005.05.005. PMID 15936730.
  6. "Depakote 500mg Tablets". electronic Medicine Compendium. Dataphram Communications Limited. Retrieved 28 September 2016.
  7. "Lamictal – FDA Prescibing Information".
  8. Healy D. 2005 Psychiatric Drugs explained 4th ed. Churchill Liviingstone: London p.110
  9. "EQUETRO(carbamazepine) Package Insert" (PDF). Validus Pharmaceuticals LLC. Retrieved 10 July 2020.
  10. Terence A. Ketter (3 May 2007). Advances in Treatment of Bipolar Disorder. American Psychiatric Pub. p. 42. ISBN 978-1-58562-666-3.
  11. Bowden CL (2005). "Atypical antipsychotic augmentation of mood stabilizer therapy in bipolar disorder". J Clin Psychiatry. 66. Suppl 3: 12–9. PMID 15762830.
  12. 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.
  13. Gao, K.; Calabrese, J. R. (2005). "Newer treatment studies for bipolar depression". Bipolar Disorders. 7 (s5): 13–23. doi:10.1111/j.1399-5618.2005.00250.x. PMID 16225556.
  14. 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
  15. 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.
  16. 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.
  17. 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.
  18. 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/
  19. Stephen M. Stahl, MD, PhD. Novel Therapeutics for Depression: L-methylfolate as a Trimonoamine Modulator and Antidepressant-Augmenting Agent. http://www.cnsspectrums.com/aspx/articledetail.aspx?articleid=1267.
  20. L-METHYLFOLATE CALCIUM- levomefolate calcium tablet, coated
  21. 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.
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