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A mood stabilizer is a psychiatric medication used to treat characterized by intense and sustained mood swing, such as bipolar disorder and the bipolar type of schizoaffective disorder.
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.
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.
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.Kozier, B et al. (2008). Fundamentals Of Nursing: Concepts, Process, and Practice. London: Pearson Education. p. 189. Long-term lithium therapy also carries risks such as hypothyroidism and chronic kidney disease, requiring periodic monitoring of thyroid and renal function.
It is also one of the few drugs with proven anti-suicidal properties, making it unique among psychiatric medications. In addition to its effects on suicide, lithium also decreases all-cause mortality in people with mood disorders.
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.
This drug can be very irritating to the stomach, especially when taken as a free acid. Requires regular 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. Weight gain is possible.
It is recommended that women of childbearing age should avoid using valproate due its Teratology potential, including the increased risk of neural tube defects, even with Folate supplementation. In the United Kingdom and European Union, valproate has been restricted for women and men under age 55 due to pregnancy and fertility concerns.
While using carbamazepine, the effectiveness of oral contraceptive is significantly decreased, and it also has Teratology potential.
There is insufficient evidence to support the use of various other anticonvulsants, such as gabapentin and topiramate, as mood stabilizers.
Most studies have been conducted on an open-label basis. One large, controlled study of a 300 mcg daily dose of Levothyroxine 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.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 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. Hypothyroidism is common among patients with bipolar disorder regardless of the mood stabilizer used.
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%), psychosis (relative risk not reported), cycle acceleration, 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.Amit BH, Weizman A. Antidepressant Treatment for Acute Bipolar Depression: An Update. Depression Research and Treatment Internet. 2012 cited;2012:1–10. Available from: http://www.hindawi.com/journals/drt/2012/684725/
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. Gitlin (2018) notes that "the potential issue of worsening suicidality in adolescents and young adults treated with antidepressants ... both controversial and infrequently seen."
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.
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. Lithium is also known to inhibit the enzyme GSK-3B, which helps regulate the circadian rhythm. If the circadian rhythm is disrupted, it may lead to key traits of bipolar disorder, like mood episodes.
Chronic use of lithium helps regulate gene transcription of brain-derived neurotrophic factor (BDNF). This boosts Neuroplasticity; 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.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. Lithium is generally neuroprotective.
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. It also decreases the expression of Glutamic acid receptors; thus decreasing neuronal excitability.
In addition, valproate blocks sodium, potassium and calcium voltage-gated channels, and this reduces how often neurons fire. 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. It is also neuroprotective.
Carbamazepine is another anticonvulsant that functions mainly as a sodium channel blocker. Voltage-gated sodium channels are found on the cell membrane of neurons and help create . Carbamazepine keeps these channels inactivated, which stops continuous action potential firing. 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.
Lamotrigine lowers excitatory nerve signaling in the central nervous system by lowering Glutamic acid release. In addition, it increases inhibitory nerve signaling by boosting GABA release. 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.
Pharmacodynamics
Pharmacodynamics refers to the study of the biochemical and cellular effects of medications, as well as their mechanisms of action. 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. This mechanism includes the reduction of inositol, a compound involved in many pathways that lead to increased cell signaling in the brain. When these pathways are inhibited or blocked, the mood stabilizing effect is accomplished. Another possible target of several mood stabilizers is the arachidonic acid cascade.
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