Mood stabilizer

A mood stabilizer is a psychiatric pharmaceutical drug used to treat mood disorders characterized by intense and sustained mood shifts, typically bipolar disorder type I or type II or schizophrenia.

Uses

Used to treat bipolar disorder,^[1] mood stabilizers suppress swings between mania and depression. Mood-stabilizing drugs are also used in borderline personality disorder^[2] and schizoaffective disorder.

Examples

The term "mood stabilizer" does not describe a mechanism, but rather an effect. More precise terminology is used to 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, 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.

• Valproic acid (Depakine), valproate semisodium (Depakote), and sodium valproate (Depacon, Epilim) – Available in extended release form. This drug can be very irritating to the stomach, especially when taken as valproic acid. Liver function and CBC should be monitored.
• Lamotrigine (Lamictal) – Particularly effective for bipolar depression. Usual dose is 100–200 mg daily, which can be built up by 25 mg every 2 weeks.^[6] The patient should be monitored for signs and symptoms of Stevens–Johnson syndrome, a very rare but potentially fatal skin condition.^[7]
• Carbamazepine (Tegretol) – CBC should be monitored, as carbamazepine can lower white blood cell count. Therapeutic drug monitoring is required. Carbamazepine was approved by the US Food and Drug Administration as a bipolar disorder treatment in 2005, but had been widely used previously.
• Oxcarbazepine (Trileptal) – Oxcarbazepine is not FDA approved for bipolar disorder. Still, it appears to be effective in about one-half of patients with bipolar disorder and is generally well tolerated.^[8]

There is insufficient evidence to support the use of various other anticonvulsants, such as gabapentin and topiramate, as mood stabilizers.^[9]

Antipsychotics

• Some atypical antipsychotics (aripiprazole, risperidone, olanzapine, quetiapine, asenapine, paliperidone, ziprasidone, and lurasidone) also have mood stabilizing effects^[10] and are thus commonly prescribed even when psychotic symptoms are absent.^[10]

Other

• It is also conjectured that omega-3 fatty acids may have a mood stabilizing effect.^[11] 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.^[12]
• 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 0.300 mg daily dose of levothyroxine (T4) found it superior to placebo for this purpose. The study, conducted in Germany, has not been published in English. In general, studies have shown T4 to be well-tolerated and to show efficacy even in patients without overt hypothyroidism.

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.^[13] 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.^[13] However, side effects are more frequent and discontinuation rates due to adverse events are higher with combination therapy than with monotherapy.^[13]

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 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, psychosis, 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.^[14] The majority of antidepressants appear ineffective in treating bipolar depression.^[14]

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 been 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."^[15] L-methylfolate (also formally known as 5-MTHF or Levofolinic 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.^[16]

Mechanism

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 has the effect relieving pressure on 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. Lithium may also increase the synthesis of serotonin.

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.^[17]

See also

• ATC code N03
• Treatment of bipolar disorder

References

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2. "NIMH and Borderline Personality Disorder".
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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.
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11. 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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13. 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. PMID 23095277.
14. 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/
15. 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.
16. L-METHYLFOLATE CALCIUM- levomefolate calcium tablet, coated
17. 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.