Continuing Education Activity

Mood stabilizers are a class of medications used in the management and treatment of bipolar disorder. This activity outlines the indications, action, and contraindications for mood stabilizers as valuable agents in managing and treating bipolar disorder. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent to members of the healthcare team in the management and treatment of patients with bipolar disorder and related conditions.

Objectives:

• Identify the mechanism of action of mood stabilizers in the treatment of bipolar disorder.
• Describe the potential adverse effects of mood stabilizers.
• Review the appropriate follow-up monitoring for mood stabilizers.
• Summarize the importance of collaboration and communication amongst the interprofessional team to improve outcomes for patients receiving treatment with mood stabilizers.

Indications

One of the strongest indications for mood stabilizers is bipolar disorder, a mood disorder comprised of two types. Bipolar I disorder is defined by at least one manic episode in a lifetime, while bipolar II disorder is defined by at least one past or present hypomanic episode with at least one past or present major depressive episode.[1] The manic and depressive characteristics of bipolar disorder require particular mood stabilizers that can cater to the patient’s individual needs.

Different agents belonging to the mood stabilizer class of medications have strengths and weaknesses owing to their indications, contraindications, and their protocol for follow-up. Clinicians are encouraged to choose a mood stabilizer keeping these different factors in mind so that patient outcomes may improve by an informed choice made in the pharmacological management of patients with bipolar disorder.

FDA-Approved Indications[1]

• Lithium has approval as monotherapy or combination therapy for acute manic episodes and as maintenance therapy in bipolar disorder.
• Divalproex is approved as monotherapy or combination therapy for acute manic episodes and may be used for complex partial, simple, and absence seizures and as migraine headache prophylaxis. 
• Carbamazepine has approval for monotherapy and combination therapy for acute manic and mixed episodes in bipolar disorder and may additionally be a treatment for seizure disorders and trigeminal neuralgia.
• Lamotrigine is approved for maintenance therapy in bipolar disorder and also as an anti-seizure medication. 

Non-FDA Approved Indications

• Lithium and divalproex may be used off-label in the treatment of mixed bipolar episodes. Clinicians may use lithium may additionally for schizoaffective disorder and divalproex as a bipolar maintenance treatment.

Mechanism of Action

Although there is still more to discover about the particulars of lithium, valproic acid/divalproex, and carbamazepine, a suggested common mechanism for their mood-stabilizing abilities is inhibition of the inositol uptake process, resulting in inositol depletion. In this proposed mechanism, the myo-inositol monophosphate transporter and its respective mRNA become downregulated by the above-mentioned three major mood-stabilizing agents.[2] The mechanisms of individual key mood-stabilizing agents are discussed in further detail below:

Lithium: Lithium’s mechanism of action is still under investigation for its neuroprotective benefits. However, the currently proposed inositol depletion hypothesis explains that lithium downregulates polyphosphoinositide signaling by acting as an uncompetitive inhibitor of inositol monophosphatase and inositol polyphosphate 1-phosphatase. Thus, lithium inhibits neuronal excitation, leading to its benefits as a mood stabilizer.[3][4]

Divalproex: Divalproex—or valproate, valproic acid—is an anticonvulsant drug that functions as a mood stabilizer and antiepileptic agent by enhancing the inhibitory effect of gamma aminobutyric-acid (GABA). This therapy reduces repetitive neuronal firing and can reduce inhibition and excitation within neuronal networks.[5][6]

Carbamazepine: Carbamazepine follows suit with the other mood-stabilizing agents mentioned, with an additional specific mechanism of action identified wherein cAMP accumulation becomes inhibited, resulting in the downregulation of the inositol transporter.[2][7]

Lamotrigine: Lamotrigine, like valproate, is an anticonvulsant. Its mechanism of action involves reducing only the frequency (and not amplitude) of excitatory postsynaptic currents in the CNS, causing a decrease in glutamate release while causing a concomitant increase in frequency and amplitude of inhibitory postsynaptic currents, which enhances GABA release. Therefore, lamotrigine causes opposite effects on glutamate and GABA transmission, downregulating glutamate release and increasing GABA release.[8]

Administration

• Lithium is currently available for use in tablets, capsules, and solution forms.[9]
• Valproic acid is available as a tablet, capsule, and solution.[10]
• Carbamazepine is available in tablet, capsule, and chewable forms.[11]
• Lamotrigine is available as a tablet in oral dissolving and chewable forms.

Adverse Effects

Lithium: Lithium may cause tremors, weight gain, or lead to hypothyroidism. Due to lithium's excretion via the kidneys, adverse effects manifest in the form of nephrogenic diabetes insipidus and, more rarely, chronic tubulointerstitial nephritis. About 20 to 40% of patients taking lithium chronically develop polyuria and polydipsia. Fortunately, the nephrogenic diabetes insipidus that occurs due to lithium therapy is managed similarly with thiazide diuretics, NSAIDs, and a low salt diet. 

Valproic Acid: Valproic acid's adverse effects include weight gain and GI disturbances such as nausea and vomiting, as well as alopecia, tremor, and easy bruising, most probably owing to its effects on coagulation. About 5 to 10% of patients placed on a long-term valproic acid regimen develop transaminitis, although a substantial amount of cases resolve on their own without necessity for discontinuing the regimen. Other more serious forms of valproic acid toxicity include encephalopathy secondary to hyperammonemia, hepatotoxicity, and acute pancreatitis. The risk of teratogenicity (especially when using valproic acid as monotherapy) is a discussion topic below.

Carbamazepine: Carbamazepine has both systemic and neurological side effects. The systemic adverse effects are dual-faceted, including GI and integumentary systems. GI upset is characterized by nausea, vomiting, diarrhea, and hyponatremia. The integumentary issues characteristically are pruritis and rash. The neurologic defects associated with carbamazepine therapy include headache, dizziness, vision changes (blurry or diplopia), lethargy, and drowsiness.

Lamotrigine:  Lamotrigine therapy has a similar adverse effect profile as carbamazepine in that it involves rash and nausea as prominent side effects. Neurologic side effects include diplopia, dizziness, and tremor.

The adverse effects of the different mood stabilizers appear in further detail under the 'Contraindications' and 'Toxicity' headings below. 

Contraindications

Prescribers need to pay attention to the metabolism and processing of the mood-stabilizing agents as their accumulation in the body can lead to their toxicities and adverse effects.

Lithium clearance is through the kidneys. As renal function decreases with age, prescribers should exercise caution in patients over the age of 60 and those with renal failure.[9] Additionally, lithium should be avoided in those with cardiac failure due to its ability to alter the functioning of the sodium-potassium transporter, which can worsen arrhythmias. Lithium should be discontinued within the first three months of pregnancy, and the decision to resume therapy is up to the patient’s psychiatrist and whether the benefits of treatment outweigh the risks. There is some evidence that lithium can cause facial malformations in infants born to mothers on lithium therapy. Lithium teratogenicity is rare compared to other mood stabilizers mentioned in this article: valproic acid, carbamazepine, and lamotrigine.[12]

Valproic acid should be avoided in pregnancy and harbors a serious adverse effect of fatal hepatotoxicity. It may also cause pancreatitis, SIADH, hyponatremia, headache, nausea, vomiting, weight gain, diarrhea, and abdominal pain.[10]

Lamotrigine and carbamazepine are both capable of causing Stevens-Johnson syndrome; therefore, patients should learn to monitor themselves for any skin changes or new rashes after initiation of a mood stabilizer regimen with either of these drugs.[11][13]

Monitoring

Before initiating lithium therapy, the clinician should perform a thorough physical exam that includes palpation of the thyroid gland and obtain creatinine, blood urea nitrogen, and thyroid function test, including T3, T4, and TSH levels, along with a urinalysis and electrocardiogram.[9]

Due to valproic acid’s ability to cause fatal hepatotoxicity, LFTs are necessary before initiating therapy to establish a baseline for the comparison of LFTs for follow-up monitoring.[10]

Toxicity

Treatment with the ion lithium affects multiple organ systems, most notably the central nervous system and the GI system, causing tremors, twitching, drowsiness, a feeling of sluggishness, vomiting, diarrhea, and loss of appetite. Most minor symptoms of toxicity are treatable by adjustment of the medication dose.[9] 

Lithium's toxicity profile is also remarkable for a decreased ability to concentrate urine, hypothyroidism, weight gain, and hyperparathyroidism. The use of lithium during pregnancy is not without risks, so assessing the benefits vs. risks is a requirement before discontinuing lithium during pregnancy. Hyperparathyroidism is a consistent finding associated with lithium use, so calcium levels should be checked before and monitored throughout the duration of pharmacotherapy. It bears mention that elderly patients are more vulnerable to lithium toxicity. In cases of lithium toxicity, dialysis can be performed and is the treatment of choice, owing to lithium's low molecular weight. Lithium clearance should be maximized in hypovolemic patients by normalizing sodium and water in patients with low-volume status.[14]

Valproic acid toxicity is manifested most commonly as central nervous system depression and potential cerebral edema, potentially leading to coma and respiratory depression. These manifestations can occur alongside pancreatitis and hyperammonemia. The healthcare team needs to recognize toxicity as management requires a focus on maintaining the airway and supportive care.[15]

Enhancing Healthcare Team Outcomes

Mood stabilizers represent a class of medications that can be expertly used in treatment regimens for bipolar mania and bipolar depression when used and managed correctly. The evaluation of specific mood-stabilizing agents must be tailored to each patient’s diagnosis and needs; this is where a team-based approach to pharmacologic management of bipolar disorder is well-deserved. The fact that the common medications included in this class have significant drug-drug interactions merits close scrutiny. Therefore, the patient’s clinician should always confer with a pharmacist to decide which agent would perform best, given the patient’s current needs.

Aside from the initial council necessary before initiating a mood stabilizer regimen, the patient will need to follow up regularly for monitoring. Nursing can play a significant role in both of these activities. This will ensure that the agent is both functional and efficacious for the patient and not causing any untoward side effects or toxicities. In this way, clinicians and their teams of vital nursing and aid staff can keep a close watch on patients to ensure that the drugs they are taking are still working in their favor.

Overall, everyone on the interprofessional healthcare team: clinicians, nurses, and pharmacists, can benefit from broadening their knowledge on the distinguishing characteristics of the different major mood stabilizers. Regarding the receiving and admitting process of patients, medical staff should be clinically knowledgeable about the various agents that their patients might be on, for it could be a reason or, at the very least, a related etiology as to their hospital or outpatient clinic visit in the first place. A more widespread knowledge about these agents would be beneficial to have or learn from any hospital standpoint.

In short, interprofessional management of mood-stabilizing medications will lead to better patient outcomes with fewer adverse events. [Level 5]