Introduction
Mania is a mood state characterised by an expansive or irritable mood, increased energy and activity, racing thoughts, pressured speech, decreased need for sleep, and reckless or impulsive behaviours that can have painful consequences. Mania is the defining feature of bipolar I disorder and also occurs in bipolar II disorder and cyclothymic disorder (American Psychiatric Association, 2013). Pharmacotherapy is the primary treatment approach for acute mania and maintenance treatment of bipolar disorder. This chapter will review the medications used to treat mania, their proposed mechanisms of action, side effect profiles, and supporting evidence from clinical trials.
Lithium
Lithium is the oldest and most well-established medication for the treatment of mania. It is a monovalent cation that is thought to work by modulating intracellular signalling cascades and gene expression (Malhi et al., 2013). Lithium inhibits the enzyme glycogen synthase kinase-3 (GSK3), which is involved in regulating circadian rhythms, neuronal plasticity, and apoptosis (Jope, 2003). GSK3 inhibition increases the activity of the transcription factor β-catenin, which may underlie some of lithium’s mood-stabilizing effects (Valvezan & Klein, 2012). Lithium also inhibits inositol monophosphatase (IMPase), leading to the depletion of inositol and the dampening of the phosphoinositide signalling system, which is overactive in mania (Berridge, 2014).
Several meta-analyses have confirmed lithium’s efficacy for acute mania (Yildiz et al., 2011; Cipriani et al., 2011). In a network meta-analysis of 68 randomized controlled trials (RCTs) involving 16,073 participants, lithium was more effective than placebo for acute mania with an effect size of 0.40 (95% credible interval 0.28 to 0.53) (Cipriani et al., 2011). Lithium had comparable efficacy to several atypical antipsychotics but was less effective than haloperidol (effect size 0.19).
Lithium also has robust evidence for maintenance treatment. In a meta-analysis of 9 RCTs with 825 patients, lithium reduced the risk of any mood episode by 42% compared to placebo over 1 year (risk ratio 0.58, 95% CI 0.46 to 0.73) (Severus et al., 2014). The number needed to treat (NNT) for the prevention of a manic episode was 6, and the NNT for the prevention of a depressive episode was 8.
Lithium has a narrow therapeutic index, so careful dosing and monitoring are required. Common side effects include nausea, diarrhoea, polyuria, polydipsia, weight gain, tremor, and cognitive impairment (Grandjean & Aubry, 2009). Lithium can also cause hypothyroidism, hyperparathyroidism, and nephrogenic diabetes insipidus. Toxic levels can lead to neurologic symptoms, seizures, coma, and death. Therapeutic drug monitoring with regular serum levels and monitoring of renal and thyroid function are necessary. The typical therapeutic range is 0.6-1.2 mEq/L, with higher levels of 0.8-1.2 mEq/L often used for acute mania (Yatham et al., 2018).
Anticonvulsants
Several anticonvulsant medications are FDA-approved for the treatment of acute mania, including valproate, carbamazepine, and lamotrigine. These medications are thought to work by modulating neuronal excitability and synaptic plasticity through effects on voltage-gated sodium and calcium channels, GABAergic neurotransmission, and intracellular signalling pathways (Rogawski & Löscher, 2004).
Valproate is an inhibitor of the enzyme histone deacetylase (HDAC), which regulates gene expression through chromatin remodelling (Phiel et al., 2001). Valproate increases the expression of neurotrophic factors and has neuroprotective effects in animal models (Yasuda et al., 2009). Valproate is highly protein bound and is metabolized hepatically via glucuronide conjugation and oxidation by cytochrome P450 enzymes (Ghodke-Puranik et al., 2013).
Valproate has demonstrated efficacy for acute mania in several RCTs and meta-analyses. A meta-analysis of 10 RCTs with 1,217 participants found that valproate reduced manic symptoms with a standardized mean difference (SMD) of 0.30 (95% CI 0.12 to 0.48) relative to placebo (Yildiz et al., 2010). Valproate had similar efficacy to lithium (SMD 0.04) and olanzapine (SMD 0.05) but was less effective than haloperidol (SMD 0.36).
For maintenance treatment, a meta-analysis of 4 RCTs with 374 patients found that valproate reduced the risk of manic or mixed episodes by 32% compared to placebo (risk ratio 0.68, 95% CI 0.49 to 0.94) but did not significantly reduce depressive episodes (Smith et al., 2010). The NNT for the prevention of a mood episode was 8.
Common side effects of valproate include gastrointestinal symptoms, sedation, tremor, weight gain, hair loss, and thrombocytopenia (Zajecka et al., 2010). Rare but serious adverse events include hepatotoxicity, pancreatitis, and hyperammonemia encephalopathy. Valproate is also a known teratogen and should be avoided in women of childbearing age if possible. Therapeutic drug monitoring is recommended, with a target serum level of 50-125 mcg/mL (Yatham et al., 2018).
Carbamazepine is an older anticonvulsant that has FDA approval for acute mania but is less commonly used due to tolerability issues and drug interactions. Carbamazepine blocks voltage-gated sodium channels and potentiates GABAergic inhibition (Ambrosio et al., 2002). It is a potent inducer of cytochrome P450 enzymes and can lower levels of many other medications.
In a meta-analysis of 8 RCTs with 875 patients, carbamazepine reduced manic symptoms with an effect size of 0.36 relative to placebo but was less effective than haloperidol or olanzapine (Yildiz et al., 2010). Carbamazepine has not consistently demonstrated efficacy for maintenance treatment in meta-analyses (Yildiz et al., 2011).
Common side effects of carbamazepine include dizziness, diplopia, sedation, ataxia, and hyponatremia (Keck et al., 2004). Rare but serious adverse effects include agranulocytosis, liver toxicity, and Stevens-Johnson syndrome. Therapeutic drug monitoring is recommended, with a target serum level of 4-12 mcg/mL.
Lamotrigine is an anticonvulsant with FDA approval for the maintenance treatment of bipolar I disorder. Its mechanism of action involves the inhibition of voltage-gated sodium channels and the modulation of glutamate release (Lees & Leach, 1993). Lamotrigine is metabolized primarily by glucuronidation and does not have significant effects on the cytochrome P450 system.
Lamotrigine has not demonstrated consistent efficacy for acute mania in RCTs or meta-analyses (Yildiz et al., 2011). However, it has shown benefits for bipolar depression and for the prevention of mood episodes, particularly depressive episodes. In a meta-analysis of 5 RCTs with 1,072 patients, lamotrigine reduced the risk of a depressive episode by 36% compared to placebo (risk ratio 0.64, 95% CI 0.44 to 0.94) but did not significantly reduce manic episodes (Geddes et al., 2009). The NNT for the prevention of a depressive episode was 11.
The most concerning adverse effect of lamotrigine is a severe rash, which rarely progresses to Stevens-Johnson syndrome or toxic epidermal necrolysis. The risk is highest in the first 2-8 weeks of treatment. Slow titration reduces the risk of rash. Other common side effects include dizziness, ataxia, somnolence, and headache (Goldsmith et al., 2003). Therapeutic drug monitoring is not necessary.
Atypical Antipsychotics
The atypical antipsychotics are a class of medications that have efficacy for both the manic and depressive phases of bipolar disorder. Several atypical antipsychotics have FDA approval for acute mania, including aripiprazole, asenapine, cariprazine, olanzapine, quetiapine, risperidone, and ziprasidone. Lurasidone is approved for bipolar depression. The primary mechanism of action of atypical antipsychotics is the blockade of dopamine D2 receptors and serotonin 5-HT2A receptors, although each medication has a unique receptor binding profile (Meltzer, 2013).
Meta-analyses have consistently demonstrated the efficacy of atypical antipsychotics for acute mania. In a network meta-analysis of 68 RCTs, 12 different atypical antipsychotics were superior to placebo, with effect sizes ranging from 0.22 to 0.66 (Cipriani et al., 2011). The most effective agents were risperidone, olanzapine, and haloperidol. Combination therapy with lithium or valproate was more effective than monotherapy for most medications.
Several atypical antipsychotics have also demonstrated efficacy for maintenance treatment. In a meta-analysis of 17 RCTs with 3,798 patients, atypical antipsychotics reduced the risk of any mood episode by 27% compared to placebo (risk ratio 0.73, 95% CI 0.65 to 0.83) (Lindström et al., 2017). The NNT for the prevention of a mood episode was 10. Olanzapine, quetiapine, and risperidone had the most robust evidence for maintenance efficacy.
The side effect profiles of atypical antipsychotics vary based on their receptor binding affinities. Common adverse effects include sedation, weight gain, metabolic disturbances, hyperprolactinemia, and extrapyramidal symptoms (Abi-Dargham & Laruelle, 2005). Clozapine and olanzapine are the most likely to cause weight gain and metabolic side effects, while risperidone and paliperidone are more likely to cause extrapyramidal symptoms and prolactin elevation. Monitoring for metabolic parameters and movement disorders is recommended.
Novel and Emerging Treatments
In addition to the established treatments for mania, several novel and emerging therapies are being investigated. Ketamine, an NMDA receptor antagonist, has shown rapid antidepressant effects in bipolar depression and may have antimanic effects as well (Diazgranados et al., 2010). Ketamine is administered as an intravenous infusion and has a risk of dissociative side effects and abuse potential.
Modafinil is a wake-promoting agent that has been studied as an adjunctive treatment for bipolar depression. In a meta-analysis of 6 RCTs with 910 patients, modafinil improved depressive symptoms with an SMD of 0.23 (95% CI 0.06 to 0.40) but did not significantly reduce manic symptoms (Goss et al., 2013). Modafinil was generally well tolerated, with the most common side effects being headache, nausea, and insomnia.
Pramipexole is a dopamine agonist that has been investigated as a treatment for both bipolar depression and mania. In a small RCT of 22 patients with acute mania, pramipexole was superior to placebo in reducing manic symptoms (Zarate et al., 2004). However, another RCT found no significant difference between pramipexole and placebo for bipolar depression (Goldberg et al., 2004). Larger trials are needed to clarify the role of pramipexole in bipolar disorder.
Inositol is a naturally occurring isomer of glucose that is involved in the phosphoinositide second messenger system. Decreased inositol levels have been associated with mania, and inositol supplementation has been proposed as a potential treatment (Chengappa et al., 2000). In a small RCT of 24 patients with acute mania, inositol was superior to placebo in reducing manic symptoms, with an effect size of 0.81 (Chengappa et al., 2000). However, this finding requires replication in larger trials.
Tamoxifen is an estrogen receptor modulator that has shown antimanic effects in preliminary studies. Tamoxifen inhibits protein kinase C (PKC), which is involved in regulating neurotransmitter release and intracellular signalling (Bebchuk et al., 2000). In a meta-analysis of 5 RCTs with 371 patients, tamoxifen was superior to placebo in reducing manic symptoms, with an SMD of 0.58 (95% CI 0.31 to 0.86) (Yildiz et al., 2016). However, tamoxifen has a risk of venous thromboembolism and endometrial cancer, so its use in bipolar disorder remains investigational.
Conclusion
In summary, pharmacotherapy is an essential component of the treatment of mania. Lithium, valproate, and atypical antipsychotics have the most robust evidence for efficacy in acute mania and maintenance treatment. Other anticonvulsants, such as carbamazepine and lamotrigine, have more limited evidence but may be useful in specific patient populations. Emerging treatments such as ketamine, modafinil, pramipexole, inositol, and tamoxifen are promising but require further study. The choice of medication should be individualized based on the patient’s symptom profile, comorbidities, and personal preferences. Careful monitoring for side effects and therapeutic response is essential. With appropriate pharmacotherapy and supportive care, many patients with bipolar disorder are able to achieve remission and lead fulfilling lives.
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