What are first generation mood stabilizers? An In-Depth Pharmacological Review

October 14, 2025 •

4 min read

An estimated 4.4% of U.S. adults experience bipolar disorder at some point in their lives, an illness often managed with cornerstone medications [1.9.1]. So, what are first generation mood stabilizers, and what role do they play in treatment?

Quick Summary

First-generation mood stabilizers are a class of medications foundational to treating bipolar disorder. This group includes lithium and anticonvulsants like valproate and carbamazepine, which help manage mood episodes.

Key Points

Core Agents: First-generation mood stabilizers primarily include lithium, valproate (valproic acid), and carbamazepine [1.2.3].
Gold Standard: Lithium is considered the 'classic' mood stabilizer, highly effective for mania and noted for its anti-suicidal properties [1.2.2, 1.2.3].
Anticonvulsant Use: Valproate and carbamazepine are anticonvulsants also used to treat bipolar disorder, especially mixed or rapid-cycling types [1.2.4].
Monitoring is Crucial: These medications require regular blood tests to monitor drug levels and check for side effects on organs like the kidneys, thyroid, and liver [1.8.1, 1.4.2].
Significant Side Effects: All first-generation agents have notable side effects, ranging from weight gain and tremors to serious risks like organ damage and severe skin reactions [1.10.3, 1.6.3].
Pregnancy Risks: Valproate is highly teratogenic and should be avoided in women of childbearing potential due to the risk of birth defects [1.2.2, 1.5.2].
Enduring Relevance: Despite newer medications, first-generation mood stabilizers remain a foundational treatment for many individuals with bipolar disorder [1.3.2].

The Foundation of Bipolar Disorder Treatment

First-generation mood stabilizers (FGMS) represent the earliest class of medications proven effective for managing the significant mood shifts characteristic of bipolar disorder [1.7.1]. Introduced between the 1960s and 1970s, these agents remain a critical part of the psychiatric medication toolkit, particularly for controlling manic episodes and preventing recurrence [1.3.2, 1.2.3]. The primary first-generation mood stabilizers include lithium, often considered the "classic" or "gold standard" treatment, and a few anticonvulsant medications, namely valproate (valproic acid/divalproex sodium) and carbamazepine [1.2.2, 1.2.3]. These medications are prescribed to treat acute manic and depressive symptoms and for long-term maintenance to prevent relapses [1.2.3]. For treatment to be most effective, it should combine medication with psychotherapy [1.2.3].

The Core First-Generation Agents

The main medications classified as first-generation mood stabilizers are:

Lithium: Approved by the FDA for bipolar disorder, lithium is highly effective in treating mania and is one of the few psychiatric medications with proven anti-suicidal properties [1.2.2, 1.2.3]. Its exact mechanism is complex, but it's known to modulate the phosphoinositol pathway in the brain [1.2.4].
Valproate (Valproic Acid / Divalproex Sodium): An anticonvulsant medication also used for mood stabilization, particularly for patients with mixed or rapid-cycling bipolar disorder [1.2.4, 1.5.3]. It is available in immediate-release and extended-release formulations, the latter of which can help reduce gastrointestinal side effects [1.5.3].
Carbamazepine: Another anticonvulsant, carbamazepine is typically considered a second-line treatment option for bipolar disorder when others are not effective [1.2.2, 1.6.2]. It acts primarily by inhibiting sodium channels [1.2.2].

Mechanism of Action and Therapeutic Use

While their chemical structures differ, first-generation mood stabilizers work by influencing various neurotransmitter systems and intracellular signaling pathways to stabilize mood. Lithium, for example, is thought to affect chemicals like serotonin in the brain [1.4.3]. Carbamazepine's primary action involves blocking sodium channels, which helps to calm brain activity [1.2.2]. These medications are crucial for managing the extreme highs (mania) and lows (depression) of bipolar disorder. Lithium is particularly revered for its effectiveness against mania, while valproate is often used for mixed states and rapid cycling [1.2.3, 1.2.4].

An essential aspect of using these medications is the need for therapeutic drug monitoring (TDM) [1.8.2]. Because agents like lithium have a narrow therapeutic index—meaning the difference between a therapeutic dose and a toxic dose is small—regular blood tests are required to ensure the drug levels are within a safe and effective range [1.2.2, 1.8.2]. Monitoring for valproate and carbamazepine is also recommended to optimize dosage and check for potential adverse effects on the liver and blood cells [1.8.1, 1.10.2].

Side Effects and Long-Term Considerations

Patients taking first-generation mood stabilizers can experience a range of side effects. Many are mild and transient, but some can be serious or develop with long-term use [1.10.2].

Lithium: Common initial side effects include nausea, thirst, frequent urination, and hand tremors [1.4.3]. Long-term use carries risks for the kidneys and thyroid gland, necessitating regular monitoring of renal and thyroid function [1.2.2, 1.4.2]. Weight gain is also a possible long-term effect [1.4.2].
Valproate: Common side effects include drowsiness, nausea, weight gain, and hair loss [1.5.5, 1.10.3]. More serious risks include liver damage, pancreatitis, and a decrease in blood platelets [1.5.5, 1.5.3]. This medication should be avoided by women of childbearing age due to a high risk of birth defects, such as neural tube defects [1.2.2, 1.5.2].
Carbamazepine: Can cause dizziness, drowsiness, ataxia (problems with coordination), nausea, and vomiting [1.6.2]. It carries a black box warning for potentially severe and fatal skin reactions like Stevens-Johnson syndrome (SJS), particularly in individuals of Han Chinese ancestry with the HLA-B*1502 gene [1.6.3, 1.6.2]. It can also cause a dangerous drop in white blood cells (agranulocytosis) [1.2.2].

Comparison of First-Generation Mood Stabilizers


Feature	Lithium	Valproate (Valproic Acid)	Carbamazepine
Primary Use	Gold standard for classic mania, maintenance, anti-suicidal [1.2.2, 1.2.4]	Mixed episodes, rapid cycling [1.2.4]	Second-line for bipolar disorder, often when other agents fail [1.2.2, 1.6.2]
Common Side Effects	Thirst, polyuria, tremor, weight gain, nausea [1.4.3, 1.10.3]	Nausea, weight gain, hair loss, drowsiness, tremor [1.5.5, 1.10.3]	Dizziness, drowsiness, ataxia, nausea, dry mouth [1.6.2, 1.6.3]
Serious Risks	Kidney and thyroid dysfunction, lithium toxicity [1.2.2, 1.4.2]	Liver toxicity, pancreatitis, thrombocytopenia, high risk of birth defects [1.5.3, 1.5.2]	Agranulocytosis, Stevens-Johnson Syndrome (SJS), liver problems [1.2.2, 1.6.3]
Monitoring	Regular blood levels, kidney & thyroid function tests [1.8.1]	Liver function tests, complete blood counts (CBCs), blood levels [1.5.3, 1.8.1]	Liver function tests, CBCs, blood levels, HLA-B*1502 screening for at-risk populations [1.6.1, 1.6.3]

Conclusion: An Enduring Legacy in Psychiatry

Despite the development of second-generation mood stabilizers (which include atypical antipsychotics), first-generation agents like lithium, valproate, and carbamazepine remain indispensable tools in pharmacology [1.7.1, 1.3.2]. Their proven efficacy, particularly lithium's unique anti-suicidal properties, ensures their continued use [1.2.3]. However, their significant side effect profiles and the need for careful monitoring require a collaborative relationship between patient and clinician. Treatment decisions must balance the benefits of mood stabilization against the potential risks, tailoring the choice of medication to the individual's specific symptoms, medical history, and tolerance.

For more information on bipolar disorder, you can visit the National Institute of Mental Health (NIMH).

Frequently Asked Questions

The three main first-generation mood stabilizers are lithium, valproate (also known as valproic acid or divalproex), and carbamazepine [1.2.3].

Lithium is often called the 'gold standard' because it was the first medication approved by the FDA for bipolar disorder, is highly effective for treating mania, and has unique anti-suicidal effects [1.2.2, 1.2.4].

Mood stabilizers like lithium are not considered addictive. They work to control mood swings rather than producing a 'high' [1.4.3].

Patients typically require regular blood tests to check the medication level in their blood, as well as tests to monitor kidney function, thyroid function (for lithium), and liver function and blood counts (for valproate and carbamazepine) [1.8.1, 1.10.2].

It is critical to discuss this with a doctor. Valproate is contraindicated for migraine prophylaxis in pregnant women and should be avoided if possible due to a high risk of birth defects [1.5.2]. Lithium and carbamazepine also carry risks and must be carefully managed by a healthcare provider during pregnancy [1.4.3, 1.6.3].

First-generation mood stabilizers include lithium and older anticonvulsants introduced in the 1960s-70s [1.7.1]. Second-generation mood stabilizers, which began emerging in the 1990s, include atypical antipsychotics (like olanzapine and quetiapine) and the anticonvulsant lamotrigine [1.7.1].

Common side effects of lithium can include increased thirst, frequent urination, hand tremor, nausea, and weight gain. Many of these may improve over time [1.4.3, 1.2.2].