Normotimics: drugs for mood stabilization

Mood stabilizers, or mood stabilizers, are a group of medications that reduce the risk of recurrent episodes of mania, hypomania, and depression and smooth out mood swings in people with bipolar disorder and certain other mood disorders. Unlike "sedatives" or sleeping pills, their goal is not simply to "calm" the here and now, but to stabilize emotional states over the long term and reduce the risk of relapse. [1]

A key area of application for mood stabilizers is bipolar disorder. Here, they are used both to relieve acute episodes (primarily mania and mixed states) and for maintenance therapy between episodes. Major modern guidelines for the treatment of bipolar disorder consider mood stabilizers to be the foundation of pharmacotherapy, with all other drug groups considered adjuncts or treatments for specific phases of the disease. [2]

Traditionally, "classic" mood stabilizers include lithium and certain antiepileptic drugs with proven mood-stabilizing effects: valproate, carbamazepine, and lamotrigine. In recent decades, some atypical antipsychotics have been added to this list, demonstrating a robust preventive effect against mania and depression. If a drug reduces the risk of recurrent episodes, acts on more than just one phase (for example, only mania), and maintains this effect with long-term use, it is considered a mood stabilizer. [3]

It's important to remember that mood stabilizers are not "mood pills" in the common sense. They are not intended for episodic sadness, grief reactions, or stress in otherwise healthy individuals. They are prescribed for diagnosed bipolar disorder, schizoaffective disorder, and certain other severe affective conditions where a reduction in the number and severity of episodes has been demonstrated. Attempts to use these medications as "mood enhancers" without a diagnosis are dangerous due to their side effects and are not justified by evidence-based medicine. [4]

Mood stabilizers differ from antidepressants in that they should not, on their own, trigger a phase reversal (for example, a transition from depression to mania). This is why, in bipolar disorder, antidepressants are typically prescribed only in conjunction with a mood stabilizer to reduce the risk of phase reversal. Current guidelines emphasize that the use of antidepressants alone in patients with bipolar disorder without the protection of a mood stabilizer is considered unsafe. [5]

Table 1. Normotimics, antidepressants and tranquilizers: what are the differences?

Drug class	The main task	How does it affect mood?	Main risks with long-term use
Normotimics	Prevention of mania and depression	Reduces the amplitude and frequency of episodes	Organ toxicity, metabolic and skin reactions
Antidepressants	Treatment of depression	Improves mood, reduces anxiety	Risk of phase inversion in bipolar disorder
Tranquilizers and sleeping pills	Rapid reduction of anxiety, improved sleep	Brief sedative effect	Addiction, memory impairment, falls

The main groups of normothymic drugs: lithium, antiepileptic drugs and atypical antipsychotics

Lithium was historically the first and remains one of the most effective mood stabilizers. It reduces the risk of recurrent episodes of mania and depression, as well as lowers the risk of suicidal behavior in people with bipolar disorder. However, lithium requires strict monitoring of blood levels and kidney and thyroid function, as therapeutic concentrations are close to toxic. Despite this, research and clinical experience continue to confirm its key role in the long-term treatment of bipolar disorder. [6]

Valproate (various salts of valproic acid) is an antiepileptic drug, but has long been used as a mood stabilizer. It is particularly effective for mania, mixed episodes, and rapid cycling. Guidelines consider it one of the primary drugs for the treatment of mania and the prevention of recurrent episodes, especially when lithium is contraindicated or poorly tolerated. However, valproate is highly teratogenic and should not be used in women of childbearing age without reliable contraception and a thorough discussion of the risks. [7]

Carbamazepine and its derivatives are also used as mood stabilizers, particularly in patients who are ineffective or intolerant to lithium and valproate. It can be useful in acute mania and in maintenance therapy, but it has numerous drug interactions and can cause serious hematological and skin reactions. Therefore, the use of carbamazepine requires regular monitoring of blood and liver function, as well as caution when taking other medications concomitantly. [8]

Lamotrigine differs from other mood stabilizers in that it is most effective in preventing depressive episodes and significantly less effective in treating acute mania. Guidelines emphasize that its primary role is the long-term prevention of depression in bipolar disorder, particularly type II. The main risk of lamotrigine is serious skin reactions, including Stevens-Johnson syndrome, so the drug is always titrated very slowly, and if a rash appears, its severity is immediately assessed. [9]

Some atypical antipsychotics (e.g., quetiapine, olanzapine, aripiprazole, lurasidone) also have a mood-stabilizing effect. They are used for both mania and depression, as well as in maintenance therapy. Some are registered for relapse prevention in bipolar disorder. However, their main "cost" for effectiveness is metabolic disturbances: weight gain, changes in glucose and lipid levels, and a possible increase in prolactin. Therefore, with long-term use, regular monitoring of body weight, sugar, and lipid profile is necessary. [10]

Table 2. Main normothymic agents: brief description

Preparation	The strongest effect	Typical role in therapy	Key risks
Lithium	Mania and depression, suicide prevention	Basic long-acting mood stabilizer	Kidney and thyroid damage, intoxication
Valproate	Mania, mixed states	Alternative to lithium, fast cycles	Teratogenicity, liver damage, weight gain
Carbamazepine	Mania	Reserve for intolerance to lithium and valproate	Hematological and skin reactions, interactions
Lamotrigine	Prevention of depression	Long-term prevention, especially for bipolar II disorder	Skin reactions, need for slow titration
Atypical antipsychotics with normothymic action	Mania, depression, support	Combinations and monotherapy in different phases	Metabolic syndrome, endocrine disorders

Indications and place of normothymic drugs in modern recommendations

The primary indication for prescribing mood stabilizers is bipolar I and II disorder. Clinical guidelines from various countries agree that lithium, valproate, carbamazepine, lamotrigine, and some atypical antipsychotics form the basis of treatment regimens for mania and relapse prevention. The choice of a specific drug depends on the current phase, medical history, tolerability, comorbidities, and patient preferences. [11]

For acute mania and mixed episodes, the first step is often a mood stabilizer, sometimes in combination with an antipsychotic. Guidelines note that combining a mood stabilizer with an atypical antipsychotic provides more rapid symptom reduction in severely ill patients than monotherapy. Valproate and carbamazepine are traditionally considered particularly useful for mixed and rapidly alternating episodes, while lithium is more effective for "classic" mania. [12]

In bipolar depression, mood stabilizers play a protective role against phase reversal. Current guidelines emphasize that antidepressants alone should not be used in bipolar disorder without the protection of a stabilizer, as this increases the risk of transitioning to mania or a mixed state. Lithium and lamotrigine, as well as some atypical antipsychotics with proven antidepressant effects, are considered standard medications for bipolar depression. [13]

In maintenance therapy, mood stabilizers are prescribed for years and often for life if the patient has had severe episodes of mania or depression, suicide attempts, or frequent relapses. Meta-analyses show that long-term lithium use reduces the frequency of episodes and lowers the risk of suicide compared to no mood stabilizer. For each patient, the benefits of prevention are weighed against the risks of long-term toxicity, which requires regular follow-up examinations. [14]

In addition to bipolar disorder, mood stabilizers can be used for schizoaffective disorders, some persistent depressive disorders with a "suspected" bipolar spectrum, and in special cases to reduce aggression and impulsivity (most often in the context of other diagnoses). However, such prescriptions extend beyond the basic indications and require the involvement of a psychiatrist with experience working with the affective spectrum. Guidelines emphasize that bipolar disorder, organic diseases, and substance abuse must be carefully excluded before expanding the indications. [15]

Table 3. Where normothymic agents are first-line therapy, and where they are a reserve

Situation	The role of normothymic agents
Bipolar disorder with mania or mixed episode	The mainstay of therapy, often in combination with an antipsychotic
Bipolar depression	Basic phase inversion protection, platform for other drugs
Maintenance therapy for bipolar disorder	Long-term prevention of relapses
Schizoaffective disorder	Combined Circuit Component
Recurrent depressive disorder with suspected bipolar spectrum	Considered individually after diagnosis clarification

How mood stabilizers are prescribed: regimens, combinations, and treatment duration

Prescribing mood stabilizers almost always begins with a slow dose titration. This is especially important for lithium and lamotrigine, where too rapid titration to a high dose increases the risk of toxicity and severe skin reactions. Lithium is titrated to maintain blood levels within the therapeutic range, which varies slightly among guidelines but always requires regular laboratory monitoring. For lamotrigine, standard protocols for gradual dose increases over several weeks apply. [16]

Mood stabilizers are often combined with antipsychotics, antidepressants, and sleep aids, depending on the phase and predominant symptoms. In acute mania or severe mixed symptoms, an atypical antipsychotic is added to the mood stabilizer, which accelerates the relief of agitation and delusional ideas. In bipolar depression, atypical antipsychotics with antidepressant properties can be added to lithium or lamotrigine. Antidepressants are used cautiously and only in conjunction with a mood stabilizer to reduce the risk of phase inversion. [17]

The duration of treatment depends on the diagnosis and medical history. After the first episode of bipolar disorder, long-term prophylactic treatment is considered, especially if the episode was severe or accompanied by suicidal behavior. After several episodes of mania or depression, a mood stabilizer is usually recommended as long-term or lifelong therapy. International guidelines emphasize that premature discontinuation of the drug significantly increases the risk of relapse, especially in the first months after discontinuation. [18]

It is important to gradually taper off mood stabilizers. For lithium and antiepileptic mood stabilizers (valproate, carbamazepine, lamotrigine), it is recommended to reduce the dose over at least several weeks, and preferably months, to reduce the risk of a sharp exacerbation of symptoms and relapse. When discontinuing atypical antipsychotics, a gradual tapering is also used, taking into account the risk of withdrawal syndrome and symptom relapse. [19]

Patient counseling is crucial. The patient must understand why they are prescribed a mood stabilizer, what changes are expected, how quickly an effect is likely, what tests are needed, and what symptoms require urgent medical attention (for example, a rash with lamotrigine, severe thirst and tremors with lithotherapy, or sudden weight changes with atypical antipsychotics). The better informed the patient, the higher their treatment adherence and the lower the risk of spontaneous discontinuation as their well-being improves. [20]

Table 4. Examples of tactics for prescribing normothymic agents (generally)

A psychiatrist always selects specific doses and regimens; the table is indicative only.

Situation	Generalized approach
The First Mania	Starting a normothymic with slow titration; in severe cases, adding an atypical antipsychotic
Recurrent episodes of mania and depression	Continuation or change of mood stabilizer, discussion of long-term prevention
Bipolar depression	Lithium or lamotrigine as basic therapy, with the addition of an atypical antipsychotic if necessary
Fast cycling	Often the emphasis is on valproate, combinations with other mood stabilizers are possible
Decision to cancel	Only gradually, with a plan to monitor symptoms

Safety of normothymic agents and necessary monitoring

Safety is a key concern when using mood stabilizers long-term. Regular blood tests are mandatory for lithium, including monitoring lithium levels, kidney function (creatinine, glomerular filtration rate), electrolyte levels, and thyroid hormones. This is due to the risk of chronic kidney damage, hypothyroidism, and possible toxicity due to dehydration and when combined with certain painkillers and diuretics. Patients are advised to maintain adequate fluid intake and exercise caution with sudden changes in diet or exercise. [21]

For valproate, the key risks are liver toxicity, coagulation disorders, and weight changes. Before and during treatment, liver enzymes, platelet levels, and sometimes ammonia are assessed, as well as weight gain and symptoms of pancreatitis. Particular attention is paid to women of childbearing age: all international and national recommendations emphasize that valproate should not be used in them without a strict contraception program due to the high risk of congenital malformations and developmental disorders in the fetus. [22]

Carbamazepine requires monitoring of a complete blood count (risk of leukopenia and agranulocytosis), liver function tests, and sodium levels, as hyponatremia is possible. Furthermore, it actively affects liver enzymes, accelerating the metabolism of many drugs, leading to decreased concentrations. This is important to consider when combining with contraceptives, anticoagulants, antipsychotics, and other medications. If a rash, fever, sore throat, or signs of infection appear, immediate examination and testing are necessary. [23]

Lamotrigine is relatively well-tolerated, but can cause severe skin reactions. Therefore, the first and foremost safety rule is slow titration and discontinuation of the drug if a worrying rash appears. The doctor will explain in detail to the patient which skin manifestations require urgent medical attention. Potential drug interactions are also taken into account: for example, valproate slows the metabolism of lamotrigine and requires even more careful dosage increases. [24]

Atypical antipsychotics with a mood-stabilizing effect are associated primarily with metabolic disturbances. Body weight, waist circumference, glucose levels, lipids, and sometimes prolactin are regularly monitored. If significant abnormalities are detected, medication modification, non-drug measures (diet, physical activity), and, if necessary, consultation with an endocrinologist are considered. Some medications also increase the risk of prolongation of the QT interval on an electrocardiogram, so individuals with cardiovascular problems require additional cardiac monitoring. [25]

Table 5. What is usually monitored when taking normothymic drugs

Drug or group	What is checked before and during the process?
Lithium	Lithium concentration, creatinine, glomerular filtration rate, electrolytes, thyroid hormones
Valproate	Liver enzymes, platelets, body weight, symptoms of pancreatitis
Carbamazepine	Complete blood count, liver enzymes, sodium levels
Lamotrigine	Skin reactions, drug interactions, liver and blood, if necessary
Atypical antipsychotics	Weight, waist circumference, glucose, lipid profile, sometimes prolactin and electrocardiogram

Special patient groups: children, the elderly, pregnant women and people with underlying medical conditions

In children and adolescents, the use of mood stabilizers requires particularly careful justification and is generally performed only by a psychiatrist familiar with childhood and adolescence. Diagnosing bipolar disorder in young patients is complex, and many cases previously considered "early bipolar disorder" are later found to have other mood or developmental disorders. Guidelines emphasize the need for long-term observation, careful diagnosis, and prioritization of psychoeducation and psychotherapy, with pharmacotherapy recommended only for severe symptoms. [26]

In elderly patients, mood stabilizers are prescribed taking into account age-related decline in renal and hepatic function, polypharmacy, and the increased risk of falls. For lithium, this means lower target concentrations, more frequent laboratory monitoring, and maximum avoidance of drug combinations that increase the risk of intoxication. For atypical antipsychotics, attention is focused on the risk of stroke, thrombosis, and metabolic syndrome, so in geriatric practice, an effort is made to use the lowest effective doses and the shortest possible courses where possible. [27]

Pregnancy and breastfeeding present particular challenges. Lithium is associated with an increased risk of certain congenital malformations when taken in the first trimester, valproate carries a high risk of neural tube defects and other serious developmental disorders, and carbamazepine also has teratogenic potential. Therefore, the choice of therapy for women with bipolar disorder planning a pregnancy or already pregnant is always individualized and is determined jointly by a psychiatrist, obstetrician, and the patient, with a discussion of all risks and alternatives, including non-pharmacological and psychotherapeutic approaches. [28]

People with severe somatic diseases (kidney, liver, heart, endocrine disorders) also require treatment adaptations. In chronic kidney disease, lithium is often contraindicated or requires replacement with other stabilizers. In cases of severe liver dysfunction, the drug with the lowest liver load is used, and regimens with a minimal number of medications are selected. It is important for the psychiatrist and somatic specialists to work together, and for the patient to understand why a particular mood stabilizer can or cannot be used in their situation. [29]

Finally, special attention is given to patients at high risk of suicide. Lithium is particularly valuable for them, as numerous studies have shown a reduction in the incidence of suicide attempts and completed suicides with long-term use. It is one of the few psychotropic drugs with such a robust antisuicide effect, which is taken into account when choosing a treatment regimen for people with severe bipolar disorder and a history of suicidal behavior. [30]

Table 6. Normotimics in special clinical situations

Situation	Main limitation or emphasis
Children and teenagers	Cautious diagnostics, priority psychotherapy, only in severe forms of the disease
Elderly	Reduced doses, frequent monitoring, avoidance of polypharmacy
Pregnancy and breastfeeding	Strict risk assessment, avoiding valproate and high doses of lithium if possible
Chronic somatic diseases	Selection of a drug taking into account organ function, interdisciplinary management
High suicide risk	Lithium is often preferred as a drug with anti-suicide effect

Frequently asked questions about mood stabilizers

Question: Is a mood stabilizer a lifelong medication?
Answer: Not always, but often – yes. For a single mild episode, a limited-time course is possible, but for recurring manic and depressive episodes, especially severe ones and those with suicidal attempts, a mood stabilizer is often recommended as long-term or lifelong therapy. The decision is always made individually, taking into account tolerability and how effectively the drug reduces the frequency of relapses in that particular person. [31]

Question: Is it possible to "come off lithium" or another mood stabilizer on your own if you feel better?
Answer: On your own – no. Abrupt withdrawal increases the risk of relapse, sometimes more severe than previous episodes. International guidelines recommend tapering the dose gradually, over weeks or months, while monitoring symptoms and testing. If you want to stop taking the medication, it's worth discussing this with a psychiatrist, who can help assess the risks and suggest a safe plan. [32]

Question: Is it possible to drink alcohol while taking mood stabilizers?
Answer: Alcohol increases mood swings, impairs sleep, increases the risk of injury, and can interact with medications, enhancing their sedative effect or affecting the liver. With lithium, it also increases the risk of dehydration and intoxication. Therefore, for bipolar disorder and those taking mood stabilizers, it is usually recommended to either completely abstain from alcohol or limit it as much as possible, and be sure to discuss this with your doctor. [33]

Question: Is a combination of several mood stabilizers and antipsychotics always necessary?
Answer: No. In many cases, it is possible to find effective monotherapy with a single drug. Combinations are used for severe, treatment-resistant forms of the disease, with rapid phase alternation, or with pronounced psychotic symptoms. However, any combination increases the risk of side effects and interactions, so the addition of a second or third drug must be carefully justified. [34]

Question: Is it possible to switch from one mood stabilizer to another if it's not suitable?
Answer: This is common clinical practice. If a medication is poorly tolerated or doesn't produce the expected effect, a doctor may suggest switching to another stabilizer or adding a second one followed by discontinuing the first. It's important that the transition be planned: one medication is tapered gradually, while the other is increased simultaneously, taking into account test results and overall well-being. Abrupt changes on your own increase the risk of relapse and complications. [35]

Table 7. What the patient can do to ensure that treatment with normothymic drugs is as safe as possible

Patient's step	Why is this necessary?
Take medications strictly as prescribed	Reduce the risk of ineffectiveness and side effects
Don't miss follow-up tests and visits	Identify toxicity early and adjust the regimen
Tell your doctor about all other medications and supplements.	Prevent dangerous interactions
Monitor your weight, sleep, and energy levels	Notice early signs of relapse and metabolic disturbances
Discuss any thoughts about stopping or changing the dose	Avoid withdrawal symptoms and sudden worsening of the condition