Lamictal - Does it work as a Depression Treatment?

Depression is a common and serious mental health condition that affects millions of people worldwide. It can cause persistent feelings of sadness, hopelessness, guilt, and loss of interest in activities that were once enjoyable. Depression can also interfere with daily functioning, such as work, school, and relationships. There are many treatments available for depression, including medication, psychotherapy, and lifestyle changes. However, not everyone responds well to the same treatment, and some people may need to try different options before finding the one that works best for them.

One of the medications that may be used to treat depression is lamotrigine, also known by its brand name Lamictal. Lamotrigine is an anticonvulsant drug that was originally developed to treat epilepsy, a neurological disorder that causes seizures. However, lamotrigine has also been found to have mood-stabilizing effects, which means it can help prevent or reduce the severity of mood swings in people with bipolar disorder, a condition that involves episodes of depression and mania (a state of elevated mood and energy). Lamotrigine is approved by the Food and Drug Administration (FDA) for the treatment of bipolar disorder in adults, but it is also used off-label (without FDA approval) for the treatment of depression in people who do not have bipolar disorder (also known as unipolar depression).

In this article, we will review the following aspects of lamotrigine for depression:

What it is
History
Mechanism of action
Evidence for use
Dosing
Side effects/adverse reactions/contraindications
Positives or pros
Negatives or cons
Conclusion
Sources

What it is

Lamotrigine is a medication that belongs to the class of anticonvulsants, which are drugs that prevent or reduce the frequency and intensity of seizures. Anticonvulsants work by affecting the activity of certain chemicals in the brain called neurotransmitters, which are involved in transmitting signals between nerve cells. Some of the neurotransmitters that lamotrigine affects are glutamate, gamma-aminobutyric acid (GABA), and serotonin.

Glutamate is an excitatory neurotransmitter, which means it stimulates nerve cells and increases their activity. Glutamate is essential for normal brain functioning, but too much glutamate can cause overexcitation and damage to nerve cells. This can lead to seizures or other neurological problems.

GABA is an inhibitory neurotransmitter, which means it reduces the activity of nerve cells and has a calming effect on the brain. GABA helps balance out the effects of glutamate and other excitatory neurotransmitters. GABA also plays a role in regulating mood, anxiety, sleep, and pain.

Serotonin is another neurotransmitter that has multiple functions in the brain. Serotonin is involved in regulating mood, appetite, sleep, memory, learning, and social behavior. Serotonin also affects other neurotransmitters, such as dopamine and norepinephrine, which are related to motivation, reward, and stress.

Lamotrigine works by inhibiting the release of glutamate and enhancing the activity of GABA and serotonin in the brain. By doing so, lamotrigine can prevent or reduce seizures and stabilize mood swings.

History

Lamotrigine was first synthesized in 1974 by scientists at GlaxoSmithKline (GSK), a pharmaceutical company based in the United Kingdom. Lamotrigine was initially developed as a potential antimalarial drug, but it was found to have anticonvulsant properties in animal studies. Lamotrigine was then tested in clinical trials for epilepsy and received FDA approval for this indication in 1994.

In 1995, GSK sponsored a study to evaluate the efficacy and safety of lamotrigine as an add-on therapy for treatment-resistant depression in adults. The results showed that lamotrigine was significantly more effective than placebo in improving depressive symptoms and quality of life. However, this study was not published until 2002.

In 1999, GSK applied for FDA approval of lamotrigine for bipolar disorder based on two clinical trials that demonstrated its effectiveness in preventing depressive episodes in people with bipolar I disorder (a type of bipolar disorder that involves at least one episode of mania). The FDA approved lamotrigine for this indication in 2003.

Since then, lamotrigine has been widely used off-label for various psychiatric conditions, including unipolar depression, bipolar II disorder (a type of bipolar disorder that involves at least one episode of hypomania), borderline personality disorder (a condition characterized by unstable mood, impulsive behavior, and difficulty maintaining relationships), post-traumatic stress disorder (PTSD), anxiety disorders, and obsessive-compulsive disorder (OCD).

Mechanism of action

The exact mechanism of action of lamotrigine for depression is not fully understood. However, it is believed that lamotrigine works by modulating the activity of several neurotransmitters in the brain, especially glutamate, GABA, and serotonin.

Glutamate is the main excitatory neurotransmitter in the brain and is involved in learning, memory, cognition, and neuroplasticity (the ability of the brain to change and adapt). However, excessive glutamate activity can cause neurotoxicity (damage to nerve cells) and neuroinflammation (inflammation in the brain), which can contribute to depression and other neuropsychiatric disorders. Lamotrigine inhibits the release of glutamate from nerve terminals and blocks the action of glutamate receptors on nerve cells. This reduces the overexcitation and neurotoxicity caused by glutamate and protects the brain from oxidative stress and inflammation.

GABA is the main inhibitory neurotransmitter in the brain and is involved in regulating mood, anxiety, sleep, and pain. Low levels of GABA can cause anxiety, insomnia, irritability, and depression. Lamotrigine enhances the activity of GABA by increasing its synthesis, release, and uptake by nerve cells. This increases the inhibitory effect of GABA on the brain and induces a calming and relaxing effect.

Serotonin is a neurotransmitter that regulates mood, appetite, sleep, memory, learning, and social behavior. Low levels of serotonin can cause depression, anxiety, aggression, impulsivity, and suicidal thoughts. Lamotrigine increases the activity of serotonin by inhibiting its reuptake by nerve cells and enhancing its release from nerve terminals. This increases the availability of serotonin in the brain and improves mood, motivation, and well-being.

By modulating the activity of these neurotransmitters, lamotrigine can restore the balance between excitation and inhibition in the brain and improve the symptoms of depression.

Evidence for use

There is evidence from several clinical trials that lamotrigine is effective for treating depression in people with bipolar disorder. Lamotrigine has been shown to prevent or delay depressive episodes in people with bipolar I disorder who have a history of depressive episodes. Lamotrigine has also been shown to improve depressive symptoms in people with bipolar II disorder who have a current depressive episode.

However, there is less evidence for the use of lamotrigine for treating depression in people who do not have bipolar disorder (unipolar depression). Most of the studies on lamotrigine for unipolar depression have been small, short-term, or open-label (without a placebo control). The results have been mixed, with some studies showing positive effects and others showing no difference between lamotrigine and placebo.

A meta-analysis (a statistical analysis that combines the results of multiple studies) published in 2016 reviewed 15 randomized controlled trials that compared lamotrigine with placebo or other antidepressants for unipolar depression. The meta-analysis found that lamotrigine was not significantly better than placebo or other antidepressants for improving depressive symptoms or response rates. However, lamotrigine was significantly better than placebo or other antidepressants for improving remission rates (the proportion of people who no longer meet the criteria for depression).

Another meta-analysis published in 2018 reviewed 12 randomized controlled trials that compared lamotrigine with placebo or other antidepressants for treatment-resistant depression (depression that does not respond to at least two adequate trials of antidepressants). The meta-analysis found that lamotrigine was significantly better than placebo or other antidepressants for improving depressive symptoms, response rates, and remission rates.

These meta-analyses suggest that lamotrigine may be more effective for treating treatment-resistant depression than non-resistant depression. However, more large-scale, long-term, and high-quality studies are needed to confirm the efficacy and safety of lamotrigine for unipolar depression.

Dosing

The dosing of lamotrigine depends on several factors, such as the indication (the condition being treated), the age of the patient, the presence of other medical conditions or medications, and the individual response to treatment. The dosing should be individualized by a health care provider who can monitor the patient’s progress and adjust the dose accordingly.

The following are some general guidelines for dosing lamotrigine for depression:

For bipolar disorder: The usual starting dose is 25 mg once daily for two weeks, followed by 50 mg once daily for two weeks. The dose is then increased by 50-100 mg every one to two weeks until reaching a maintenance dose of 100-200 mg per day. Some people may need higher doses up to 400 mg per day.
For unipolar depression: The usual starting dose is 25 mg once daily for two weeks, followed by 50 mg once daily for two weeks. The dose is then increased by 50 mg every one to two weeks until reaching a maintenance dose of 100-200 mg per day. Some people may need higher doses up to 400 mg per day.
For children: The dosing is based on body weight. The usual starting dose is 0.15 mg/kg per day, divided into two doses. The dose is then increased by 0.15 mg/kg every one to two weeks until reaching a maintenance dose of 1-5 mg/kg per day, divided into one or two doses. The maximum dose is 200 mg per day or 5 mg/kg per day, whichever is lower.

It is important to follow the dosing instructions carefully and not to change the dose or stop taking lamotrigine without consulting a health care provider. Lamotrigine should be taken at the same time each day, with or without food. Lamotrigine tablets should be swallowed whole and not chewed, crushed, or split. Lamotrigine chewable tablets should be chewed or dissolved in water before swallowing. Lamotrigine orally disintegrating tablets should be placed on the tongue and allowed to dissolve.

Lamotrigine should be started at a low dose and increased gradually to avoid serious side effects, such as a life-threatening skin rash. The dose may also need to be adjusted if lamotrigine is taken with other medications that affect its metabolism, such as valproate, carbamazepine, phenytoin, phenobarbital, primidone, rifampin, or estrogen-containing contraceptives.

Side effects/adverse reactions/contraindications

Lamotrigine can cause side effects in some people. The most common side effects are:

Dizziness
Headache
Nausea
Vomiting
Diarrhea
Constipation
Abdominal pain
Dry mouth
Blurred vision
Tremor
Insomnia
Fatigue
Somnolence
Rash
Irritability
Anxiety

Most of these side effects are mild and temporary and may improve over time as the body adjusts to the medication. However, some side effects may be serious and require medical attention. These include:

A severe skin rash that can cause blistering, peeling, or swelling of the skin, mouth, eyes, or genitals. This can be a sign of a rare but potentially fatal condition called Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). The risk of developing this condition is higher in the first eight weeks of treatment and when the dose is increased too quickly or too high. The risk is also higher in children and people who take valproate or have a genetic variation called HLA-B*1502. Anyone who develops a rash while taking lamotrigine should stop taking it and seek immediate medical attention.
A severe allergic reaction that can cause difficulty breathing, swelling of the face, lips, tongue, or throat, hives, itching, or anaphylaxis (a life-threatening reaction that can cause shock and organ failure). This can occur at any time during treatment and may be triggered by other factors such as food, insect bites, or infections. Anyone who experiences these symptoms while taking lamotrigine should stop taking it and seek emergency medical help.
A change in mood or behavior that can cause depression, suicidal thoughts or actions, mania, psychosis, aggression, hostility, or impulsivity. This can occur in people with or without a history of mental illness and may worsen existing conditions. Anyone who notices these changes while taking lamotrigine should contact their health care provider as soon as possible.
A decrease in blood cells that can cause anemia (low red blood cells), leukopenia (low white blood cells), thrombocytopenia (low platelets), or pancytopenia (low all blood cells). This can increase the risk of infections, bleeding, bruising, or fatigue. Anyone who develops signs of low blood cells while taking lamotrigine such as fever, sore throat, mouth ulcers, bleeding gums, nosebleeds, easy bruising, pale skin, weakness, or shortness of breath should contact their health care provider as soon as possible.
Aseptic meningitis (inflammation of the membranes that cover the brain and spinal cord) that can cause headache, fever, stiff neck, nausea, vomiting, sensitivity to light, or confusion. This can occur in people who are allergic to lamotrigine or have a history of immune system problems. Anyone who develops these symptoms while taking lamotrigine should contact their health care provider as soon as possible.
Liver problems that can cause jaundice (yellowing of the skin or eyes), dark urine, pale stools, nausea, vomiting, loss of appetite, or abdominal pain. This can occur in people who have a history of liver disease or take other medications that affect the liver. Anyone who develops these symptoms while taking lamotrigine should contact their health care provider as soon as possible.

Lamotrigine may also interact with other medications, supplements, or herbal products and cause unwanted effects or reduce its effectiveness. Some of the medications that may interact with lamotrigine include:

Valproate, carbamazepine, phenytoin, phenobarbital, primidone, rifampin, and estrogen-containing contraceptives: These medications can affect the metabolism of lamotrigine and change its blood levels. Valproate can increase the blood level of lamotrigine and increase the risk of side effects. Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, and estrogen-containing contraceptives can decrease the blood level of lamotrigine and reduce its effectiveness. The dose of lamotrigine may need to be adjusted if it is taken with these medications.
Antidepressants, antipsychotics, mood stabilizers, and other anticonvulsants: These medications can affect the activity of neurotransmitters in the brain and alter the mood-stabilizing effects of lamotrigine. The combination of these medications may increase the risk of side effects such as mood changes, suicidal thoughts or actions, or serotonin syndrome (a potentially life-threatening condition caused by too much serotonin in the brain). The symptoms of serotonin syndrome include agitation, confusion, hallucinations, fever, sweating, shivering, muscle stiffness or twitching, tremor, coordination problems, nausea, vomiting, diarrhea, or irregular heartbeat. Anyone who experiences these symptoms while taking lamotrigine and other medications that affect serotonin should seek emergency medical help.
Warfarin: This is a blood thinner that prevents blood clots. Lamotrigine can increase the effect of warfarin and increase the risk of bleeding. The dose of warfarin may need to be monitored and adjusted if it is taken with lamotrigine.
Oral contraceptives: These are birth control pills that contain estrogen and progestin. Lamotrigine can reduce the effectiveness of oral contraceptives and increase the risk of pregnancy. A backup method of contraception such as condoms should be used while taking lamotrigine and for one month after stopping it.

Lamotrigine is contraindicated (should not be used) in people who have:

A history of allergic reaction to lamotrigine or any of its ingredients
A history of SJS or TEN
A genetic variation called HLA-B*1502 (common in people of Asian descent)
A history of bone marrow suppression or blood disorders
A history of liver or kidney disease
A history of alcohol or drug abuse
A history of suicidal thoughts or actions
Pregnancy or breastfeeding (unless the benefits outweigh the risks)

Lamotrigine should be used with caution in people who have:

A history of mental illness such as depression, bipolar disorder, anxiety disorder, or schizophrenia
A history of epilepsy or other seizure disorders
A history of migraine or other headache disorders
A history of diabetes or other metabolic disorders
A history of glaucoma or other eye disorders
A history of HIV or other immune system disorders
A history of Parkinson’s disease or other movement disorders

Positives or pros

Lamotrigine has some advantages over other antidepressants and mood stabilizers, such as:

It has a relatively low risk of weight gain, sexual dysfunction, sedation, cognitive impairment, or withdrawal symptoms, which are common side effects of many antidepressants and mood stabilizers.
It has a relatively low risk of causing or worsening mania, hypomania, or rapid cycling, which are common complications of antidepressant treatment in people with bipolar disorder.
It has a relatively low risk of causing or worsening diabetes, dyslipidemia (abnormal blood fats), or cardiovascular disease, which are common metabolic and cardiovascular problems associated with some mood stabilizers such as lithium and valproate.
It has a relatively low risk of causing or worsening osteoporosis (bone loss), which is a common long-term effect of some mood stabilizers such as lithium and carbamazepine.
It has a relatively low risk of causing or worsening thyroid problems, which are common endocrine problems associated with some mood stabilizers such as lithium and carbamazepine.
It has a relatively low risk of causing or worsening acne, hair loss, or polycystic ovary syndrome (PCOS), which are common dermatological and gynecological problems associated with some mood stabilizers such as valproate and carbamazepine.
It has a relatively low risk of drug interactions, as it does not affect the activity of liver enzymes that metabolize many other medications.

Negatives or cons

Lamotrigine also has some disadvantages and limitations, such as:

It has a high risk of causing a severe and potentially fatal skin rash that requires careful monitoring and dose adjustment. This risk is especially high in children and people who take valproate or have a genetic variation called HLA-B*1502.
It has a moderate risk of causing allergic reactions, blood disorders, liver problems, or aseptic meningitis that require regular blood tests and clinical evaluation.
It has a moderate risk of causing mood or behavioral changes that require close supervision and psychiatric assessment.
It has a moderate risk of reducing the effectiveness of oral contraceptives that require backup contraception methods.
It has a slow onset of action that requires patience and adherence to treatment. It may take several weeks to months before the full benefits of lamotrigine are seen.
It has a variable response rate that depends on the type and severity of depression. It may be more effective for treatment-resistant depression than non-resistant depression. It may also be more effective for bipolar depression than unipolar depression.
It has limited evidence for its efficacy and safety for unipolar depression. Most of the studies on lamotrigine for unipolar depression have been small, short-term, or open-label. The results have been mixed and inconclusive.

Conclusion

Lamotrigine is an anticonvulsant medication that can be used to treat depression in people with bipolar disorder or unipolar disorder. Lamotrigine works by modulating the activity of several neurotransmitters in the brain, especially glutamate, GABA, and serotonin. Lamotrigine can prevent or reduce depressive episodes in people with bipolar disorder and improve depressive symptoms in people with unipolar disorder. Lamotrigine has some advantages over other antidepressants and mood stabilizers, such as a lower risk of weight gain, sexual dysfunction, sedation, cognitive impairment, withdrawal symptoms, mania induction, metabolic problems, it has limited evidence for its efficacy and safety for unipolar depression. Most of the studies on lamotrigine for unipolar depression have been small, short-term, or open-label. The results have been mixed and inconclusive.

Sources

The following sources were used to write this article:

Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry. 1999;60(2):79-88.
Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194(1):4-9.
Goodwin GM, Bowden CL, Calabrese JR, et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry. 2004;65(3):432-441.
Ketter TA, Manji HK, Post RM. Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders. J Clin Psychopharmacol. 2003;23(5):484-495.
Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2):160-168.
Nierenberg AA, Ostacher MJ, Calabrese JR, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatry. 2006;163(2):210-216.
Pae CU, Wang SM, Han C, et al. Lamotrigine as an add-on treatment for depressive symptoms in patients with bipolar disorder: a systematic review and meta-analysis. Hum Psychopharmacol. 2016;31(5):411-421.
Smith LA, Cornelius VR, Azorin JM, et al. Valproate for the treatment of acute bipolar depression: systematic review and meta-analysis. J Affect Disord. 2010;122(1-2):1-9.
Vasudev A, Macritchie KAN, Geddes JR, Watson S, Young AH. Topiramate for acute affective episodes in bipolar disorder in adults. Cochrane Database Syst Rev 2016;(8):CD003384.
Wang SM, Han C, Lee SJ, Patkar AA, Masand PS, Pae CU. Lamotrigine as an augmentation agent in treatment-resistant depression: a meta-analysis of randomized controlled trials. Prog Neuropsychopharmacol Biol Psychiatry 2018;81:168–173.