Lamotrigine is a synthetic phenyltriazine chemical with anticonvulsant and analgesic properties initially sold by GlaxoSmithKline under the brand name Lamictal. It was first approved by the FDA in 1994 for the treatment of partial seizures in adults, and was subsequently approved in 1998 for the management of Lennox-Gastaut syndrome – a severe form of epilepsy in which individuals experience multiple types of seizures (tonic-clonic and/or atonic) plus neurodevelopmental deficits. Thereafter, lamotrigine received FDA approval in 2003 as an intervention for pediatric partial seizures, and also as a maintenance therapy for bipolar (Type 1) disorder.
As more research was conducted evaluating the therapeutic properties of lamotrigine, mounting evidence suggested that it may be safe and effective in treating conditions for which it has not received FDA approval. Based on this evidence, medical professionals occasionally prescribe lamotrigine off-label [as an adjunct or monotherapy] to help manage: cluster headaches, major depressive disorder, migraines, peripheral neuropathy, and trigeminal neuralgia. Although relatively underinvestigated as an intervention for anxiety disorders, some believe that lamotrigine facilitates a robust anxiolytic effect and should be utilized more frequently in anxiety sufferers.
Preliminary data support the idea that lamotrigine attenuates symptoms of OCD and PTSD, each of which are specific types of anxiety disorders. Furthermore, there are numerous anecdotal accounts documenting significant anxiety reduction from taking lamotrigine. That said, anyone contemplating the usage of lamotrigine for anxiety disorders should understand its mechanism of action, the benefits/risks associated with its usage, and the scientific literature evaluating its anxiolytic potential.
How Lamictal (Lamotrigine) May Treat Anxiety (Mechanisms of Action)
To determine how lamotrigine may alleviate symptoms of anxiety, it’s necessary to examine its mechanism of action. Although the mechanism of lamotrigine’s action isn’t fully elucidated, research indicates that it functions predominantly as a presynaptic inhibitor of voltage-gated sodium channels (VGSCs) whereby it stabilizes neuronal membranes and inhibits the release of glutamate. Most would speculate that modulation of voltage-gated sodium channel activity and the corresponding downstream effects associated with this modulation generate the majority of its anxiolytic effect.
Additionally, some studies suggest that lamotrigine modulates voltage-gated calcium channels, enhances GABA, and inhibits serotonin reuptake – each of which may also contribute [in varying degrees] to the attenuation of anxiety. That said, it is reasonable to assume that the significance of anxiolytic benefit derived from lamotrigine will be contingent upon the underlying neurochemistry and physiology of the user. Persons with anxiety who exhibit abnormalities in the neurochemical systems targeted by lamotrigine should be expected to derive more substantial anxiolytic benefit than others.
Sodium (Na+) channel blocker: Researchers Qiao, Sun, Clare, et al. (2014) suggest that the primary therapeutic target of lamotrigine is voltage-gated sodium channels, specifically the alpha-subunits NaV1.1, NaV1.2, NaV1.3, and Nav1.6. Their research using cell cultures indicates that lamotrigine facilitates a significant shift in steady-state inactivation of the four aforestated alpha-subunits with highest binding affinity for the NaV1.1 subunit. Furthermore, when compared to other anticonvulsant agents, lamotrigine exhibits a prolonged binding duration.
Though the role of voltage-gated sodium channels in anxiety disorders remains unknown, it’s possible that decreasing voltage-gated sodium channel activity could facilitate anxiolytic effects. That said, it’s necessary to contemplate how a blockade of voltage-gated sodium channels from lamotrigine might reduce anxiety. When lamotrigine is administered, it’s molecular weight of ~256 allows it to penetrate deep within the voltage-gated sodium channel, likely through the hydrophilic pore or hydrophobic cell membrane whereby it inhibits activity.
The inhibition of voltage-gated sodium channel activity decreases the release of excitatory neurotransmitters, stabilizes neuronal membranes, and protects neurons from excitotoxicity. Due to the fact that a subset of individuals with anxiety disorders exhibit excessive or hyperexcitable neurotransmission in certain regions of the brain, it’s logical to suspect that a voltage-gated sodium channel blockade facilitated by lamotrigine could attenuate anxious symptoms. Moreover, due to its slower unbinding time from alpha-subunits and its high affinity for the NaV1.1 alpha-subunit in particular, lamotrigine’s action as a voltage-gated sodium channel blocker may generate a more substantial anxiolytic effect than other anticonvulsants.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/24283699
Glutamate reduction: Lamotrigine’s modulation of voltage-gated sodium channels, and to a lesser extent, modulation of voltage-gated calcium channels, is understood to suppress the release of glutamate. Researchers Dursun and Deakin (2001) describe lamotrigine as being a “glutamate excess release inhibitor” and suggest that it may be useful for the treatment of neuropsychiatric disorders in which glutamatergic dysregulation is observed. Work by Wang, Sihra, and Gean (2001) indicates that lamotrigine inhibits the release of glutamate from cerebrocortical nerve terminals of rats in a dose-dependent manner.
Among a subset of individuals, it’s possible that glutamatergic abnormalities may be causally implicated in the pathogenesis of anxiety. A study by Modi, Rana, Kaur, et al. (2014) utilized magnetic resonance spectroscopy (MRS) neuroimaging to investigate and compare the neurochemistry of persons with high and low anxiety. Results indicated a significant correlation between levels of glutamate and glutamine within the anterior cingulate cortex (ACC) and anxiety, such that the greater the glutamate in the ACC, the more debilitating a person’s anxiety.
Oppositely, individuals with low levels of anxiety exhibited lower concentrations of glutamate and glutamine. Based on associations between anxiety and elevated glutamate in specific regions of the brain, it’s reasonable to think that inhibition of excess glutamate may alleviate symptoms of anxiety. Cortese and Phan (2005) discuss the fact that modifying glutamatergic transmission can effectively treat various types of anxiety in animal models.
They also note that glutamatergic modulators have shown preclinical efficacy in human trials for the treatment of generalized anxiety disorder, OCT, PTSD, and social phobia. Amiel and Mathew (2007) suggest that novel modulators of the glutamate system (receptors, ion channels, transporters, etc.) may treat anxiety disorders with fewer side effects than current first-line anxiolytics. In brief, knowing that glutamate levels in certain regions of the brain may correlate with severity of anxiety, and that lamotrigine appears to decrease glutamate release, it’s plausible that lamotrigine may attenuate anxiety through its anti-glutamatergic effect.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/11769825
- Source: https://www.ncbi.nlm.nih.gov/pubmed/11447345
- Source: https://www.ncbi.nlm.nih.gov/pubmed/25156662
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- Source: https://www.ncbi.nlm.nih.gov/pubmed/17880858
Calcium (Ca+) channel blocker: Another mechanism of lamotrigine’s action that may contribute to the generation of an anxiolytic effect involves the blockade of calcium channels. Research suggests that lamotrigine blocks various types of calcium channels including: L-type, N-type, P-type, Q-type, R-type, and to a lesser extent, T-type. As of current, evidence suggests that lamotrigine’s calcium channel antagonism may be more significant than initially suspected, potentially contributing to a therapeutically-relevant anxiolytic effect.
A study by Stefani, Spadoni, Siniscalchi, and Bernardi (1996) reported dose-dependent inhibition of high-voltage-activated calcium (Ca+) currents in cortical neurons of rats. Based on the results of this study, it was speculated that lamotrigine’s inhibition of calcium channels decreases the release of excitatory molecules in the corticostriatal pathway. Other research by Stefani, Spadoni, and Bernardi (1997) documented significant decreases in high-voltage-activated calcium channels from lamotrigine.
A paper by Balon and Ramesh (1996) questions whether calcium channel blockade may be a viable mechanism for the treatment of anxiety disorders. The authors noted that there are several case reports in which calcium channel blockers verapamil, diltiazem, and nimodipine successfully treated panic disorder. However, since there were no randomized controlled trials testing the potential of calcium channel blockers for the treatment of anxiety, more research is warranted to determine whether calcium channel blockade is an anxiolytic mechanism of action.
Assuming a significant calcium channel blockade occurs after the administration of lamotrigine, researchers speculate that this could decrease glutamatergic transmission in various regions of the brain such as the ventral striatum. It is possible that a calcium channel antagonism-mediated anti-glutamatergic effect within certain regions of the brain might attenuate symptoms of anxiety. Although there are no convincing data to support calcium channel blockade as a viable mechanism of lamotrigine’s anxiolytic action, it necessitates consideration. Moreover, it may be worth mentioning that gabapentin, a clinically-relevant anxiolytic, functions in part via [alpha-2-delta] calcium channel blockade, possibly contributing to its anxiolytic mechanism.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/8831112
- Source: https://www.ncbi.nlm.nih.gov/pubmed/9294408
- Source: https://www.ncbi.nlm.nih.gov/pubmed/8986318
GABA modulation: GABA (gamma-aminobutyric-acid) is the chief inhibitory neurotransmitter in the CNS and it is well-understood that modulation of central GABA signaling is an effective way to decrease a person’s arousal and reduce their anxiety. Increased GABA signaling is associated with the pronounced anxiolytic effect derived from benzodiazepines. Benzodiazepines allosterically modulate GABA receptors, which in turn, increases the efficiency of chloride channel opening after ligand binding to the receptor, thereby hyperpolarizing neurons to decrease CNS excitability.
Though the data are mixed regarding whether lamotrigine modulates the neurotransmission of GABA, this may be another mechanism by which it reduces anxiety. A study by Kuzniecky, Ho, and Pan (2002) discovered that administration of lamotrigine to healthy adults increased cerebral GABA concentrations by 25% after 4 weeks. Research by Hassel, Taubøll, and Gjerstad (2001) revealed that chronic administration of lamotrigine to rats (10 mg/kg/day for 90 days) increased concentrations of hippocampal GABA by 25% and enhanced GABA turnover.
Other work by Wang, Sun, Chen, and Young (2002) discovered that lamotrigine enhanced expression of GABA-A receptor beta-3 subunits in hippocampal neurons of rats, supporting the hypothesis that lamotrigine exerts a GABAergic effect. Additionally, a study by Braga, Aroniadou-Anderjaska, Post, and Li (2002) noted that lamotrigine inhibits GABAA receptor-mediated signaling through its presynaptic impact upon the influx of calcium ions. Overall, there appears to be support for some degree of GABAergic action facilitates by lamotrigine.
It warrants mentioning that a subset of anxiety disorders may be caused directly by deficits in central GABA signaling. Research by Mann, Oquendo, Watson, et al. (2014) discovered that persons with anxiety and comorbid depression exhibit abnormally low concentrations of GABA in cerebrospinal fluid (CSF) compared to others. That said, irrespective of whether GABAergic deficits are causally implicated in a person’s anxiety, enhancement of GABAergic signaling via lamotrigine may adequately attenuate anxious symptoms.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/11839834
- Source: https://www.ncbi.nlm.nih.gov/pubmed/11164704
- Source: https://www.ncbi.nlm.nih.gov/pubmed/11927166
- Source: https://www.ncbi.nlm.nih.gov/pubmed/11955522
- Source: https://www.ncbi.nlm.nih.gov/pubmed/24865448
Other possible mechanisms of lamotrigine’s anxiolytic action…
Although the bulk of lamotrigine’s anxiolytic effect is derived from the blockade of voltage-gated sodium channels, voltage-gated calcium channels, downregulation of glutamate, and upregulation of GABA – these are not its only actions. To a less significant extent, lamotrigine also modulates voltage-gated potassium channels, the HPA axis, and possibly oxidative stress and/or the 5-HT1A receptors. It’s reasonable to suspect that the effect of lamotrigine upon these additional targets could modestly contribute to its total anxiolytic effect.
Potassium (K+) channel modulation: In addition to blocking various voltage-gated sodium and calcium channels, lamotrigine appears to modulate voltage-gated potassium channels. Data from a study by Zona, Tancredi, Longone, et al. (2002) indicate that lamotrigine bolsters 4AP-sensitive potassium (K+)-mediated hyperpolarizing currents in cortical neurons of rats. Another study by Huang, Huang, Liu, and Wu (2004) indicated that lamotrigine inhibits potassium channels to increase neuronal excitability of H19-7 hippocampal neurons.
Though evidence suggests that lamotrigine modulates potassium channels, it remains unclear as to whether the specific channels modulated and/or the degree of modulation in human lamotrigine users would contribute to an anxiolytic effect. Nevertheless, there are studies supporting the idea that modulation of certain potassium channels could prove therapeutically effective for anxiety. Research by Hansen, Waroux, Seutin, et al. (2008) documents that neuronal Kv7 potassium channels influence central signaling of dopamine and serotonin.
When these Kv7 potassium channels are activated, they limit repetitive firing of excitatory neurotransmitters and also inhibit the release of monoamines. If lamotrigine were to modulate any of the Kv7 channels, it would correspondingly affect downstream dopaminergic and serotonergic activity, possibly inducing an anxiolytic effect in a subset of persons. Other studies also indicate that potassium channel activity affects anxiety.
For example, Mitra, Ferguson, and Sapolsky (2009) discovered that overexpression of a certain potassium channel known as “SK2” in the amygdala leads to inhibition of action potentials and lower stress-related corticosterone secretion, whereby anxiety is less likely to occur. Work by Atchley, Hankosky, Gasparotto, and Rosenkranz (2012) reports that the activation of calcium-activated potassium channels within the brains of rats reverses stress-induced amygdala hyperexcitability whereby anxiolytic-like effects are observed. Additionally, preliminary testing of potassium channel modulators reveals that they could prove useful as anxiolytics. For this reason, it’s possible that lamotrigine-mediated potassium channel modulation may decrease anxiety.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/12102669
- Source: https://www.ncbi.nlm.nih.gov/pubmed/15230694
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HPA axis regulation: There’s some evidence to suggest that lamotrigine may exert an anxiolytic effect through modulation of the HPA axis whereby it restores balance to correct dysregulation. A paper by Faravelli, Lo Suaro, Lelli, et al. (2012) highlights the fact that abnormalities in HPA (hypothalamic pituitary adrenal) axis activation are observed across nearly every type of anxiety disorder, including: generalized anxiety disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, social phobia, etc. As a result of HPA axis dysregulation, stress hormones such as ACTH and cortisol are secreted more frequently, ultimately potentiating activation of the sympathetic nervous system (e.g. the freeze-fight-flight response) which is known to induce states of anxiety and fear.
A host of deleterious biological also changes occur with chronic HPA dysregulation, including: alteration in expression of receptors (e.g. glucocorticoid, melanocortin, etc.), functional neural connectivity changes, and shifts in glucose concentrations – just to name a few. Even if abnormalities within the HPA axis weren’t the predominant underlying cause of a person’s anxiety, it’s easy to see how stress-related dysregulation of the HPA axis might keep someone stuck in a chronically anxious or disordered state for an extended duration. For this reason, many experts believe that modulating HPA axis activity is an effective way to treat anxiety.
It is known that administration first-line medications for anxiety such as SSRIs stabilize the HPA axis, likely an indirect mechanism of their anxiolytic action. Coincidentally, research by Leśkiewicz, Budziszewska, and Lasoń (2008) suggests that lamotrigine stabilizes ACTH/cortisol secretion in rats. Although lamotrigine-mediated HPA axis stabilization hasn’t been confirmed in humans, it is a plausible contributing mechanism of lamotrigine’s anxiolytic effect.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/22632471
- Source: https://www.ncbi.nlm.nih.gov/pubmed/19205363
Oxidative stress reduction: Among the majority of individuals with anxiety disorders, oxidative stress is unlikely to be the primary underlying cause, however, it may play still play a causal role. Research in animal models indicates that oxidative stress is likely causally implicated in various neurobiological signatures of anxiety. Furthermore, even if oxidative stress isn’t causally implicated in an anxiety disorder, it is known that chronic anxiety can upregulate oxidative stress within the brain.
If someone has been dealing with anxiety for awhile, there’s a chance that oxidative biomarkers may have increased as a result. An increase in oxidative biomarkers can disrupt homeostatic neurotransmission, provoke inflammation, and create a vicious feedback loop such that a person’s anxiety continues to increase. Some researchers believe that interventions aimed at decreasing abnormally high oxidative stress may [at least partially] alleviate symptoms of anxiety in a subset of patients.
It turns out that lamotrigine may exert an antioxidant effect whereby it reduces oxidative stress. Research by Eren, Naziroğlu, and Demirdaş (2007) administered lamotrigine to rats exposed to chronic mild stress (CMS) and determined how it affected oxidative biomarkers in their brains. Results indicated that administration of lamotrigine significantly increased antioxidant status, thereby counteracting oxidative stress. Moreover, the increases in antioxidant valuates from lamotrigine exceeded those derived from other medications such as aripiprazole and escitalopram.
The results from this animal study suggests that lamotrigine may have significant, overlooked antioxidant effects. That said, it is unclear as to whether lamotrigine exerts as potent of an antioxidant effect in the brains of human users. Assuming lamotrigine enhances antioxidant status of humans, patients with anxiety disorders caused and/or associated with high oxidative stress may benefit from this mechanism.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/17401662
5-HT1A receptor modulation: There are some preclinical data from animal studies indicating that lamotrigine modulates activity of the 5-HT1A receptor. It is possible that modulation of 5-HT1A receptors by lamotrigine may play a role in attenuating symptoms of anxiety. Support for the idea that 5-HT1A receptors may be a therapeutically relevant-target in the treatment of psychiatric disorders, including anxiety, is derived from a report by Celada, Bortolozzi, and Artigas (2013).
In the report, it was mentioned that 5-HT1A receptor expression in mice can be transgenically modified whereby it influences their susceptibility to anxiety. Further stated was the fact that neuropsychiatric medications acting upon 5-HT1A receptors are sometimes effective treatments for patients with anxiety disorders. One such example is buspirone, a 5-HT1A partial agonist that’s approved by the FDA to treat symptoms of generalized anxiety disorder (GAD).
The modulatory effect induced by lamotrigine upon 5-HT1A is somewhat unclear, however, work by Vinod and Subhash (2002) discovered that administration of lamotrigine downregulates cortical 5-HT1A receptor density in animals. Additional research by Bourin, Masse, and Hascoët (2005) revealed that a single-dose of lamotrigine to animals modifies activation of postsynaptic 5-HT1A receptors. Though we cannot assume lamotrigine alters 5-HT1A receptor expression and/or activity the same in humans as it does in animals, its action at these receptors deserves consideration as potentially contributing an anxiolytic effect.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/23757185
- Source: https://www.ncbi.nlm.nih.gov/pubmed/11792461
- Source: https://www.ncbi.nlm.nih.gov/pubmed/16049571
Note: It is necessary to note that there might be additional targets for lamotrigine’s action, including: 5-HT3 receptors, the sigma-1 receptors, and alpha-2-beta-4 nicotinic acetylcholine receptors. Furthermore, experimental data imply that lamotrigine might modulate extracellular concentrations of monoamines (serotonin, dopamine, norepinephrine) in certain regions of the brain, and inhibit dihydrofolate reductase. Although it is unlikely that any of these mechanisms are substantial enough to [even modestly] contribute to lamotrigine’s anxiolytic effect warrants investigation.
Benefits of Lamictal (Lamotrigine) for Anxiety Disorders (Possibilities)
Although an unproven intervention, there are many potential benefits that might be attained from utilizing lamotrigine as an off-label treatment for anxiety. The most obvious potential benefit is that lamotrigine may turn out to be the single most useful anxiolytic medication that a person with an anxiety disorder has ever tried. Other potential benefits associated with utilizing lamotrigine for anxiety may include its: ability to treat comorbidities, low cost, neuroprotective properties, and novel mechanism of action. Moreover, nearly all preliminary data support the idea that lamotrigine can be helpful for a subset of patients with anxiety.
- Adjunctive potential: Currently there are zero trials that have evaluated lamotrigine as a standalone treatment for anxiety, however, it has been evaluated as an adjunct intervention. All published trials that investigated lamotrigine’s adjunct efficacy suggested that it facilitates a significant anxiolytic effect. Most of these trials administered lamotrigine along with a serotonergic antidepressant (SSRI or TCA) to treat refractory forms of anxiety. That said, several case reports documented success with lamotrigine as an adjunct to anticonvulsants (e.g. divalproex) and benzodiazepines. Based on the promising results from adjunct trials of lamotrigine to treat anxiety, one might speculate that it’s antiglutamatergic action synergizes with other medications to yield greater symptomatic reduction than each medication as a monotherapy. Additionally, data suggest that adjunct lamotrigine is generally well-tolerated with a low likelihood of interaction effects when prescribed by a psychiatrist.
- Anecdotal support: Various medications are hypothesized to generate anxiolytic effects, however, many haven’t been tested in a single trial for the treatment of anxiety, and worse, they may entirely lack anecdotal support. Though anecdotal support does not provide strong evidence to suggest that an intervention is effective as a treatment, having some anecdotal support is better than none. Lamotrigine is a medication that has considerable mounting anecdotal support to suggest that it is capable of treating anxiety disorders. There are numerous formally-documented case reports in medical journals describing the attenuation of anxiety-related symptoms after treatment with lamotrigine. Furthermore, there are anonymous self-reports on the internet from patients who received lamotrigine for the treatment of a non-anxiety-related psychiatric condition, but found that it worked incredibly well as an anxiolytic. Some of these reports claim that lamotrigine is the single best medication for anxiety that they’ve ever tried.
- Anxiety subtypes: Another possible benefit of using lamotrigine as an anxiolytic is that it may treat numerous diagnostic subtypes of anxiety including OCD, PTSD, panic disorder, and possibly even generalized anxiety disorder or social phobia. Thus far there is strongest evidence to support the efficacy of lamotrigine for the treatment of OCD, followed by PTSD, then panic disorder. Furthermore, it appears as though lamotrigine is an effective adjunct for treating comorbid symptoms of anxiety among patients with bipolar disorder. The fact that lamotrigine may treat many diagnostic subtypes of anxiety makes it an appealing off-label anxiolytic intervention, especially compared to medications that are limited to a particular subtype. Also, among anxiety sufferers, it is known that individuals often exhibit different neurobiological signatures and causal underpinnings of their disorder. For patients in which glutamate dysregulation is apparent, lamotrigine may be a targeted and more effective intervention than first-line serotonergic medications.
- Cognitive enhancement: Although many first-line anxiolytics are highly-effective for the treatment of anxiety disorders, one complaint from patients is that these medications cause brain fog and/or induce cognitive deficits. It may become difficult to think clearly, retrieve memories, and/or perform cognitively demanding tasks on serotonergic anxiolytics (e.g. SSRIs, TCAs, MAOIs), and even more difficult on benzodiazepines. By comparison, lamotrigine is suggested to enhance domains of cognitive performance. Among patients with bipolar disorder, lamotrigine was discovered to improve aspects of verbal and working memory. Among persons with epilepsy, lamotrigine provides a slight, yet significant improvement in overall cognitive performance. Furthermore, lamotrigine has been shown to bolster cognition in patients undergoing chronic steroid therapy. Some may prefer to use lamotrigine for anxiety based entirely on the fact that it doesn’t appear to interfere with cognitive function.
- Comorbidities: Another favorable attribute of lamotrigine is that it is FDA approved to treat bipolar disorder and epilepsy. This means that any patients with an anxiety disorder plus comorbid bipolar disorder and/or epilepsy might find that lamotrigine monotherapy effectively attenuates all unwanted neuropsychiatric symptoms. In other words, taking a single lamotrigine pill each day may effectively manage symptoms of multiple or several neuropsychiatric disorders. Assuming lamotrigine is effective for the treatment of multiple neuropsychiatric disorders, using it as a standalone would be preferable over administering separate drugs for each condition due to cost, potential interactions, and side effects. It should also be mentioned that individuals with anxiety disorders plus comorbid: major depressive disorder, migraines, peripheral neuropathy, and personality disorders – may also benefit from lamotrigine (as it is sometimes prescribed off-label for these conditions).
- Effective: Results from preliminary trials and case reports in which lamotrigine was administered for the treatment of anxiety disorders are unanimous in support of the hypothesis that lamotrigine may be an effective anxiolytic. There are zero studies in humans and animal models in which the results suggest lamotrigine may be ineffective. Although much of the research is of low quality, it is somewhat surprising that no reports indicate that lamotrigine appears ineffective. In fact, one case report documented that lamotrigine managed a patient’s comorbid anxiety and epilepsy for a 5-year duration. Presently, there’s good reason to suspect that lamotrigine is an effective anxiolytic.
- Fast-acting: Though research suggests that lamotrigine yields a clinically-relevant anxiolytic effect after 8-16 weeks of administration, it may be faster-acting. In most studies, researchers didn’t compare the efficacy of lamotrigine to that of a placebo at earlier checkpoints. Although animal model findings cannot be extrapolated to humans, a rat study found that a single dose of lamotrigine substantially decreased anxiety-like behavior. Many accounts claim that lamotrigine improved their psychological status on the very first day of its administration. Considering its mechanism of action, lamotrigine may deliver an anxiolytic effect quicker than other first-line agents such as serotonergic antidepressants. Serotonergic antidepressants usually require 4 to 8 weeks to desensitize autoreceptors and reach peak anxiolytic effect, whereas lamotrigine does not.
- Formats: Another benefit of lamotrigine as an intervention for anxiety is that it is manufactured in multiple formats including: IR (immediate-release) and XR (extended-release). The only major difference is that the IR version of lamotrigine releases the drug immediately whereas the XR does it gradually. Some may prefer the IR version because it is lower cost and may be more useful for patients who derive benefit from taking lamotrigine on an “as-needed” basis. Although “as-needed” administration of lamotrigine is not recommended by professionals and hasn’t been evaluated in the literature, some report that this works well to control unexpected symptom flare-ups. Those who want and/or need a longer-acting form of lamotrigine may prefer the XR version which controls its dissolution rate over a span of 12-15 hours whereby serum concentrations of lamotrigine gradually increase.
- Low cost: The good news for lamotrigine users is that the IR (immediate-release) format of the drug is extremely affordable. For 60 tablets of lamotrigine at a 100 mg dose, it’ll cost between $10 and $17. Under the assumption that you pay $17 for your 60 lamotrigine IR tablets at the 100 mg dose, this equates to a price of approximately $0.28 per tablet. If you’re only taking one tablet per day, the $17 prescription should last around 2 months. The low cost of lamotrigine is related to the fact that the its patent has expired, allowing all pharmaceutical companies to sell it for cheap. Compared to newer anxiolytics that are still under patent and cost hundreds of dollars for a monthly prescription, lamotrigine is a bargain.
- Mood enhancement: Most individuals with anxiety struggle with comorbid depression and/or have a difficult time maintaining a healthy mood. Anxiety can directly cause a person to feel depressed, agitated, and/or angry. Fortunately, in addition to its anxiolytic effect, lamotrigine may act as a mood enhancer. Among patients with refractory depression, there’s evidence that adjunct lamotrigine effectively attenuates depressive symptoms. In patients with bipolar disorder, lamotrigine can stabilize mood. Moreover, trials of lamotrigine in patients undergoing steroid therapy suggest that it substantially enhances mood. The fact that lamotrigine may also enhance your mood in addition to treating your anxiety is another bonus.
- Monotherapy: Though no studies have been conducted to determine the effectiveness of lamotrigine as a monotherapy for anxiety disorders, there’s reason to think that it could work. In one trial, lamotrigine was administered as a standalone to a drug-naïve patient and it significantly reduced symptoms of panic disorder. Other case reports imply that lamotrigine facilitates a bulk of the anxiolytic benefit. Additionally, in studies among patients with refractory cases of anxiety and/or comorbid anxiety, symptoms only decreased after initiation of lamotrigine treatment. This suggests that lamotrigine likely could be useful as an anxiolytic monotherapy.
- Neuroprotective agent: In addition to its potential usefulness as a treatment for anxiety, and confirmed efficacy for the treatment of bipolar disorder and epilepsy – lamotrigine appears to act as a neuroprotective agent. As a result of its pharmacodynamics involving the blockade of sodium and calcium ion channels, lamotrigine prevents spikes in concentrations of excitatory neurotransmitters such as glutamate. Substantial elevations in excitatory neurotransmitters are known to damage neurons and kill brain cells through excitotoxicity. Ongoing treatment with lamotrigine protects against this excitotoxicity to preserve the condition and functionality of brain cells.
- Novel pharmacodynamics: Many individuals struggle to derive adequate relief from first-line anxiolytic medications such as SSRIs, benzodiazepines, and azapirones. A subset of these individuals might even test unconventional interventions such as beta blockers for anxiety without noticing any change in their symptoms. Among those who don’t respond to first-line nor second-line anxiolytics, it’s possible that the general pharmacodynamics of these medications are neurobiologically incompatible with the users. One reason lamotrigine is an alluring option for the treatment of anxiety is that it exhibits novel pharmacodynamics. Rather than modulating monoamines or GABA, lamotrigine primarily modulates voltage-gated ion channels to alleviate anxious symptoms. This atypical mechanism of anxiolytic action may prove effective for persons who don’t respond to traditional interventions.
- Refractory anxiety: Lamotrigine may be an extremely useful option for patients with treatment-resistant forms of anxiety who fail to respond to conventional anxiolytic interventions. As was already discussed, lamotrigine exerts a different neurochemical effect than first-line and second-line anxiolytics. It functions predominantly through the blockade of voltage-gated sodium and calcium channels. Patients with anxiety disorders who respond poorly to serotonergic antidepressants and/or GABAergic benzodiazepines aren’t usually left with many treatment options for their anxiety. That said, preliminary evidence suggests that lamotrigine is helpful [as an adjunct] for patients with severe, treatment-resistant OCD, a subtype of anxiety disorder.
- Safety: An advantage of using lamotrigine to treat anxiety is that it’s been thoroughly evaluated in humans over an extended period of time and appears safe. Lamotrigine first hit the market in 1994 when it was approved by the FDA for the treatment of partial seizures in adults. Ever since, lamotrigine has been approved for other conditions such as bipolar disorder and has been prescribed off-label to help manage various other medical conditions. This means lamotrigine has been in circulation for over 2 decades without evidence to suggest that the drug is somehow poorly tolerated and/or associated with increased risk of adverse reactions compared to other neuropsychiatric medications. Most would agree that lamotrigine is safe when prescribed by a medical professional and properly administered by patients.
- Tolerability: Like any medication, lamotrigine can cause some side effects. That said, the side effects associated with lamotrigine may be more tolerable than side effects induced by other anxiolytic medications. As was already mentioned, lamotrigine does not appear to impair cognitive function and may even provide a modest boost in cognition. Additionally, long-term trials suggest that lamotrigine is a “weight neutral” drug such that it has no effect on body weight. Considering that lamotrigine doesn’t interfere with cognition nor increase weight, some may perceive it as advantageous over various first-line anxiolytics.
Drawbacks of Lamictal (Lamotrigine) for Anxiety Disorders (Possibilities)
Although some benefits may be attained from using lamotrigine as an anxiolytic, there are some serious potential drawbacks to contemplate as well. Among the most significant of potential drawbacks associated with utilizing lamotrigine to treat anxiety is that it may exacerbate a person’s preexisting symptoms of anxiety. Other potential drawbacks of using lamotrigine as an anxiolytic include: adverse reactions, high cost, inefficacy, long-term effects, side effects, and withdrawal symptoms upon discontinuation.
- Adverse reactions: In rare cases, individuals may experience adverse reactions to lamotrigine, some of which could be life-threatening. Medical documentation suggests that lamotrigine can cause life-threatening skin reactions including: DRESS syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN). Though these serious skin reactions usually occur within the first 8 weeks of treatment, they can sometimes occur after dosing adjustments and/or from stopping then resuming treatment. Despite the fact that few individuals taking lamotrigine will develop a potentially-fatal skin condition, up to 10% will develop a rash which could affect appearance and self-esteem of the patient. Other serious adverse reactions that have been documented among lamotrigine users include: aseptic meningitis, leukopenia, neuroleptic malignant syndrome (NMS), and suicidal ideation. For some individuals, even a low risk of the aforestated adverse reactions may be enough to dissuade them from testing lamotrigine as an anxiolytic.
- Contraindications: Even if lamotrigine helped with anxiety, a subset of patients would be unable to use it due to preexisting medical contraindications. Examples of medical conditions that ae listed as being contraindicated with lamotrigine include: allergies to lamotrigine, anemia, bone marrow failure, hepatic dysfunction, low white blood cell levels or neutrophils, meningitis, renal dysfunction, skin conditions (acute urticaria, angioedema, pruritus, mucosal ulceration, rash). Though lamotrigine has fewer contraindications than most medications, patients with any of the aforestated conditions may perceive lamotrigine as an unfavorable medication due to the fact that they cannot safely use it.
- High cost: Although the immediate-release (IR) format of lamotrigine is affordable for most individuals, the extended-release (XR) is very expensive. Even though both IR and XR formats of lamotrigine are generic, the XR format retails within the price range of $377 to $400 for just 30 tablets of the 100 mg dose. Assuming you have a rock-solid health insurance plan that picks up a majority of the tab, you probably aren’t concerned with the cost. However, if you have a mediocre or poor health insurance plan, you may need to pay out-of-pocket. If you pay $400 for a 30-day supply of lamotrigine at 100 mg, this equates to paying around $13.33 per pill – not a very good deal for those who prefer the XR format.
- Ineffective: Since lamotrigine hasn’t undergone any large-scale randomized controlled trials to test its efficacy as an anxiolytic, it is unclear as to whether it is a legitimately effective intervention for the treatment of anxiety disorders. In the future, we may learn that lamotrigine exerts zero therapeutically-relevant anxiolytic effect. That said, even if lamotrigine turned out to be effective for a majority of patients with anxiety does not mean that it will work for everyone. It may only treat anxiety in a subset of patients with specific neurobiological signatures of anxiety (e.g. glutamate dysregulation). Anyone considering lamotrigine as to manage anxiety should understand that it might not be effective like they had hoped.
- Interactions: Another drawback of using lamotrigine for anxiety is that it may interact with another drug and/or supplement that you’re using. Although lamotrigine is well-tolerated as an adjunct to many medications, it can provoke an interaction effect when administered with agents that are excreted via the organic cationic transporter 2 (OCT2) such as dofetilide. Some suspect that lamotrigine may sometimes interact with other anticonvulsants (e.g. valproate) to cause skin rashes and/or neurotoxicity. It is also theorized that individuals using monoaminergic modulators may also be at increased risk for serotonin syndrome if administered along with lamotrigine.
- Off-label: Due to the fact that lamotrigine hasn’t received FDA approval as an anxiolytic, it’ll likely be fairly tough to attain among persons hoping to use it for anxiety. The only way you may have a chance of receiving lamotrigine for an anxiety disorder is if you’ve gone through trials of all conventional monotherapies and augmentation strategies without adequate symptomatic remission. In other words, you’ll need to have tried many antidepressants (from multiple classes), benzodiazepines, buspirone, adjunct combinations (e.g. SSRI + benzo OR SSRI + buspirone), and evidence-based off-label interventions (e.g. gabapentin) – without sufficient symptomatic reduction before a professional might consider prescribing lamotrigine. Individuals with the best shot at receiving lamotrigine to help manage anxiety are those with an anxiety disorder plus a comorbid neuropsychiatric condition for which it is approved (e.g. bipolar disorder). Moreover, since lamotrigine is an off-label intervention for anxiety, if you ever switch doctors from the one who prescribed it, another may disagree with this decision and insist that you switch to another treatment.
- Side effects: Although the adverse effects associated with lamotrigine are somewhat scary, they are fairly uncommon. Still, there are general side effects that are commonly reported by patients including: balance problems, blurred vision, cognitive impairment, coordination deficits, dizziness, drowsiness, dry mouth, gastrointestinal distress, insomnia, nausea, runny nose, sleep disturbances, visual abnormalities, and weight changes. Some of these side effects (e.g. coordination deficits) may interfere with your ability to safely operate a motor vehicle and/or heavy machinery. Furthermore, while cognitive impairment and weight changes are uncommon, they may occur from lamotrigine in a subset of users.
- Tolerance: There are case reports in which a stable dose of lamotrigine was administered to help treat comorbid symptoms of anxiety. This suggests that lamotrigine may be an effective long-term anxiolytic. That said, it is understood that neuroadaptation can occur in regular long-term users of any neuropsychiatric drug whereby they become tolerant to the drug’s effect. Receptors may upregulate or downregulate to accommodate the frequent administration of lamotrigine, and its formerly-noticeable anxiolytic effect may diminish and/or cease altogether. Some may incrementally increase their dosage to offset the tolerance only to find that adverse reactions and/or side effects occur at elevated doses.
- Withdrawal symptoms: Assuming you take lamotrigine for awhile, but then opt to discontinue treatment, you may experience some fairly debilitating lamotrigine withdrawal symptoms. These symptoms can include things like: rebound anxiety, mood swings, anger, fatigue, and vomiting. Some former lamotrigine users report that it can take months before discontinuation symptoms subside after their final dose of lamotrigine.
- Worsening of anxiety: Listed as a potential side effect of lamotrigine on various medical websites is anxiety. If you’re administering lamotrigine with the intent of treating anxiety, you may be concerned to read that can sometimes cause anxiety. In some cases, individuals taking lamotrigine may find that it makes their anxiety significantly worse. Since not everyone with anxiety exhibits the same neurochemical abnormalities, it’s reasonable to suspect that some might notice an intensification of anxious symptoms while taking lamotrigine.
Lamictal (Lamotrigine) For Anxiety (Review of Research)
To understand the anxiolytic potential of Lamictal, it is necessary to examine preexisting scientific literature in which the effectiveness of lamotrigine is evaluated as a treatment for anxiety. As of current, there aren’t any large-scale randomized controlled trials (RCTs) that have sought to determine the standalone efficacy lamotrigine specifically for the treatment of anxiety disorders other than OCD. Nonetheless, some preliminary data indicate that lamotrigine might be effective for treating comorbid symptoms of anxiety among patients with bipolar disorder or major depression. Included below are synopses of the trials and reports in which lamotrigine’s anxiolytic potential was evaluated or discussed.
2016: Lamotrigine Augmentation Versus Placebo in Serotonin Reuptake Inhibitors-Resistant Obsessive-Compulsive Disorder: A Randomized Controlled Trial.
A randomized controlled trial by Khalkhali, Aram, Zarrabi, et al. (2016) investigated the therapeutic efficacy of adjunct lamotrigine for the treatment of refractory OCD. The authors noted that many individuals with OCD fail to derive adequate therapeutic benefit from first-line interventions such as SSRIs (selective-serotonin reuptake inhibitors). They also point out that there’s a hypothesis suggesting that glutamatergic dysfunction throughout various regions of the might cause OCD.
Understanding the glutamate hypothesis of OCD, researchers sought to determine whether lamotrigine, a glutamate modulator, might alleviate symptoms among patients with refractory OCD when administered along with a first-line SSRI. Researchers organized a randomized controlled trial and managed to recruit 53 patients diagnosed with refractory OCD to participate. All participants were assigned at random to receive either: 100 mg/day lamotrigine (26 participants) OR a placebo (27 participants) along with an SSRI – for a 12-week duration.
To determine whether adjunct lamotrigine provided therapeutic benefit, researchers compared the severity of each patient’s OCD symptoms (with the Yale-Brown Obsessive Compulsive Scale) prior to the trial (at baseline) and at the trial endpoint (12 weeks). A therapeutically-relevant response to lamotrigine was considered at least a 25% score reduction on the Yale-Brown Obsessive Compulsive Scale from baseline to endpoint. Results indicated that augmenting an SSRI with lamotrigine appears tolerable and effective for patients with severe, difficult-to-treat OCD.
- Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947218/
2016: The Therapeutic Role of Lamotrigine and Topiramate in a Depressive Patient with Anxiety Symptoms and Cognitive Decline: Neurometabolic Correlates.
A case report was presented by Hanoglu, Yulug, Cakir, et al. (2016) in which a 67-year-old woman received lamotrigine plus topiramate simultaneously to treat anxiety and cognitive impairment. Opposite to expectation, the combination of lamotrigine plus topiramate synergistically enhanced cerebral glucose metabolism. Researchers theorized that the substantial increase in cerebral glucose metabolism was the primary reason for the amelioration of the woman’s symptoms.
Additionally, it was suggested that the multi-drug combination modulates neural activity within the cortico-subcortical network and might favorably bolster connectivity between the hippocampus and cingulate. It was emphasized that the aforestated findings are from a case report and cannot be applied to the general population. More research is needed to confirm the safety and therapeutic efficacy of the lamotrigine plus topiramate as an intervention for anxiety and cognitive decline. Nonetheless, this supports the idea that lamotrigine may be effective as an adjunct anxiolytic.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/27592837
2015: Role of lamotrigine augmentation in treatment-resistant obsessive compulsive disorder: a retrospective case review from South Asia.
It is known that a subset of patients diagnosed with OCD (obsessive-compulsive disorder) exhibit refractory symptoms that respond insufficiently to first-line pharmacological interventions. A treatment strategy that some believe could prove efficacious in treating select cases of refractory OCD involves the augmentation of first-line medications with glutamate modulators. One such glutamate modulator that appears promising among patients with OCD, as well as other anxiety disorders, is the anticonvulsant drug lamotrigine.
For this reason, researchers Hussain, Dar, Wani, et al. (2015) conducted a retrospective study to investigate the adjunct efficacy of lamotrigine among patients taking SSRIs. The study involved searching for medical records of patients in South Asia who exhibited SSRI-resistant OCD, and as a result, received lamotrigine to augment the inadequately-effective SSRI. A total of 22 patients met inclusion criteria for the retrospective analysis, and of these patients, 20 exhibited clinically-significant attenuation of OCD symptoms after the administration of adjunct lamotrigine.
Researchers noted that the patients received adjunct lamotrigine for an average of 16 weeks at a dosage of ~150 mg/day. After receiving adjunct lamotrigine, the severity of OCD symptoms dropped by 67.23% [as evidenced by the Yale-Brown Obsessive Compulsive Scale score], and a significant improvement in quality of life was observed [as evidenced by a World Health Organization scale]. It was concluded that lamotrigine augmentation to a preexisting SSRI may prove efficacious for the treatment of refractory OCD, a specific anxiety disorder characterized by a disruptive, uncontrollable combination of obsessions and compulsions.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/25969599
2014: Post-traumatic Stress Disorder Symptoms in a Female Patient Following Repeated Teasing: Treatment with Gabapentin and Lamotrigine and the Possible Role of Sensitization.
Kishimoto, Goto, and Hashimoto (2014) documented a case report in which a 15-year-old Japanese female was diagnosed with mixed anxiety and depression, psychosomatic disorder, and PTSD – in accordance with ICD-10 criteria. The patient was believed to have developed these neuropsychiatric conditions after chronic teasing from multiple classmates of the opposite sex. The repetitive teasing over an extended duration lead the patient to experience psychological and physical symptoms of anxiety including headaches, insomnia, and stomach aches.
Eventually, symptoms became so severe that the patient felt unable to attend her school and visited a psychiatric clinic. Initially she was treated with the drug flunitrazepam (2 mg) and an analgesic while at the clinic, but returned to school. The incessant bullying continued and a criminal report was filed against the bullies whereby the police were involved and media (TV and newspapers) covered the story.
After filing of the criminal report, bullying initially stopped and her psychiatric symptoms improved significantly. That said, within 2 weeks she was bullied again by another student and her psychiatric symptoms returned including: headaches, stomach aches, vomiting, flashbacks, shaking, and palpitations. Professionals diagnosed her with PTSD and initiated treatment with gabapentin (400 mg) and she returned to school without issues for 4 months.
Following the 4-month period devoid of significant symptoms, she was questioned by police as part of the criminal report investigation, whereby her flashbacks and nightmares returned in full-force. Professionals prescribed lamotrigine (25 mg/day) to augment gabapentin (400 mg/day) and her flashbacks and nightmares decreased by 50% within just 2 weeks. Increasing the lamotrigine dose to 50 mg/day yielded more substantial symptomatic relief such that flashbacks and nightmares ceased within 3 weeks of lamotrigine augmentation.
It was noted that the patient continued taking a daily medication cocktail of flunitrazepam (2 mg), lamotrigine (50 mg), and fluvoxamine (150 mg) with success after graduation from junior high. Since nightmares and flashbacks never occurred in subsequent encounters with her bullies, treatment with gabapentin and fluvoxamine were stopped. The patient continued receiving lamotrigine (50 mg/day) with flunitrazepam (2 mg) with symptomatic remission.
Authors of the case report postulate that lamotrigine may facilitate anxiolytic effects through the modulation of GABA (gamma-aminobutyric-acid). Analysis of this case indicates that lamotrigine may be useful in a subset of persons with anxiety disorders when utilized as an adjunct or monotherapy. Nonetheless, randomized controlled trials are needed to determine whether the anxiolytic efficacy of lamotrigine extends beyond this single patient to others suffering with anxiety.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/25598830
2013: Lamotrigine in psychiatric disorders.
Reid, Gitlin, and Altshuler (2013) conducted a literature review to determine the therapeutic efficacy of lamotrigine when administered as an off-label treatment for psychiatric conditions, including anxiety. For the review, researchers compiled all studies published between 1990 and 2012 in which lamotrigine was administered to treat psychiatric conditions for which it does not have FDA approval. A total of 29 randomized controlled trials (RCTs), 6 open-label trials, 10 retrospective case reviews, and 4 case series were discovered.
Upon analysis of the data compiled for review, researchers discovered that lamotrigine is well tolerated by most patients. The extracted evidence suggested that lamotrigine was most useful for the treatment of bipolar disorder and as a prophylactic for bipolar depression. Other evidence indicated that lamotrigine may provide modest benefit as an intervention for acute bipolar depression and various symptoms in unipolar major depressive disorder.
Researchers were unable to determine whether lamotrigine was effective for the management of borderline personality disorder, but mentioned that preliminary data are encouraging for this indication. That said, the data did not suggest benefit of using lamotrigine as an off-label treatment for anxiety or schizophrenia. Although there are certain psychiatric conditions that may benefit from off-label treatment with lamotrigine, authors are dubious of its efficacy for those with anxiety.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/23945444
2012: Lamotrigine in the treatment of unipolar depression with and without comorbidities: a literature review.
Zavodnick and Ali (2012) conducted a review of literature investigating the therapeutic potential of lamotrigine among patients with unipolar depression and comorbidities. For their review, researchers compiled data from studies in which lamotrigine was evaluated for the treatment of depression with comorbidities such as: anxiety, PTSD, OCD, and personality disorders. In their literature search, it was noted that researchers uncovered a “large number of trials.”
Results indicated that patients with unipolar depression derived the most significant benefit from lamotrigine if they had a comorbid anxiety disorder OR borderline personality disorder. Based on these findings, it was concluded that patients with treatment-resistant forms of depression plus either comorbid anxiety or borderline personality disorder are likely to benefit more from lamotrigine compared to persons with other comorbidities. Moreover, higher dosages of lamotrigine appeared to facilitate greater benefit than lower ones.
Despite these findings, there were some limitations associated with the data included in this review. The most substantial limitation was that much of the data were collected from studies in which lamotrigine was administered for an extremely short duration. This makes it difficult to predict whether therapeutic responses would’ve been maintained over a long-term. That said, it appears as though lamotrigine could be helpful for treating comorbid symptoms of anxiety among persons with a primary diagnosis of unipolar depression.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/22322995
2012: Lamotrigine augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study.
Bruno, Micò, Pandolfo, et al. (2012) conducted a randomized controlled trial (RCT) to determine the effectiveness of augmenting an SSRI with lamotrigine for the treatment of refractory OCD. Researchers recruited 33 patients with treatment-resistant OCD to participate in the trial, all of whom had been receiving stable doses of SSRIs without adequate symptomatic remission. Participants were assigned at random to receive either: lamotrigine (100 mg/day) or a placebo for a 16-week duration to augment their ongoing SSRI treatment.
The effectiveness of adjunct lamotrigine for the treatment of refractory OCD was gauged based upon degree of change on the Yale-Brown Obsessive Compulsive Scale (YBOCS) from pre-treatment (baseline) to the trial endpoint (16 weeks). In addition to tracking the efficacy of lamotrigine for OCD, researchers assessed whether lamotrigine impacted mood and cognitive function with the HAM-D and a neurocognitive analysis, respectively.
Trial results indicated that recipients of adjunct lamotrigine exhibited significant reductions in OCD symptoms as evidenced by marked changes in YBOCS scores from baseline. Secondary outcome measures revealed that adjunct lamotrigine improved mood (according to changes in HAM-D scores) and enhanced the semantic fluency, a domain of cognitive performance. Researchers concluded that lamotrigine augmentation of SSRIs appears tolerable and might be therapeutic for a subset of patients with unremitting OCD.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/22351381
2011: Lamotrigine treatment of a patient affected by epilepsy and anxiety disorder.
Sepić-Grahovac, Grahovac, Ružić-Baršić, et al. (2011) highlighted the fact that individuals with epilepsy often exhibit comorbid psychiatric disorders, discussing that early detection plus management of these comorbidities is critically important for their social wellbeing. Furthermore, it was noted that a majority of patients with epilepsy suffer more substantially from inadequate social support than their actual seizures. Researchers documented the most frequently diagnosed psychiatric comorbidities among patients with epilepsy respectively including: anxiety, depression, panic, behavioral dysfunction, and psychosis.
For this reason, researchers mention the potential advantages of taking a single antiepileptic agent capable of treating epilepsy and psychiatric comorbidities simultaneously. Various advantages of taking a single antiepileptic agent to simultaneously manage seizures and comorbidities may include: improved adherence [due to taking just a single medication], lower medication costs, fewer side effects, and negation of possible multi-drug interaction effects. That said, antiepileptic agents haven’t been subject to thorough investigation for the treatment of many neuropsychiatric comorbidities, hence the reason professionals may prefer a multi-drug approach – one to target the epilepsy, and another for the specific comorbidity.
Nonetheless, authors presented a case report in which a patient responded extremely well to standalone lamotrigine for the treatment of epilepsy and comorbid anxiety disorder. The patient was a 35-year-old married man with 2 children and a history of one minor concussion in teenage years and a tragic immediate family death in his 20s. Within a year of the tragic death, he developed psychiatric symptoms such as: agitation, fear, irritability, tension, etc. – and also exhibited somatic symptoms, suspecting that he would or had developed a cardiac or GI disease.
After visiting a psychiatrist, the patient was diagnosed with anxiety disorder, receiving a prescription for alprazolam (1.5 mg/day) and sulpiride (100 mg/day) and psychotherapy was recommended. Shortly after initiation of treatment, the patient sought evaluation from a neurologist due to paroxysmal attacks, altered perception, and psychomotor agitation. During these attacks, the patient was unable to communicate, his face became pale, and was observed by others.
The neurologist collected an EEG recording from the patient which showed irregularities in the left temporal region of his brain. A SPECT neuroimaging scan also indicated frontotemporal hypoperfusion. Upon assessment of the EEG recording, the SPECT scan, and the symptoms presented by the patient, the neurologist made a diagnosis of complex partial epilepsy whereby a prescription of lamotrigine (25 mg/day) was initiated.
The lamotrigine dosage was increased every 2 weeks until the patient had titrated up to a dose of 500 mg/day. Approximately 6 months after initiation of lamotrigine treatment, the patient reported experiencing balance issues while walking, fatigue, and confusion – but had no epileptic attacks and his EEG recording significantly improved from pre-treatment baseline. The dosage of lamotrigine was titrated downward from 500 mg/day to 200 mg/day over a 2-month period and his balance issues, fatigue, and confusion abated.
For a 5-year duration, the patient received frequent neurological evaluations and his seizures were sufficiently controlled with the lamotrigine. Additionally, the patient’s anxiety was effectively attenuated with the stable dose of lamotrigine at 200 mg/day. Though this is certainly a unique case report in regards to the subtypes of epilepsy and anxiety presented, it supports the idea that an individually-calibrated dosage of lamotrigine may alleviate symptoms of anxiety.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/21448112
2010: Lamotrigine as an augmentation agent in treatment-resistant obsessive-compulsive disorder: a case report.
Uzun (2010) authored a case report in which a 59-year-old woman exhibited treatment-resistant symptoms of OCD. The patient was initially put on the tricyclic antidepressant clomipramine at a dosage of 225 mg/day, but failed to adequately respond. As a result of the inadequate response to clomipramine monotherapy, professionals prescribed lamotrigine at a dosage of 150 mg/day to be administered as an adjunct.
The patient complied with the combination treatment of clomipramine (225 mg/day) plus lamotrigine (150 mg/day) and after a 10-week duration, her symptoms of OCD significantly decreased. The symptomatic reduction was supported by a substantial change in her score on the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Uzun concluded that this case provides some preliminary evidence to support the idea that lamotrigine may prove therapeutically effective in the treatment of OCD.
Nonetheless, since this is merely a case report and not a randomized controlled trial, it’s difficult to rule out the potential of a placebo effect and/or an individual-specific outcome that may not apply to other OCD sufferers. Furthermore, it’s unknown as to whether there’s some unique synergy between lamotrigine and clomipramine that facilitated therapeutic benefit or if similar effects are derived from augmentation of another serotonergic antidepressant with lamotrigine. In any regard, this case report provides additional support for the concept that lamotrigine is likely to help with anxiety disorders such as OCD.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/19010977
2010: Lamotrigine administration in panic disorder with agoraphobia.
Masdrakis, Papadimitriou, Oulis (2010) report that several anticonvulsants appear effective for the treatment of panic disorder – with or without agoraphobia, however, [possibly due to lack of evaluation], lamotrigine was not one. For this reason, researchers sought to test the efficacy of lamotrigine among patients diagnosed with panic disorder. This involved administering lamotrigine (200 mg/day) to 4 patients with panic disorder over a 14-week duration.
Of the 4 patients with panic disorder, 3 had also been diagnosed with chronic/severe agoraphobia. These 3 patients were assigned to receive lamotrigine (200 mg/day) as an adjunct to their current treatment regimen. The remaining patient of the 4 was drug-naïve (i.e. never previously treated with psychiatric medications) and was assigned to receive lamotrigine (200 mg/day) as a monotherapy.
Examination of results indicated that the patient receiving lamotrigine as a monotherapy exhibited substantial symptomatic improvement over the 14-week duration. Out of the remaining 3 patients, 2 experienced some symptomatic improvement from lamotrigine augmentation. This experiment indicates that lamotrigine may be therapeutically effective in a subset of patients with panic disorder when administered as a monotherapy or adjunct.
Still, it is possible that the favorable responses by patients to lamotrigine were explainable by a placebo effect. Additionally, this was an extremely small-scale proof-of-concept trial with a highly-specified population, making it difficult to know whether lamotrigine is legitimately useful for the treatment of panic disorder. A large randomized controlled trial is needed to generate more accurate data regarding lamotrigine’s anxiolytic efficacy.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/20502131
2009: Improvement of obsessive-compulsive disorder with divalproex and lamotrigine in two patients with bipolar II disorder.
Among individuals with bipolar disorder, it is estimated that between 10% and 25% of patients experience comorbid OCD (obsessive-compulsive disorder). This comorbidity typically decreases quality of life for patients and often makes the primary diagnosis of bipolar disorder more difficult to manage. Experts know that bipolar disorder with comorbid OCD is often difficult to treat with conventional medications such as SSRIs because they may trigger manic switching and/or rapid cycling.
Although atypical antipsychotics are another viable alternative to SSRIs for the treatment of comorbid OCD among those with bipolar disorder, antipsychotics are associated with serious side effects and potentially deleterious long-term effects. For this reason, Bisol and Lara (2009) highlight cases of multiple patients with bipolar 2 disorder and comorbid OCD who derive substantial symptomatic reduction from treatment with anticonvulsants. Since lamotrigine is the only anticonvulsant relevant to this article, it is the only case that we will discuss.
The case presented in which lamotrigine was administered involved a 36-year-old female who had been diagnosed with panic disorder major depression with treatment-resistant symptoms earlier in life. After years, she reportedly developed other symptoms such as irritability, racing thoughts, pressured speech, reduced sleep, paranoia, episodes of compulsive buying, and bouts of depression. Based on newer symptom set, the woman was diagnosed with bipolar 2 disorder and received lamotrigine up to 100 mg/day.
In addition to the lamotrigine, the patient received paroxetine at a dose of 20 mg/day to help counteract her longstanding comorbid symptoms of OCD, however, this induced hypomania and was quickly discontinued. Thereafter, treatment was initiated with divalproex at a dose of 500 mg/day to augment lamotrigine. The combination of lamotrigine (100 mg/day) and divalproex (500 mg/day) successfully managed the woman’s bipolar 2 disorder and comorbid OCD.
It was reported that the patient’s pre-treatment score on the Yale-Brown Obsessive-Compulsive Scale was 46, and after a 6-month administration of the anticonvulsant combination, her score dropped to just 4. The patient was said to have remained stable on the anticonvulsant combination for approximately 2 years. Results from this case report support the potential of lamotrigine for attenuating symptoms of bipolar disorder and comorbid OCD in a subset of patients.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/19153947
2009: Open-label trial of lamotrigine focusing on efficacy in vulvodynia.
Meltzer-Brody, Zolnoun, Steege, et al. (2009) organized an open-label trial in which lamotrigine was tested as an intervention for the treatment of vulvodynia, a chronic pain condition affecting the vulvar region of women. It was noted that among women diagnosed with vulvodynia, comorbid psychiatric disorders and/or symptoms are common. Researchers hypothesized that the antiepileptic agent lamotrigine might address the primary symptoms of vulvodynia, while simultaneously attenuating comorbid psychiatric symptoms.
A total of 43 women diagnosed with chronic pelvic pain (CPP) were recruited from a specialized clinic to participate in this trial. Of the 43 women recruited, 31 completed the full 8-week trial duration. To determine the efficacy of lamotrigine for the attenuation of symptoms, researchers measured symptomatic severity of each patient prior to the trial with the following scales: McGill Pain Rating Index, Hamilton Depression Rating Scale, and Hamilton Anxiety Rating Scale.
Results indicated that lamotrigine (200 mg, b.i.d.) significantly reduced symptoms of chronic pelvic pain, depression, and anxiety at 8-week and 12-week evaluations – compared to pre-treatment baseline. Average 8-week scores dropped from 19.46 to 13.66 on the McGill Pain Rating Index, 12.26 to 9.26 on the HAM-D, and 12.52 to 9.61 on the HAM-A. Average 12-week scores decreased from 17.48 to 11.68 on the McGill Pain Rating Index, 11.29 to 6.96 on the HAM-D, and 10.9 to 6.8 on the HAM-A.
It was concluded that lamotrigine appears helpful for the treatment of chronic pelvic pain and comorbid neuropsychiatric symptoms among women. Based on the significant HAM-A score reductions at 8-week and 12-week evaluations, it appears as though lamotrigine (200 mg, b.i.d.) may be effective for the treatment of anxiety. That said, additional research is needed in a randomized controlled trial to rule out a placebo effect.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/19370903
2008: Olanzapine or lamotrigine addition to lithium in remitted bipolar disorder patients with anxiety disorder comorbidity: a randomized, single-blind, pilot study.
Maina, Albert, Rosso, and Bogetto (2008) carried out a randomized, single-blinded, pilot trial to evaluate the efficacy of utilizing multiple mood stabilizers among individuals with bipolar disorder plus comorbid anxiety. For the study, researchers recruited 47 patients that had been in remission from bipolar disorder for a minimum of 2 months while taking lithium monotherapy. In addition, all patients exhibited scores of at least 12 on the HAM-A (Hamilton Rating Scale for Anxiety), indicative of an anxiety disorder.
The 47 patients were divided into 2 groups and randomly assigned to receive 50-200 mg/day lamotrigine (23 patients) OR 5-10 mg/day olanzapine (24 patients) – for a duration of 12-weeks as an adjunct to lithium. The primary outcome measure was change in HAM-A score from pre-treatment through the 12-week trial duration, and the secondary outcome measures included the CGI-S (Clinical Global Impressions-Scale) and the GAF (Global Assessment of Functioning scale). A total of 18 patients receiving lamotrigine and 22 patients receiving olanzapine completed the entire 12-week trial.
Results indicated that augmentation of lithium with either lamotrigine or olanzapine significantly reduced HAM-A scores from pre-treatment baseline. Additionally, both lamotrigine and olanzapine substantially improved secondary outcome measures as evidenced by changes on the CGI-S and GAF scales. Though olanzapine appeared more effective than lamotrigine after 6-week and 12-week evaluations, a visit-wise analysis revealed no differences on HAM-A and GAF scores between the two at the Week 12 endpoint.
This study supports the idea that lamotrigine is effective for the treatment of anxiety disorders among patients with bipolar disorder when administered to augment lithium. That said, it is unclear as to whether lamotrigine would prove effective as an adjunct treatment for anxiety disorders among non-bipolar patients and/or non-lithium users, especially when considering that some derive benefit from using standalone lithium for anxiety. Moreover, this was an extremely small-scale study without a placebo control, ultimately leaving questions regarding the strength of lamotrigine’s anxiolytic effect.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/18294024
2007: The role of anticonvulsant drugs in anxiety disorders: a critical review of the evidence.
Mula, Pini, and Cassano (2007) documented that antiepileptic drugs have been successfully administered for the management of mood disorders, leading researchers to question their potential efficacy for the treatment of other neuropsychiatric conditions. One classification of neuropsychiatric conditions hypothesized to derive therapeutic benefit from antiepileptic drugs is anxiety disorders. Based on this hypothesis, researchers sought to review the literature investigating the therapeutic potential of antiepileptic agents among persons with anxiety.
For the review, researchers searched MEDLINE for articles published between 1970 and 2006 investigating antiepileptic drugs (e.g. lamotrigine, topiramate, valproate), and various types of anxiety (e.g. agoraphobia, GAD, OCD, PTSD). The investigation yielded over 70 articles and 38 published studies. Next, researchers evaluated the quality of evidence presented in each of the articles based on the type of study conducted (e.g. meta-analysis/review, RCT, case report, etc.).
Results indicated that there were robust data to support the efficacy of pregabalin for the treatment of social phobia and generalized anxiety disorder; gabapentin for social phobia; and lamotrigine for PTSD. Overall, it appears as though lamotrigine and other select antiepileptic agents are unconventional, yet viable alternative interventions for a subset of anxiety disorders. Researchers recommend conducting further research to determine which patients with anxiety are most likely to benefit from antiepileptic agents.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/17502773
2005: Lamotrigine has an anxiolytic-like profile in the rat conditioned emotional response test of anxiety: a potential role for sodium channels?
In the early 2000s, anticonvulsant agents like lamotrigine were gaining popularity for the off-label treatment of neuropsychiatric disorders other than epilepsy, including anxiety disorders. Due to the increased off-label usage of anticonvulsants for anxiety disorders, researchers Mirza, Bright, Stanhope, et al. (2005) sought to assess their effect in an animal model of anxiety. They organized a study in which lamotrigine, valproate, and carbamazepine were administered to rats subjected to a conditioned emotional response (CER) test.
The primary outcome measure was change in the rats’ conditioned emotional response (CER) test from pre-treatment baseline to post-treatment. Results indicated that administration of lamotrigine between 30 mg/kg and 80 mg/kg dose-dependently facilitated a significant anxiolytic response on the CER test; the significance of this anxiolytic response was analogous to that generated by benzodiazepines. Agents with similar pharmacodynamics to lamotrigine (Na+ channel blockers), including carbamazepine (20-40 mg/kg) and riluzole (10 mg/kg) also showed anxiolytic efficacy.
Comparatively, valproate (100-600 mg/kg) was ineffective as an anxiolytic, possibly due to its different action upon Na+ channels. Other agents including paroxetine (SSRI), propofol (GABAA modulator), memantine (NMDA antagonist), and nifedipine (Ca2+ channel blocker) – were all ineffective for reducing anxiety on the CER test. Researchers were able to inhibit lamotrigine’s anxiolytic effect by activating Na+ channels with veratine (0.1 mg/kg), suggesting that blockade of Na+ channels reduces anxiety in rats.
It was concluded that lamotrigine appears effective for the attenuation of anxiety in animal models through inhibition of Na+ channels. Though drugs that are effective in animal models of anxiety are not always effective for humans with anxiety disorders, this study supports the idea that lamotrigine’s anxiolytic potential is worth exploring in humans. Individuals who derive insignificant benefit from conventional anxiolytics may respond better to lamotrigine’s atypical anxiolytic mechanism of action involving Na+ channel blockade.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/15682295
1999: A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder.
Hertzberg, Butterfield, Feldman, et al. (1999) suspected that the anticonvulsant lamotrigine might help manage symptoms of PTSD. For this reason, they organized a 12-week trial in which the efficacy of lamotrigine was compared to a placebo for the treatment of PTSD. A total of 15 patients diagnosed with PTSD were recruited for trial participation and assigned at random to receive either lamotrigine or a placebo in a respective 2:1 ratio – for a duration of 12 weeks.
Lamotrigine was administered at a dosage of 25 mg/day and titrated upwards every 1-2 weeks until a peak dosage of 500 mg/day was reached (only if tolerable). Of the 15 participants, 14 completed the full 12-week trial. Results indicated that 50% of lamotrigine recipients (5/10) and 25% of placebo recipients (1/4) experienced clinically significant improvement in PTSD symptoms.
Those receiving lamotrigine exhibited significant reduction on specific symptoms of PTSD such as avoidance, numbing, and re-experiencing – compared to placebo recipients. Since lamotrigine was well-tolerated, investigators concluded that lamotrigine might be effective as a primary intervention for PTSD – regardless of whether associated with combat. Moreover, although the results support the idea that lamotrigine may alleviate unwanted symptoms among PTSD sufferers, larger-scale trials are needed to confirm preliminary findings.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/10331117
Verdict: Lamictal (Lamotrigine) possibly effective for a subset of persons with anxiety disorders
Since lamotrigine hasn’t undergone extensive testing via large-scale randomized controlled trials (RCTs) to determine its anxiolytic efficacy, no strong conclusions can be made regarding its therapeutic value in the treatment of anxiety disorders. Nonetheless, nearly every study in which the anxiolytic efficacy of lamotrigine was evaluated provides preliminary evidence to support the hypothesis that it is capable of attenuating anxious symptoms. In other words, virtually all preliminary data is unanimous in suggesting that lamotrigine administration may be therapeutically effective for the treatment of anxiety.
What’s more, there don’t appear to be any convincing data from studies (animal or human) indicating that lamotrigine may be ineffective or useless for the treatment of anxiety disorders. Although there isn’t much animal model data, the available data from work by Mirza, Bright, Stanhope, et al. (2005) suggests that lamotrigine induces an anxiolytic-like effect. The anxiolytic-like effect was observed in the rat conditioned emotional response (CER) test of anxiety, likely through blockade of voltage-gated sodium channels, and the significance of this effect was comparable to that observed after the administration of benzodiazepines.
In humans, one of the first trials investigating the anxiolytic potential of lamotrigine was conducted by Hertzberg, Butterfield, Feldman, et al. (1999) and involved patients with PTSD. The trial implemented a placebo control, but was extremely small-scale with just 15 participants. Despite these limitations, results documented that the administration of lamotrigine (up to 500 mg/day) over a 12-week duration significantly reduced PTSD symptoms in 50% (5/10) recipients. Later, in a “critical review of the evidence” by Mula, Pini, and Cassano (2007) discussing the usefulness of anticonvulsants to treat anxiety, it was mentioned that lamotrigine might have a therapeutic role in the treatment of PTSD.
Additionally, it appears as though lamotrigine is effective for the treatment of comorbid symptoms of anxiety among patients with other neuropsychiatric conditions. For example, a trial by Maina, Albert, Rosso, and Bogetto (2008) reported that augmentation of lithium with lamotrigine significantly attenuated comorbid anxiety among patients with bipolar disorder. Zavodnick and Ali (2012) discovered that patients with comorbid anxiety and a primary diagnosis of major depressive disorder often respond well to lamotrigine.
Based on the aforestated findings, it is logical to surmise that lamotrigine is facilitating some sort of anxiolytic effect. Additional evidence supporting the anxiolytic effectiveness of lamotrigine is seen in numerous case studies. A case report presented by Sepić-Grahovac, Grahovac, Ružić-Baršić, et al. (2011) noted that lamotrigine at a dosage of 200 mg/day successfully treated epilepsy plus an anxiety disorder in a 35-year-old man, keeping symptoms in remission for over 5 years.
Another case report documented by Kishimoto, Goto, and Hashimoto (2014) indicated that lamotrigine (50 mg/day) played an instrumental role in treating refractory anxiety, PTSD, and depression in a teenage patient. Moreover, a case report outlined by Hanoglu, Yulug, Cakir, et al. (2016) mentioned that lamotrigine plus topiramate modulated neural connectivity and metabolism to counteract anxiety and cognitive decline in an elderly patient. Although a literature review by Reid, Gitlin, and Altshuler (2013) emphasized that there are currently inadequate data to support the usage of lamotrigine as an off-label treatment for anxiety, this paper should not be misinterpreted as implying that lamotrigine is somehow automatically ineffective as an anxiolytic.
Strongest data to support the efficacy of lamotrigine in anxiety disorders is derived from trials in which adjunct lamotrigine is administered to patients with refractory OCD (obsessive-compulsive disorder). For example, a randomized controlled trial by Bruno, Micò, Pandolfo, et al. (2012) conducted among 33 patients with refractory OCD indicated that adjunct lamotrigine significantly reduced OCD symptoms when administered over a 16-week duration – compared to a placebo. A larger RCT by Khalkhali, Aram, Zarrabi, et al. (2016) conducted among 53 patients with refractory OCD documented that adjunct lamotrigine substantially decreased OCD symptoms when administered over a 12-week duration compared to a placebo.
What’s more, a retrospective analysis by Hussain, Dar, Wani, et al. (2015) discovered that augmentation of an SSRI with lamotrigine significantly reduced symptoms of OCD after 16 weeks. Since patients were not responding to serotonergic antidepressant (e.g. SSRI) monotherapy prior to the administration of lamotrigine, it’s reasonable to suspect that lamotrigine facilitated a bulk of the relevant anxiolytic effect. Additionally, even in patients without clinically diagnosable neuropsychiatric disorders, lamotrigine appears to lower anxiety.
An open-label trial of lamotrigine conducted by Meltzer-Brody, Zolnoun, Steege, et al. (2009) found that lamotrigine mitigated anxious symptoms among patients with vulvodynia. Despite the favorable preliminary evidence supporting the efficacy of lamotrigine for the treatment of anxiety, the jury is still out as to whether lamotrigine can prove effective as an anxiolytic in large-scale randomized controlled trials. That said, when considering results from preliminary trials, case reports, and lamotrigine’s pharmacodynamics – it’s not unreasonable to suspect that lamotrigine could serve as a novel, efficacious anxiolytic for a subset of individuals with anxiety disorders.
Limitations associated with Research of Lamictal for Anxiety
There are a host of limitations associated with the currently-available research of lamotrigine for the treatment of anxiety. Perhaps the biggest limitation is that lamotrigine hasn’t been evaluated as an anxiolytic monotherapy among patients with anxiety disorders. Other limitations include: sample sizes, study designs, and the overall lack of research testing lamotrigine’s anxiolytic effect in humans. As a result of these limitations, there’s currently inadequate quality evidence to determine if lamotrigine is an effective off-label anxiolytic among patients with anxiety disorders.
- Anxiety subtypes: There are many specific types of anxiety disorders including: generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social phobia. As of current, lamotrigine hasn’t been tested insomuch as a proof-of-concept trial for the treatment of generalized anxiety disorder or social phobia. Since both generalized anxiety disorder and social phobia are common subtypes of anxiety, it would be useful to know whether lamotrigine could prove helpful for these conditions. Furthermore, it’s possible that lamotrigine may prove more effective for specific anxiety disorders than others. In other words, research may eventually show that lamotrigine is effective for OCD, but not fro PTSD – or vice-versa. In addition to determining whether lamotrigine may be helpful for specific diagnostic subtypes of anxiety, it would also be useful to know whether any specific neurobiological signatures of anxiety (e.g. glutamatergic dysregulation) respond better to lamotrigine than others.
- Lack of quality studies: Another limitation of the research is the sheer lack of quality studies in which lamotrigine has been investigated as an intervention for anxiety. Of the available studies, most are small-scale and implement proof-of-concept designs devoid of randomization and controlling. This makes it impossible to know whether results from these studies might apply to the general population. Other studies are larger-scale with more robust designs, but they do not administer lamotrigine as a monotherapy. Additionally, there are various “case reports” suggesting benefit from adjunct lamotrigine, however, in these cases is difficult to rule out a placebo effect and/or know whether therapeutic effects may be limited to the specific individual – rather than apply to the general population. Significantly more quality studies are needed to understand if lamotrigine is useful as an anxiolytic.
- Limited incentive: Another substantial limitation is that there’s no major financial incentive to investigate the anxiolytic potential of lamotrigine. Most researchers rely on external funding from pharmaceutical companies to conduct large-scale randomized controlled trials. Although lamotrigine is a potentially novel treatment for anxiety, its patent has expired. Due to patent expiry, pharmaceutical companies won’t receive a big enough return on their investment to justify funding a randomized controlled trial of lamotrigine for anxiety. Unless there’s some sort of incentive to test the efficacy of lamotrigine for anxiety, it will likely remain untested in favor of allocating resources to test patented compounds.
- Monotherapeutic testing: Arguably the most prominent limitation of the research is that lamotrigine has never been formally tested as a monotherapy among patients with anxiety disorders. It should be noted that there’s currently one small-scale uncontrolled study with 4 participants in which 1 drug-naïve participant received standalone lamotrigine as an intervention for panic disorder with success. That said, other than this single isolated participant, there don’t appear to be any studies nor case reports in which lamotrigine monotherapy was administered for the management of anxiety. An evaluation of lamotrigine as a monotherapy would give us a better idea as to whether it might help reduce anxiety.
- Participants: Another limitation with the research assessing lamotrigine as an anxiolytic is that most studies recruit patients with extreme and/or severe symptoms. For example, the randomized controlled trials in which lamotrigine was evaluated as an intervention for OCD recruited participants with treatment-resistant symptoms. Other evaluations of lamotrigine as an anxiolytic involved patients with primary diagnoses of bipolar disorder or major depression with secondary diagnoses of comorbid anxiety. Research is needed in which participants are recruited with primary diagnoses of anxiety and symptoms of normative severity.
- Sample sizes: A problem with most trials of lamotrigine for anxiety is the utilization of small sample sizes. The smaller the sample size, the greater the likelihood that results of a trial may inaccurately reflect its effect in the general population of anxiety sufferers. To become confident in lamotrigine’s anxiolytic efficacy, it needs to undergo evaluation in a large sample (hundreds of participants) with a randomized controlled design. Currently the largest trials in which lamotrigine is tested for types of anxiety have implemented moderate sample sizes of 30 to 60 participants. While moderate sample sizes are better than smaller ones, just because lamotrigine appears effective in a moderately-sized trial for the management of anxiety does not mean that we should have confidence in its anxiolytic effect. For this reason, larger samples sizes are needed to improve the quality of evidence.
- Study designs: A limitation associated with trials of many off-label drugs for anxiety, including lamotrigine, is that poor quality study designs are implemented. While uncontrolled, non-randomized designs may be useful to confirm safety of a drug, they fail to yield reliable data regarding a drug’s efficacy. For this reason, more studies with randomized, double-blinded, and placebo controlled designs are needed to accurately understand whether lamotrigine has a reasonable likelihood of working for various anxiety disorders. Thus far, there are only a few trials that implemented randomized controlled designs when testing lamotrigine’s efficacy for an anxiety disorder (refractory OCD).
Which diagnoses might benefit from Lamictal for anxiety?
Not everyone will respond well to lamotrigine for anxiety, in fact, some may find that it makes them feel even worse due to individual variation. Based on preliminary research, it appears as though there are more data to support the usefulness of lamotrigine for certain types of anxiety than others. Individuals with primary diagnoses for which lamotrigine is intended to treat such as epilepsy or bipolar disorder are likely be ideal candidates to receive lamotrigine with the hope that it may also attenuate comorbid anxiety. Others who may respond well to lamotrigine include patients with anxious depression, refractory OCD, PTSD, and/or a glutamatergic anxiety.
- Bipolar disorder plus comorbid anxiety: Lamotrigine is FDA approved for the treatment of bipolar depression and also approved as a maintenance therapy in bipolar 1 disorder. Most consider lamotrigine a favorable intervention for bipolar depression because it is capable of ameliorating depressive symptoms without triggering mania or hypomania. A few studies suggest that lamotrigine may be effective as an adjunct to divalproex or lithium to reduce comorbid symptoms of anxiety among patients with bipolar disorder. When considering that lamotrigine is approved for usage in patients with bipolar disorder, as well as the fact that it appears to reduce anxiety, it may be an ideal intervention for anyone with bipolar disorder plus comorbid anxiety.
- Epilepsy plus comorbid anxiety: Lamotrigine was initially approved for the treatment of partial seizures in adults and remains commonly prescribed as a first-line intervention for epilepsy. Research suggests that many patients with epilepsy exhibit comorbid neuropsychiatric conditions, one of which might be anxiety. Since lamotrigine is approved to treat epilepsy, and appears capable of reducing anxiety, it’s logical to hypothesize that a subset of individuals with epilepsy plus comorbid anxiety may respond extremely well to lamotrigine monotherapy for symptom management.
- Major depression plus comorbid anxiety: A subset of patients with neuropsychiatric disorders exhibit “anxious depression,” usually characterized as major depressive disorder with comorbid symptoms of anxiety. Individuals with anxious depression are less likely than persons with non-anxious depression to derive benefit from conventional pharmacotherapies. Since some regard lamotrigine as effective in the treatment of unipolar depression, and preliminary evidence indicates that it may mitigate anxiety, lamotrigine could be an intriguing option for a subset of persons with the anxious depression subtype.
- Refractory anxiety: Other individuals who might respond well to lamotrigine as an intervention for anxiety are persons with treatment-resistant symptoms. Specifically, there are data to support the idea that lamotrigine may prove effective for the treatment of refractory OCD, as well as PTSD. There’s low quality data suggesting that it might also prove effective for patients with chronic/severe panic disorder. Any individual that’s tried several antidepressants [from each class], benzodiazepines, azapirones, nonpharmacologic anxiolytics, evidence-based off-label anxiolytics, and various combinations of evidence-based options may respond well to lamotrigine due to its distinctive mechanism of action.
- Glutamatergic anxiety: Assuming you were able to analyze the inner neurochemical workings of your brain and determined that there was significant glutamatergic dysregulation, and that this glutamatergic dysregulation was probably culpable for your anxiety, it would be reasonable to try lamotrigine as an anxiolytic intervention. Lamotrigine functions by blocking voltage-gated sodium and calcium channels, thereby limiting excessive glutamatergic transmission. If your anxiety has glutamatergic underpinnings, lamotrigine may be a targeted, effective medication to counteract anxious symptoms.
What dosage of Lamictal should you take for anxiety?
Because lamotrigine is not FDA approved for the treatment of anxiety disorders, no dosage guidelines have been established for this indication. If you were to test the efficacy lamotrigine as an intervention for your anxiety, it is necessary to work with a knowledgeable psychiatrist who can first ensure that lamotrigine is safe to administer in accordance with your current medical status, medical history, and/or other substances (e.g. medications or supplements) that you use. Some individuals will be unsuited to administer lamotrigine due to the fact that they have a medical contraindication and/or are taking another drug that would cause a serious interaction.
Assuming lamotrigine is safe for you to take, a psychiatrist will likely initiate treatment with a low dose (e.g. 25 mg) and gradually titrate it upwards until your symptoms subside. By gradually titrating the dosage upwards, your nervous system is given adequate time to adjust to the effects of lamotrigine whereby the likelihood of serious adverse reactions is minimized. Since everyone is different based on factors such as age, body size (height, weight, etc.), genetics, neurochemistry, and health – not everyone should expect to respond to the same amount of lamotrigine.
The goal should be for a professional to find the minimal effective dose, or the lowest quantity of lamotrigine needed to alleviate your symptoms. Finding the lowest effective quantity of lamotrigine will ensure that you don’t experience side effects that may accompany an unnecessarily-high dose. Although no formal dosing guidelines have been created for the off-label usage of lamotrigine to treat anxiety, it may help to assess the literature and document the doses at which recipients derived therapeutic benefit.
For the treatment of refractory OCD, 4 studies documented substantial benefit from the administration of lamotrigine as an adjunct to serotonergic antidepressants (3 studies with SSRIs, 1 with a TCA) at dosages of either 100 mg/day (2 studies) or 150 mg/day (2 studies). Based on these findings, perhaps a useful dosing guideline of lamotrigine for the treatment of refractory OCD is 100-150 mg/day. Among patients with bipolar disorder plus comorbid anxiety, administration of lamotrigine at a dose between 50 mg/day and 200 mg/day appears to effectively augment lithium to attenuate anxiety.
Preliminary data indicate that patients with severe panic disorder may respond well to 200 mg/day lamotrigine as an adjunct or monotherapy. A single case report suggests that lamotrigine may be therapeutic for the treatment of epilepsy plus comorbid anxiety at a dosage of 200 mg/day with minimal side effects. A different case report indicated that lamotrigine at a dosage of 100 mg/day to augment divalproex helped treat bipolar 2 disorder with comorbid OCD.
Lastly, a case report of a pediatric patient documented significant benefit from lamotrigine at a dosage of 50 mg/day along with flunitrazepam for the treatment of refractory PTSD. Overall, it appears as though individuals with anxiety respond to lamotrigine at doses from 50 mg/day to 200 mg/day when its administered as an adjunct. It is unclear as to whether greater dosages would be necessary if administered as a standalone, monotherapeutic intervention for anxiety. Keep in mind that dosages of lamotrigine can also be subject to variation based on the specific type and/or severity of a person’s anxiety disorder.
Have you tried Lamictal (lamotrigine) for anxiety?
If you were prescribed lamotrigine to treat a neuropsychiatric condition (e.g. bipolar disorder, epilepsy, etc.) and were surprised to find that it reduced your anxiety, share your experience in the comments section below. From your perspective, would you say that lamotrigine was: ineffective, slightly helpful, or effective – for the treatment of your anxiety? Assuming you had to rate the anxiolytic efficacy of lamotrigine on a scale of 1 to 10 (with “1” being ineffective and “10” being maximal efficacy), which numeric rating would you assign it?
To help others get a better understanding of your situation, provide some personal details such as: the dosage and format of lamotrigine you take (e.g. 100 mg/day XR), whether you administer other substances along with it (e.g. medications, supplements, etc.), your anxiety disorder diagnosis (e.g. generalized anxiety disorder), and the duration over which you’ve been taking it. If you happened to find lamotrigine as effective for the attenuation of your anxiety, how long did it take after treatment initiation for you to notice an anxiolytic effect? Do you have another neuropsychiatric condition for which your doctor originally recommended lamotrigine, or did your doctor prescribe it off-label specifically for anxiety?
How many medications did your doctor require you to try before deciding to test lamotrigine? Among those that have used lamotrigine for a long-term (e.g. years), were you able to maintain a stable dose with consistent anxiolytic efficacy or did you end up increasing its dosage as a result of tolerance? In your experience, do the anxiolytic effects generated by lamotrigine outweigh its side effects?
In closing, lamotrigine is a drug that many may find helpful for the treatment of an anxiety disorder. Preliminary evidence supports the idea that it could be therapeutically useful, especially for the treatment of refractory anxiety disorders such as OCD and PTSD. That said, more research is needed before its off-label usage, especially as a monotherapy, can be justified among patients with anxiety disorders.