The final assignment for this class will be a 10-page critical review of the drug treatment for a psychiatric disorder (broadly defined to include psychological and neurological disorders as well). Th

ORIGINAL PAPER Lamotrigine in the Treatment of Unipolar Depression with and Without Comorbidities: A Literature Review Adam Daniel Zavodnick •Rizwan Ali Published online: 10 February 2012 Springer Science+Business Media, LLC 2012 AbstractTo review the available data behind the use of lamotrigine in unipolar depression and common comorbid conditions. A PubMed based literature review was conducted using keywords related to lamotrigine, depression, anxiety, post traumatic stress disorder (PTSD), obsessive–compulsive disorder (OCD), and personality disorders. A large number of trials using lamotrigine for unipolar depression and various comorbid conditions were reviewed. A major limitation behind the majority of studies was a limited course of the treatment phase. The most robust data was found among studies that followed patients for over 8 weeks, and used higher dosages. Patients with comorbid anxiety states appeared to bene t. Patients with borderline personality disorder also appeared to bene t. The bene ts of lamotrigine in unipolar depression have been inconsistently noted in a number of studies. This is due in part to short treatment phases, atypical domains of bene t and different patient populations across studies. Patients with more treatment-resistance, comorbid anxiety and borderline personality disorder may be more able to bene t from lamotrigine.

Introduction The history of lamotrigine in the management of psychiatric illness is complex. Initially developed as an anticonvulsant, its effectiveness was at rst thought to be due to its antagonism of folate synthesis [1]. However its antagonism in this regard was modest and it was subsequently found to block voltage dependent sodium channels and modulate the A. D. Zavodnick (&) Department of Psychiatry and Behavioral Medicine, Carilion Clinic-Virginia Tech Carilion School of Medicine, Roanoke, VA, USA e-mail: [email protected] A. D. Zavodnick Veterans Affairs Medical Cente, 1970 Roanoke Boulevard—116A7, Salem, VA 24153, USA R. Ali Psychiatry Service, Veterans Affairs Medical Center, Salem, VA, USA 123 Psychiatr Q (2012) 83:371–383 DOI 10.1007/s11126-012-9208-4 release of the excitatory neurotransmitter glutamate. Calcium channel blockade as well as other properties of this compound also may contribute to its effect on mood [2].

There have been a variety of studies using lamotrigine in the treatment of bipolar disorder and treatment-resistant unipolar depression. Fewer studies have looked at con- ditions which are often comorbid with affective illness such as anxiety disorders and personality disorders.

Some of the more recent double blind placebo controlled studies on lamotrigine in mood disorders have not shown bene t in some of the primary outcome measures, however there have been notable limitations with these studies, the most prominent being the short duration of the trials. In addition, many of the comorbid conditions such as personality disorders had been selected out through exclusion criteria.

To our knowledge, there have been no articles analyzing all of the studies in unipolar depression and comorbid anxiety or personality disorders. The present review is performed to assess what was known about the effects of lamotrigine in the treatment of unipolar depression, anxiety disorders and borderline personality disorder.

This literature review includes the following objectives:

1. What is known about the effects of lamotrigine in unipolar depression, both in acute treatment and long-term maintenance trials?

2. Which outcome measures are altered by treatment with lamotrigine?

3. Are there other conditions which are often comorbid with unipolar depression that are effected by treatment with lamotrigine?

Method A PubMed based literature search was conducted. Relevant keywords such as ‘‘lamotri- gine’’ ‘‘depression’’ ‘‘borderline personality disorder’’ ‘‘PTSD’’ and ‘‘OCD’’ were used.

Several hundred studies were found, with the majority excluded as they did not meet the objectives of the study. Review articles were studied and reference lists were searched for additional studies for inclusion. A total of 13 published articles using lamotrigine in the treatment of unipolar depression were reviewed and categorized in Table1. Unpublished studies were reviewed and discussed but were not categorized in Table1. In addition, 3 studies assessing the role of lamotrigine in the management of borderline personality disorder and 3 studies assessing the role of lamotrigine in anxiety disorders were also reviewed. Additional studies of interest are also cited where relevant to the discussion.

Results The History of Lamotrigine and Psychiatric Disorders Lamotrigine and its effect on mood was a serendipitous discovery, observed by neurolo- gists nearly 20 years ago. Smith et al. [3] demonstrated this effect in a study in 1993.

Domains such happiness, self-esteem, sense of mastery, anxiety, depression and appetite were included. It was through this comprehensive evaluation that a strong bene t was observed in the spheres of happiness and mastery. This bene t was not explained by better seizure control and was highly signi cant with a p value of .003. It is worth noting that the bene ts of lamotrigine in that patient population might not have been appreciated had the 372 Psychiatr Q (2012) 83:371–383 123 Table 1Comparison of trials of lamotrigine in unipolar depression StudyNtype of study limitations Other pertinent observationsLength Dosage Measurement Result Conclusion Smith et al.

[3]N81 Cross over Excluded sev mental illness16–18 weeks 400 mg (AED adjunct) 200 mgHealth related questionnaire (affect, mood, esteem, mastery)Happiness mastery Signi cance independent of seizure control Kumar and Khanna [20]N8 Case series4 weeks Max 100 mg YBOCS, CGI-S, and CGI-I1 pt improved NS Barbee and Jamhour [10]N31 Retrospect Chart review No placebo Pts had been tried on an average of 13.27 past antidepressants.

[90% with comorbid anxiety disordersAvg 41.80 weeksAvg dose 112.90CGI and GAF 40.5% much improved 21.6% mildly improved 37.8% unchangedEffective especially in less depressed, fewer failed trials, comorbid anxiety Obrocea et al.

[8]N45 35 bipolar 10 unipolar Placebo controlled double-blind randomized controlled trial Mixed patient population LTG was used as monotherapy rather than an adjunct6 weeks Avg dose 274 Max dose 500 mg Abrupt titrationCGI Response LTG 51% vs 28% Gabapen vs 21% PboResponse associated w/bipolar diagnosis, male gender, fewer med trials Normann et al. [9]N40 Placebo controlled double-blind randomized controlled trial9 weeks 200 mg/day Ham-D and CGI Selected response (depressed mood, guilt, work/interest) CGI, fewer benzos, fewer withdrawalsExcel response to SSRI Rocha and Hara [11]N25 Retrospective chart review1 mont at target doseAvg 155 mg/ dayCGI 76% improved Comorbidity decreased response Barbosa et al.

[12]N 13-LTG N10-Pbo Placebo controlled double-blind randomized controlled trial BP II and unipolar patients25–100 mg over 6 wks100 mg/day HAM-D, MADRS, and CGICGI HAM-D MADRSImproved CGI No improvement in HAM-D or MADRS.

No signi cant difference between mdd/bp II Psychiatr Q (2012) 83:371–383 373 123 Table 1continued StudyNtype of study limitationsOther pertinent observationsLength Dosage Measurement Result Conclusion Gutierrez et al. [13]N34 Retrospect chart review356 days Avg dose 43 mg Max dose 113 mg/day‘‘Med Visit by MD’’ Improvement in multiple domains Improvement in multiple domains by 30 days Gabriel [14]N14 Open study Heterogeneous population Highly resistant population—use of MAOIs, TCAs, antipsychotics, 1 past hospitalization 2 failed ECT/TMS trials6 months Max 200 mg/ dayCGI-S and MADRS Improvement in CGI MADRS Social/Occ FunctioningImprovement by 8 weeks Schindler and Anghelescu [15]N34 Open study No placebo Li vs LTG8 weeks Max dose 250 mg Avg dose 152.94HAM-D Improvement in both arms Improvement in both arms Santos et al.

[16]N34 Treatment resistant depression with at least 2 failed med trials High rate of placebo response No details on benzo use No details on anxiety No HAM-D No suicidality No psychosis No Axis II8 weeks 200 mg/day for the last 4 weeksMADRS, CGI-S, and CGI-INS NS 3 pts left LTG arm b/c of adverse effects and non- compliance 2 left placebo arm b/c of worsening dep.

1 left b/c of mania 374 Psychiatr Q (2012) 83:371–383 123 Table 1continued StudyNtype of study limitationsOther pertinent observationsLength Dosage Measurement Result Conclusion Barbee et al.

[17]N48-LTG N48-Pbo Placebo controlled double-blind randomized controlled trial More past episodes and anxiety in the LTG arm10 weeks At least 100 mg/day for 5 weeks At least 200 mg/day for last 4 weeksMADRS, HDRS-17, CGI-S, and CGI-IPrimary outcome measures negative Post hoc analysis suggested bene t in severely depressed patients.

Completer analysis suggested bene t LTGLamotrigine Psychiatr Q (2012) 83:371–383 375 123 only measures of well being been restricted to the Hamilton Rating Scale for Depression (HAM-D) or the Montgomery-A sberg Depression Rating Scale (MADRS).

Subsequent studies into the use of lamotrigine in a variety of psychiatric ill- nesses followed. The most robust and consistent ef cacy was found for bipolar depression [1,4–6].

As observations regarding lamotrigine and improvement in mood were being noted, GlaxoSmithKline became interested pursuing an indication for lamotrigine in the treatment of bipolar disorder. It sponsored three relatively brief (7–8 week) studies investigating lamotrigine in the management of unipolar depression. 1All were negative and in one instance neither lamotrigine nor desipramine was able to separate from placebo. Investi- gation was done as part of the process for obtaining a bipolar indication. 2Subsequent published studies showing ef cacy of lamotrigine in unipolar depression followed.

Unipolar Depression, Anxiety Disorders, Personality Disorders and Lamotrigine Over the past decade there have been several published studies evaluating lamotrigine in the treatment of unipolar depression [7–17]. Also studied have been conditions which are frequently comorbid with depression such as anxiety disorders [18], speci cally general- ized anxiety disorder (GAD) [19], OCD [20], PTSD [21] as well as borderline personality disorder [22–24].

Preliminary Case Reports and Retrospective Chart Reviews of Lamotrigine in Unipolar Depression Maltese [25] wrote a case report in which a patient with treatment-resistant depression responded to lamotrigine in 1999. Following that piece there were several retrospective chart reviews [10,11,13] and open studies [14,15] in depression. In a retrospective chart review Barbee and Jamhour [10] found bene t in less severely depressed patients and in those with comorbid anxiety, however all patients were treatment-refractory. In a sub- sequent retrospective chart review, Rocha and Hara [11] found bene t with lamotrigine but no association between treatment response and current depressive morbidity or past epi- sodes. He found comorbidity adversely predicted response to lamotrigine, again all patients were treatment-refractory to some extent. 1Unpublished studies available online.

GlaxoSmithKline. An eight-week, multicenter, double-blind, randomized, xed-dose evaluation of the ef cacy and safety of lamotrigine (200 mg/day), desipramine (200 mg/d and, and placebo in outpatients with unipolar depression (result summary for the study SCAA2011 [105-613]).http://download.gsk-clinical studyregister.com/ les/1666.pdf. Ver ed December 12, 2011.

GlaxoSmithKline. A randomized, multicenter, double-blind, placebo-controlled, xed-dose, 7-week evaluation of the ef cacy and safety of lamotrigine in patients with major depression (result summary for study SCA20022.http://download.gsk-clinicalstudyregister.com/ les/1661.pdf. Veri ed December 12, 2011.

GlaxoSmithKline. A randomized, multicenter, double-blind, placebo-controlled, xed-dose, 7-week evaluation of the ef cacy and safety of lamotrigine in treatment of a major depressive episode in unipolar depressed patients (result summary for study SCA20025).http://download.gsk-clinicalstudyregister.com/ les/1663.pdf. Veri ed December 12, 2011.

2GlaxoSmithKline internal data.

376 Psychiatr Q (2012) 83:371–383 123 Open Studies Gabriel [14] performed an open study in treatment-resistant depression in 2006. He found a robust response to lamotrigine as early as 8 weeks, however patients were followed for 6 months. Strangely there was an appreciable response in some domains as early as week 2 when the dosage was quite low. This could be attributed to placebo response or a syner- gistic effect between lamotrigine and selective serotonin reuptake inhibitor (SSRI), which would be consistent with the ndings of Normann et al. [9], who found that lamotrigine may have accelerated the response to SSRI treatment. Schindler and Anghelescu [15] performed an open trial comparing lamotrigine augmentation to lithium augmentation in treatment-resistant depression. That study found no signi cant difference between the two treatment arms at 8 weeks.

The nature of these studies such as absence of placebo arm make them more prone to bias. However they also allow for longer follow up than many of the prospective studies.

For example Barbee and Jamhour [10] retrospectively followed patients for over 41 weeks while Gutierrez et al. [13] followed patients for almost a full year.

Double-Blind Studies There have been 5 published separate double-blind randomized placebo-controlled studies of lamotrigine in depression [7,9,12,16,17]. Obrocea et al. [8] performed a subsequent analysis on patients rst investigated by Frye et al. [7]. Unfortunately all studies were relatively brief (6–10 weeks) and this time period included the lengthy lamotrigine titra- tion. This was also true of the three unpublished studies from GlaxoSmithKline footnoted above. With the exception of the study by Frye et al. [7] and Obrocea et al. [8] all were negative regarding primary outcome measures such as composite HAM-D and MADRS scores. However, the outcome measure Clinical Global Impression Scale (CGI) consis- tently showed improvement in the majority of published studies [7–9,12]. Normann et al.

[9] showed bene t in speci c elements of HAM-D and potential acceleration of the response to SSRI in addition to improved CGI score. In contrast to the retrospective and open studies previously mentioned, Barbee et al. [17] found bene t among more treatment- resistent patients and in those with comorbid anxiety. Only Santos et al. [16] found no bene t in realms assessed, MADRS and CGI.

Individual Study Analysis Obrocea et al. [8] followed patients rst investigated by Frye et al. [7]. That study investigated lamotrigine monotherapy in patients with unipolar depression (N10) and depression due to bipolar disorder type II (N35). While unipolar patients did improve, a more robust effect was seen in those with bipolar disorder type II. Fewer failed medication trials and male gender were also associated with a favorable response. Only 6 weeks in duration, it was fairly brief, however the titration schedule was more aggressive (maximum dosage of 500 mg/day with mean dosage of 274 mg/day) than subsequent studies; thus patients were on a therapeutic concentration for a longer period of time. This might explain why lamotrigine was so prominently superior to placebo (51% vs 21%) and why there were more drop outs secondary to intolerance among the lamotrigine group.

Investigating lamotrigine augmentation of paroxetine for depression in unipolar and bipolar type II depression, Normann et al. [9] found improvement in CGI and also speci c domains of HAM-D (depressed mood, guilt, work/interest). More patients in the Psychiatr Q (2012) 83:371–383 377 123 lamotrigine arm remained in the study and there were fewer benzodiazepines used among the lamotrigine group. This is consistent with the retrospective study by Barbee and Jamhour [10], showing improvement among those with anxiety and with the works by Masdrakis et al. [19] and Hertzberg et al. [21], both of which showed bene cial effects of lamotrigine for anxiety disorders (GAD and PTSD respectively).

Barbee and Jamhour [10] performed a retrospective chart review of 37 individuals with treatment-resistant unipolar depression, 35 of whom had comorbid anxiety disorders.

Using CGI as the principle ef cacy measure, 62% of patients showed some degree of improvement, 40.5% of which were much/very much improved. Those with fewer failed trials and those with comorbid anxiety disorders appeared to bene t more.

Barbosa et al. [12] investigated lamotrigine with concomitant uoxetine administration in those with unipolar depression and those with depressive episodes of bipolar disorder type II. He found improvement in CGI, however here too no differences were seen in the MADRS or HAM-D. There was no difference between unipolar and bipolar type II depression in respect to response to lamotrigine.

Santos et al. [16] found no signi cant differences in all domains assessed, inclusive of CGI and MADRS. There were several limitations of the study. HAM-D was not assessed.

There was no mention of, need for or number of prior inpatient hospitalizations, use of ECT or past suicidality. Quantity of benzodiazepines used and frequency of comorbid anxiety were not reported. Exclusion criteria included those with organic illness, ‘‘severe clinical disease,’’ acute depression with risk of suicide, psychosis, bipolar disorder, per- sonality disorders and disorders related to alcohol and other drugs. As will be further discussed below, the treatment-resistance was not as pronounced as some of the earlier studies.

The most recent double-blind randomized control trial was performed by Barbee et al.

[17]. After being started on Paroxetine or Paroxetine CR, patients were randomized to either lamotrigine (N48) or placebo (N48) and followed for 10 weeks. Administering lamotrigine or placebo for 10 weeks, it was the longest running double-blind randomized controlled trial of lamotrigine treating exclusively unipolar depressed patients. While primary outcome measures (MADRS, HAM-D, CGI) did not show a statistical difference, the signi cantly greater chronicity in the lamotrigine arm (14.33 prior episodes of depression vs 3.93 episodes in placebo arm) may have skewed the ndings. Twice the number of patients with anxiety were in the lamotrigine arm (13 patients vs 6 patients).

Indeed, post hoc analyses found that among the more severely ill patients the bene ts of lamotrigine approached signi cance (P=.06). Completer analysis favoring lamotrigine neared signi cance as well. Exclusion criteria included severe personality disorders, psychosis and substance abuse in the 6 months prior to study initiation.

Comorbid Diagnoses As was alluded to earlier, comorbid conditions are often excluded from prospective trials in an effort to eliminate confounding variables. For example, the studies by Santos et al. [16] and Barbee et al. [17] excluded those with prominent personality disorders. This has the potential to limit the assessment of an agent’s utility in common comorbid states, such as borderline personality disorder and anxiety disorders.

Such may have been the case for lamotrigine, as it had been found to be effective for both speci c anxiety disorders, such as GAD [19], PTSD [21] and symptoms associated with borderline personality disorder [22–24].

378 Psychiatr Q (2012) 83:371–383 123 Anxiety Disorders While Kumar and Khanna [20] did a small case series on 8 patients af icted with OCD in which no bene t was found, it was very brief (4 weeks), relatively low dose (100 mg/day) and included the lamotrigine titration.

A more persuasive, albeit small study evaluating lamotrigine in PTSD was conducted by Hertzberg et al. [21]. 10 patients received lamotrigine and 4 patients received placebo over 12 weeks. 50% of the lamotrigine group compared with 25% of the placebo group responded to treatment, with improvements in re-experiencing, detachment and numbing.

Patients were on 100 mg by the beginning of week 5 and dosages were increased to a maximum of 500 mg/day by week 10.

A more recent case series by Masdrakis et al. [19] demonstrated improvement in 3 of 4 patients with panic disorder with agoraphobia. Lamotrigine was titrated up to 200 mg/day over 6 weeks and kept at this dosage for an additional 8 weeks. This is yet another example in which bene t was shown when patients were followed for an extended period of time beyond initial titration.

Borderline Personality Disorder There have been three double-blind randomized placebo controlled studies evaluating the use of lamotrigine in borderline personality disorder (BPD). The rst was by Tritt et al. [22] in 2005, in which 24 patients were assigned to lamotrigine or placebo in a 2:1 manner for 8 weeks. Primary outcome measures were self-reported changes on the anger scales of the Trait Anger Expression Inventory (STAXI). There was a highly signi cant reduction in this measure when compared to placebo. Leiberich et al. [23] performed an 18 month follow up study in 2008, demonstrating that gains associated with lamotrigine were maintained.

The most recent study evaluating lamotrigine in borderline personality disorder was by Reich et al. [24] in 2009. That study speci cally evaluated the affective lability associated with borderline personality disorder. 15 patients received lamotrigine and 13 were assigned to placebo over 12 weeks. Affective instability was assessed by the Affective Lability Scale (ALS) and the affective instability score of the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD). Both scores were reduced (P\0.05).

Discussion The Inconsistencies in the Studies Referenced Above Are Challenging to Interpret.

How Can These Findings Be Reconciled?

Clearly there are many potential confounding variables. The clearest element is the pro- longed titration schedule that is needed to minimize the risk of Stevens-Johnsons Syn- drome. However it is also possible that the antidepressant effects of this medication take longer than most studies are equipped to run for.

For example, among bipolar studies there were many negative short-term trials but lamotrigine often separated from placebo among trials that ran for over 20 weeks or involved aggregate data [4–6]. One unpublished double-blind placebo-controlled ran- domized study by GlaxoSmithKline (Study 611), which was referenced by Goldsmith et al.

[26] followed rapid cycling patients for 32 weeks. While non-signi cant in the primary outcome measure of time to intervention for an emerging mood episode, fewer lamotrigine Psychiatr Q (2012) 83:371–383 379 123 recipients required intervention for a depressive episode compared with those receiving placebo (P=0.007). Lamotrigine was signi cantly more effective than placebo at delaying time to an emerging depressive episode (P=0.047), however not at delaying time to an emerging manic/hypomanic episode.

Among unipolar studies a similar trend was appreciable. In a retrospective study, Guiterrez et al. [13] found bene t as early as one month but followed patients for almost a full year. In an open study, Gabriel [14] found differences appreciable at 8 weeks but followed patients for 6 months. The double-blind studies were not as promising but patients were only on therapeutic quantities for 4–5 weeks.

The degree of treatment-resistance is another variable that deserves attention. Barbee and Jamhour [10] examined patients who had failed an average 13.27 different antide- pressants in the past. 9 were on MAOIs, other medications included antipsychotics. The side effects of these medications attest to the highly resistant nature of these patients. Over 90% of patients had comorbid anxiety disorders inclusive of PTSD. 2 of the 14 patients examined by Gabriel [14] had failed ECT or transcranial magnetic stimulation and 1 had been hospitalized in the past.

In contrast, a failed trial of ECT was a speci c exclusion criterion in the study by Barbee et al. [17]. Many of the patients who were treatment-resistant in the study by Santos et al. [16] had been on less than 3 antidepressants in the past. Patients were on a variety of agents inclusive of TCAs but there was no mention of past trials with ECT, past use of MAOIs or other agents such at lithium or atypical antipsychotics.

This underscores the importance of careful quanti cation of ‘‘treatment-resistance.’’ Patients who fail multiple antidepressant regimens and remain outpatients may be quite different from those who fail two trials of antidepressants and are subsequently hospital- ized for a prolonged period.

A full discussion of the different criteria used to assess resistance is beyond the scope of this article. However there are important differences in the Thase Rush Scale [27] and the Massachusetts General Hospital criteria [28] used in these studies. For example, according to the Massachusetts General Hospital criteria, a patient who failed 5 trials of different antidepressants in the same class would have the same score as a patient who had been on a TCA and subsequently went on to fail a trial of ECT. In contrast, Thase Rush categorizes patients based on the various classes of medications used rather than the cumulative number of trials.

Among patients with depression, those who are more treatment-resistant are often less likely to respond to augmentation strategies than less severely ill patients [29]. So why would those who are more treatment-resistant appear to bene t more from lamotrigine when compared to those who are less severely depressed? One explanation would be that the effect of lamotrigine is modest, so a more ill patient population is needed to show effect. Alternatively, it could be that those who are more treatment-resistant and those with more past episodes represent a distinct type of unipolar depression, an entity that is more similar to bipolar disorder. Saggese et al. [30] articulates this viewpoint, noting that patients with highly recurrent unipolar depression (HRUP) often have family histories of bipolar disorder and are more likely to respond to mood stabilizers. Concordant with this viewpoint is the observation that highly treatment-resistant MDD patients frequently go on to be treated with atypical antipsychotics, lithium and other mood stabilizers.

Another confounding variable has been the range of dosages across trials. Two of the double-blind randomized trials, which showed bene t used higher dosages of lamotrigine.

Obrocea et al. [8] used a maximum dosage of 500 mg, while Schneider and Anghelescu [15] used a maximum dosage of 250 mg. Among bipolar studies dosages as high as 380 Psychiatr Q (2012) 83:371–383 123 500 mg have been used [4]. While beyond the scope of this paper, lamotrigine has been used for psychosis in dosages as high as 400 mg/day [31].

Setting aside the parameter of treatment length, dosage and speci c differences in patient populations across studies, it would appear that lamotrigine is a dif cult drug to study. The most common outcome measures frequently fail to capture its bene t and yet there are clearly patients who respond quite well. Why is this the case?

Looking back to Smith et al. [3], it was happiness that was statistically signi cant between treatment arms, not depression. In this regard it is worth remembering that lamotrigine’s mechanism of action involves glutamatergic modi cation and is quite dif- ferent than the serotonergic and noradrenergic agents routinely used as rst line medica- tions. It should not be surprising if the course and nature of symptom reduction is differently expressed. As more glutamatergic agents become available, older screening tools may need to be reassessed for sensitivity.

It might be that the patients who are best helped by lamotrigine are selected out of the more rigorous studies. Axis II pathology, PTSD, past hospitalizations and suicidality are frequent in routine clinical practice but not in many of the double-blind trials referenced above.

The role of cognition deserves mention. While not routinely assessed by HAM-D or MADRS, there is abundant data on the detrimental effects of mood disorders on cognition, both in acute episodes and during interepisode recovery [32]. There is also data behind the neuroprotective properties of mood stabilizers such as lamotrigine [2]. Paradoxically it is also known that many mood stabilizers actually impair cognition. In this respect lamo- trigine appears superior, having little negative impact on cognition [33] and may be demonstrably bene cial [34]. In keeping with this, Tiihonen et al. [35] found bene cial effects of lamotrigine in both negative and positive psychotic symptomatology of Schizophrenic patients resistant to clozapine.

Future studies will likely need to be of longer duration and with more sensitive detection modalities to better characterize the bene ts of this compound.

At this point it would appear that lamotrigine is somewhat of an atypical antidepressant.

When all of the available studies are reviewed, bene t appears most robust in the long-term management of treatment-resistant severe mood disorders. Outcome measures such as HAM-D and MADRS appear to be less sensitive than CGI at recording improvement.

Given the data in isolated anxiety disorders such as panic with agoraphobia [19] and PTSD [21], it is quite feasible that those patients with depression and comorbid anxiety disorders will bene t more than others. The study by Barbosa et al. [12] also suggested a role of lamotrigine for depression with comorbid anxiety.

Patients with borderline personality disorder often have depressive symptoms in addi- tion to affective instability and aggression. There is strong evidence for the use of lamo- trigine in the treatment of certain aspects of this disorder as well [22–24].

While speculative at this point, the neuro-protective role of lamotrigine may translate into its use among depressed patients with comorbid cognitive disorders such as mild cognitive impairment.

Lamotrigine’s unique mechanism of action allows it to be safely added to traditional serotonergic agents without increasing risk of serotonin syndrome. It has been associated with weight loss as well [2]. Patients with comorbid migraine or seizure disorders may also bene t from the dual ef cacy of this agent. Finally lamotrigine may be good option for those depressed patients whose history is less than straightforward and where there are suspicions of borderline personality disorder or bipolar disorder.

Going forward let us remember the history of this medication. The effects of lamotri- gine on mood were rst observed by neurologists looking to understand the whole patient Psychiatr Q (2012) 83:371–383 381 123 [3]. Over the course of months, measures of self-esteem, mastery, happiness and anxiety were assessed, alongside seizure frequency and duration. It was because of this meticulous analysis that the bene cial effects of lamotrigine on mood were rst discovered. Sub- sequent studies on mood were not as prolonged or as thorough and this likely contributed to the confusion in reconciling the aforementioned results.

There is much that the psychiatric community can learn from the investigations of lamotrigine for affective disorders. The length of trials, the speci c measures used to assess ef cacy, reproducibility of results and impact of comorbid conditions are all essential when going about careful investigation. Overly narrow patient populations can lead to ndings which may not be relevant to the clinician working with a heterogeneous patient popu- lation. The bene ts of lamotrigine are not as a straightforward as other agents and it may be that it will work best for those patients who are also less than straightforward.

References 1. Kemp DE, Muzina DJ, Gao K, Calabrese JR, Lamotrigine. In: Schatzberg AF, Nemeroff CB (Eds). The American Psychiatric Publishing textbook of psychopharmacology. Arlington, American Psychiatric, 2009 2. Ketter TA, Manji HK, Post RM. Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders. Journal of Clinical Psychopharmacology 23(5):484–495, 2003 3. Smith D, Baker G, Davies G, Dewey M, Chadwick DW. Outcomes of add-on treatment with lamo- trigine in partial epilepsy. Epilepsia 34(2):312–322, 1993 4. Calabrese JR, Bowden CL, Sachs G, et al.: A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. Journal of Clinical Psychiatry 64:1013–1024, 2003 5. Bowden CL, Calabrese JR, Sachs G, et al.: A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder.

Archives of General Psychiatry 60:392–400, 2003 6. Goodwin GM, Bowden CL, Calabrese JR, et al.: A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. Journal of Clinical Psychiatry 65:432–441, 2004 7. Frye MA, Ketter TA, Kimbrell TA, Dunn RT, Speer AM, Osuch EA, Luckenbaugh DA, Cora-Ocatelli G, Leverich GS, Post RM: A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. Journal of Clinical Psychopharmacology 20(6):607–614, 2000 8. Obrocea GV, Dunn RM, Frye MA, Ketter TA, Luckenbaugh DA, Leverich GS, Speer AM, Osuch EA, Jajodia K, Post RM: Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders. Biological Psychiatry 51(3):253–260, 2002 9. Normann C, Hummel B, Scha¨ rer LO, Ho¨ rn M, Grunze H, Walden J: Lamotrigine as adjunct to par- oxetine in acute depression: a placebo-controlled, double-blind study. Journal of Clinical Psychiatry 63(4):337–344, 2002 10. Barbee JG, Jamhour NJ: Lamotrigine as an augmentation agent in treatment-resistant depression.

Journal of Clinical Psychiatry 63(8):737–741, 2002 11. Rocha FL, Hara C: Lamotrigine augmentation in unipolar depression. International Clinical Psycho- pharmacology 18(2):97–99, 2003 12. Barbosa L, Berk M, Vorster M: A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with uoxetine for resistant major depressive episodes. Journal of Clinical Psychiatry 64(4):403–407, 2003 13. Gutierrez RL, McKercher RM, Galea J, Jamison KL. Lamotrigine augmentation strategy for patients with treatment-resistant depression. CNS Spectr. IEEE Transactions on Pattern Analysis and Machine Intelligence 10(10):800–805, 2005.

14. Gabriel A. Lamotrigine adjunctive treatment in resistant unipolar depression: an open, descriptive study.

Depress Anxiety 23(8):485–488, 2006 15. Schindler F, Anghelescu IG: Lithium versus lamotrigine augmentation in treatment resistant unipolar depression: a randomized, open-label study. International Clinical Psychopharmacology 22(3):179–182, 2007 382 Psychiatr Q (2012) 83:371–383 123 16. Santos MA, Rocha FL, Hara C: Ef cacy and safety of antidepressant augmentation with lamotrigine in patients with treatment-resistant depression: a randomized, placebo-controlled, double-blind study.

Primary Care Companion to the Journal of Clinical Psychiatry 10(3):187–190, 2008 17. Barbee JG, Thompson TR, Jamhour NJ, Stewart JW, Conrad EJ, Reimherr FW, Thompson PM, Shelton RC: A double-blind placebo-controlled trial of lamotrigine as an antidepressant augmentation agent in treatment-refractory unipolar depression. Journal of Clinical Psychiatry 72(10):1405–1412, 2011 18. Mula M, Pini S, Cassano GB: The role of anticonvulsant drugs in anxiety disorders: a critical review of the evidence. Journal of Clinical Psychopharmacology 27(3):263–272, 2007 (Review) 19. Masdrakis VG, Papadimitriou GN, Oulis P: Lamotrigine administration in panic disorder with agora- phobia. Clinical Neuropharmacology 33(3):126–128, 2010 20. Kumar TC, Khanna S. Lamotrigine augmentation of serotonin re-uptake inhibitors in obsessive-com- pulsive disorder. Australian and New Zealand Journal of Psychiatry 34(3):527–528, 2000 21. Hertzberg MA, Butter eld MI, Feldman ME, Beckham JC, Sutherland SM, Connor KM, Davidson JR.

A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder. Biological Psy- chiatry 45(9):1226–1229, 1999 22. Tritt K, Nickel C, Lahmann C, Leiberich PK, Rother WK, Loew TH, Nickel MK. Lamotrigine treatment of aggression in female borderline-patients: a randomized, double-blind, placebo-controlled study.

Journal of Psychopharmacology (3):287–291, 2005 23. Leiberich P, Nickel MK, Tritt K, Pedrosa Gil F. Lamotrigine treatment of aggression in female bor- derline patients, Part II: an 18-month follow-up. Journal of Psychopharmacology 22(7):805–808, 2008 24. Reich DB, Zanarini MC, Bieri KA. A preliminary study of lamotrigine in the treatment of affective instability in borderline personality disorder. International Clinical Psychopharmacology 24(5):270–275, 2009 25. Maltese TM: Adjunctive lamotrigine treatment for major depression. American Journal of Psychiatry 156(11):1833, 1999 26. Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM. Lamotrigine: a review of its use in bipolar disorder.

Drugs 63(19):2029–2050, 2003 (Review) 27. Thase ME, Rush AJ: When at rst you don’t succeed: sequential strategies for antidepressant nonre- sponders. Journal of Clinical Psychiatry 58(suppl 13): 23–29, 1997 28. Fava M: Diagnosis and de nition of treatment-resistant depression. Biological Psychiatry 53:649–659, 2003 29. Rush AJ, Trivedi MH, Wisniewski SR, et al.: Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. American Journal of Psychiatry 163(11):1905–1917, 2006 30. Saggese JM, Lieberman DZ, Goodwin FK: The role of recurrence and cyclicity in differentiating mood disorder diagnoses. Primary Psychiatry 13(11):43–48, 2006 31. Kremer I, Vass A, Gorelik I, Bar G, Blanaru M, Javitt DC, Heresco-Levy U: Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia. Biological Psychiatry 56:441–446, 2004 32. Wilder-Willis KE, Sax KW, Rosenberg HL, Fleck DE, Shear PK, Strakowski SM: Persistent attentional dysfunction in remitted bipolar disorder. Bipolar Disorders 3(2):58–62, 2001 33. Gualtieri CT, Johnson LG: Comparative neurocognitive effects of 5 psychotropic anticonvulsants and lithium. MedGenMed 23;8(3):46, 2006 34. Marciani MG, Stanzione P, Mattia D, Spanedda F, Bassetti MA, Maschio M, Bernardi G: Lamotrigine add-on therapy in focal epilepsy: electroencephalographic and neuropsychological evaluation. Clinical Neuropharmacology 21(1):41–47, 1998 35. Tiihonen J, Wahlbeck K, Kiviniemi V: The ef cacy of lamotrigine in clozapine-resistant schizophrenia:

a systematic review and meta-analysis. Schizophrenia Research 109(1–3):10–14, 2009 (Review) Author Biographies Adam Daniel Zavodnick, MDis a psychiatry intern with the Department of Psychiatry and Behavioral Medicine Carilion Clinic—Virginia Tech Carilion School of Medicine, Roanoke, Virginia.

Rizwan Ali, MDis a staff psychiatrist at Veterans Affairs Medical Center, Salem, Virginia and Assistant Professor with the Department of Psychiatry and Behavioral Medicine Carilion Clinic—Virginia Tech Carilion School of Medicine, Roanoke, Virginia.

Psychiatr Q (2012) 83:371–383 383 123 Copyright of Psychiatric Quarterly is the property of Springer Science & Business Media B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.