At the 2015 meeting of the International Society for Bipolar Disorders, researcher John Geddes presented an important study showing in inadequate responders to quetiapine that compared to adding placebo, adding the anticonvulsant lamotrigine to their treatment improved depression rapidly and lastingly. Some psychiatrists have been prescribing this combination to patients for some time, but this is the first formal clinical trial documenting its efficacy. The article was published online in December in the journal Lancet Psychiatry.
Researcher Guy Goodwin described details of the study, called CEQUEL, at the meeting. It included 202 patients with bipolar I or II disorder who required treatment for a depressive episode. Participants who did not respond completely to 14 days of treatment with quetiapine were prescribed either an additional dose of lamotrigine or a placebo. Lamotrigine was very slowly titrated up to maximum doses of 200mg/day. Its antidepressant effects were striking. They began early and persisted for 50 weeks. (The published article covers only the first 12 weeks.) Response rates for the combination of quetiapine and lamotrigine were 52%, compared to 22% for quetiapine alone. Remission rates were 35% for quetiapine and lamotrigine and 12% for quetiapine alone.
Folic acid interaction
Another part of the study assessed whether folic acid supplements could improve outcomes, but in fact they did the opposite, reversing the benefits of adding lamotrigine. Geddes did not have an explanation for why this might be the case. Lamotrigine can inhibit folate metabolism, and it had been thought that adding folate would be useful. Until further data are gathered on folate augmentation in patients taking the combination of lamotrigine and quetiapine, folate should be used cautiously if at all in these patients.
Possible combination with lithium
In Goodwin’s talk, he also noted lithium’s potential to lower suicide rates, premature mortality, and cognitive impairment, and to increase hippocampal and cortical volume.
Since lamotrigine was shown to potentiate the antidepressant effects of lithium in a study by Van der Loos and colleagues, and quetiapine is approved by the Food and Drug Administration for the prevention of depression as an adjunct to lithium (or valproate), there might be theoretical acute and long-term benefits to combining the three: lithium, quetiapine, and lamotrigine.
At a recent scientific meeting, researcher John Geddes and colleagues reported that compared to adding placebo to the treatment of bipolar depressed patients already receiving the atypical antipsychotic quetiapine, adding the mood stabilizing drug lamotrigine led to significant improvements in their illness. Lamotrigine was slowly titrated to doses of 200mg/day. (Slowly increasing dosage is important because a serious rash is a possible side effect of lamotrigine, occuring in about one in 5,000 individuals exposed.)
Researcher Charles Bowden found in 2000 that adding lamotrigine to valproate improved its effectiveness, as Marc van der Loos found in 2008 with lamotrigine and lithium. Thus it appears that adding lamotrigine to a mood stabilizer or to an atypical antipsychotic like quetiapine is a good second-line option in the treatment of bipolar depression. While lamotrigine is not FDA-approved for the acute treatment of depression, this approach is worthy of consideration, and could be of immediate clinical use. It provides an alternative to adding a unimodal antidepressant, which recent meta-analyses have indicated is not effective and which can increase switches into mania, cycle acceleration, or even treatment resistance in patients with bipolar disorder.
At the 2014 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Robert Findling reported on a double blind, placebo controlled 36-week study of lamotrigine for children and adolescents with bipolar I disorder. The doses designed for maintenance treatment averaged about 225 mg/day, achieved by very slow increases over time in order to reduce the risk of a serious rash.
Findling found that lamotrigine was more effective than placebo in extending the time until a patient required an intervention for a new mood episode among the older children in the study (aged 13 to 17). Among the younger children in the study (aged 10 to 12), lamotrigine’s effects were not statistically significant compared to placebo. Findling and colleagues concluded that lamotrigine appeared effective in delaying time to onset of a new episode in adolescents with bipolar I disorder.
Lamotrigine is approved by the Federal Drug Administration (FDA) for bipolar disorder in adults only.
Lithium is known for protecting neurons by inducing neurotrophic factors and inhibiting cell death factors. In a new study, other mood-stabilizing drugs had similar neuroprotective and neurotrophic effects on cultured neurons from the hippocampus.
At the 2014 meeting of the International Society for Bipolar Disorders, CH Lee et al. presented evidence that lithium, carbamazepine, valproic acid, and lamotrigine all increase the outgrowth of dendrites from these cultured neurons. Therapeutic levels of these drugs increased the production of proteins like brain-derived neurotrophic factor (BDNF), postsynaptic density protein-95 (PSD-95), neurolignin 1 (NLG 1), beta-neurexin, and synaptophysin. However, so far only lithium has been shown to increase the volume of the human hippocampus as measured with MRI.
Methylene blue is a chemical compound that has been used to treat a variety of medical conditions. This drug has some actions that resemble lithium’s: it inhibits guanylate cyclase, which generates second messenger cyclic GMP, and decreases nitric oxide. New evidence shows it may help depression and anxiety in bipolar disorder when added to lamotrigine.
In patients with bipolar disorder who were all treated with lamotrigine, an active 65mg dose of methylene blue three times per day (for a daily total of 195mg) versus 15mg/day (an inactive dose that produces the same side effect of blue urine) was more effective at treating depression and anxiety in a 12-week crossover study. Side effects, in addition to blue urine, included infrequent nausea, diarrhea, headache, and a burning sensation in the urinary tract. Of the 37 randomized study participants, 27 completed both phases of the entire six-month study. Martin Alda, a researcher who presented the double-blind randomized crossover data at the 2014 meeting of the International Society for Bipolar Disorders, indicated that he has also used this preparation clinically with success, although the pharmacy staff who prepared the capsules were not too happy, because everything the drug touches turns blue.
A 2012 study by Kemp et al. in the journal Bipolar Disorders found that lamotrigine added to combination treatment with lithium and valproate was no more effective than placebo in patients with rapid cycling bipolar disorder. Only 14% (19 out of 133) of rapid cycling patients stabilized upon initial treatment with the open combination of lithium and valproate, a startlingly low rate. In the next phase of the study, 49 patients who were not stabilized were given adjunctive treatment with either lamotrigine (n=23) or placebo (n=26) on a double-blind basis, but no significant difference was observed.
Editor’s Note: This study has two pieces of not-so-good news. The first is that it was so difficult to stabilize these patients with rapid cycling bipolar disorder. The second is that the add-on of lamotrigine, which is highly effective in the prevention of depressions in bipolar disorder, was in this case no more effective than placebo.
This study again demonstrates that rapid cycling bipolar disorder is difficult to treat, and even the use of three proven mood stabilizers in combination is not always effective. Many doctors would recommend an atypical antipsychotic as the next clinical option.
A 30-year observational study published by Andrew Leon and colleagues in the American Journal of Psychiatry has found that anticonvulsants used in epilepsy and for bipolar depression (carbamazepine, lamotrigine, and valproate) do not increase suicidal behavior in bipolar patients.
Editor’s Note: The FDA gave a warning in 2009 that these anticonvulsants were associated with suicidal ideation. This was based on studies of a mixed group of psychiatry and neurological patients in acute placebo-controlled studies, where suicidal ideation is typically a reason for exclusion from the study. Leon et al. used more powerful longitudinal methods to compare the risk of suicidal ideation in individuals taking and not taking anticonvulsants and found no such increase in suicidal behavior.
This is like the FDA warning for antidepressants and suicide, which was based on data from placebo-controlled clinical trials in acute depression (where suicidal patients are excluded). When investigators used the same longitudinal methods as Leon et al. in the anticonvulsant study, they found that antidepressants actually reduced suicidal behavior by 30%.
The bottom line is that the use of anticonvulsants for bipolar disorder should not be discouraged based on the FDA warning about suicidal ideation in mixed neurological and psychiatric patients. In bipolar patients, anticonvulsants do not increase the risk of suicidal behaviors, i.e. suicidal acts or completed suicides.
At the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), Melissa P. DelBello presented a poster on the design of a maintenance study in bipolar youth to determine characteristics of patients who stabilized on adjunctive lamotrigine. The study included children aged 10 to 17 who had been diagnosed with bipolar disorder. Of a total 244 potential subjects, 160 individuals or 66% stabilized on lamotrigine during the open (not blind) portion of the study. Of these, 143 were randomized to either lamotrigine continuation or placebo.
Seventeen participants did not enter the randomized phase of the study, primarily because of withdrawal of consent, presumably because they were reluctant to be placed in the placebo group. The authors concluded that a study design involving randomization to medication continuation versus withdrawal with placebo substitution could underestimate the true level of treatment response.
However, the high stabilization rate of 66% using adjunctive lamotrigine in the open phase of the study suggests that the drug is effective. Clearly confirmation of this in the double-blind randomized phase is needed to confirm this prediction.
Memantine (Namenda), which is approved by the Federal Drug Administration (FDA) for use in Alzheimer’s Dementia, is increasingly being used for other conditions. Some doctors prescribe memantine for hyperactivity and attention problems in attention deficit hyperactivity disorder (ADHD), for obsessive compulsive disorder (OCD), and most recently as an adjunct to lamotrigine in bipolar depression. We wrote about the findings of Amit Anand et al. on the use of memantine and lamotrigine in January. These findings have just been published in Bipolar Disorders. The study indicates that the combination of lamotrigine with memantine brought about a rapid onset and greater magnitude of antidepressant effects than the combination of lamotrigine and placebo. The initial dose of memantine was 5mg/day, which was increased to 20mg/day during the study.
Editor’s Note: The potential mechanism of this effect makes sense. Lamotrigine decreases release of glutamate, and memantine blocks glutamate’s actions at the NMDA receptor. Thus the two together would more efficiently decrease glutamate’s effects.
It is possible that memantine could be effective without effecting the normal functions of glutamate. The drug blocks NMDA glutamate receptors that are situated away from the synapse, while allowing NMDA glutamate receptors at the synapse to fulfill their normal functions that support learning and memory. The blocking of only those receptors outside the synapse (extra-synaptic) could explain why memantine has relatively few side effects.
In a long-term study of bipolar patients taking lithium published in Bipolar Disorders last year, the addition of lamotrigine (or paroxetine for those who did not respond to lamotrigine) was significantly better than the addition of placebo. Patients taking lamotrigine with lithium averaged 10 months until a recurrence of a depressive or manic episode, while patients taking placebo with lithium averaged 3.5 months until an episode.