Archive for the ‘New Health Info’ Category

Fine-Tuning our Understanding of the ADHD Brain

The greater our understanding of an illness state, the better we are able to treat it.  As one of the core disorders in our practice, we constantly review and update our knowledge on ADHD. In the course of a recent review, I came across a wonderful compilation issue on ADHD in Biological Psychiatry (Biol Psychiatry June 15 2011, vol. 69).  The review issue covers a wide range of topics from psychostimulants as cognitive enhancers to the molecular genetics of ADHD.  The most relevant and clinically applicable article, however, was Amy Arnsten’s paper on “Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks” (Biol Psychiatry. 2011 June 15;69(12):e89-99).  She does a masterful job of presenting complex material in a clear and elegant manner.  Dr. Arnsten is able to capture the fluidity and dynamics of cortical functions associated with ADHD while still giving the reader anchor points that are useful in everyday clinical practice.

Dr. Arnsten’s article focuses on the effects of dopamine (DA) and norepinephrine (NE) on the dorsolateral prefrontal cortex (PFC).  This area of the brain has long been associated with executive function and working memory – the two primary problem areas associated with ADHD.  Executive functions are the neuropsychological capacities involved in planning, prioritizing and organizing tasks.  Working memory is the mind’s ability to keep and utilize information in short term storage, like the random access memory on a computer.  Though dopamine was held to be the primary neurotransmitter involved with ADHD, recent evidence has demonstrated that norepinephrine plays a significant role as well.  Working backwards from the evidence that medications used to treat ADHD such as methylphenidate and atomoxetine affect catecholamine (NE and DA) transmission in the PFC, Arnsten honed in on the specific receptors affected by these medications.  In her investigation, she found that the α2A receptor and D1 receptor had particular relevance to ADHD.

Recent studies found that norepinephrine strengthens PFC signaling through post- synaptic stimulation of α2A receptors on PFC neurons.   Conversely, dopamine acts at D1 receptors to decrease the signal to noise ratio by inhibiting stimulation from non-relevant external cues.  They also found that there is a “sweet spot” in the amount of norepinephrine and dopamine being released in the system, i.e. too much or too little markedly impairs PFC function. To break it down to a clinical level – medications such as methylphenidate or atomoxetine affect both norepinephrine and dopamine levels.  Appropriately increased levels of these neurochemicals then cause two actions to treat the symptoms of ADHD.  First, the norepinephrine ramps up signal strength for relevant stimuli through effects on α2A receptors, and second, the dopamine reduces the signal strength of non-relevant stimuli.

How do these ideas translate into the clinical realm?  Let’s imagine a person with ADHD working on a report on the computer.  Suddenly, an email pops up or the phone rings.  Untreated, his/her attention is immediately diverted to the new stimuli and a cascade of distractions ensues.  The report is left half -finished and the person doesn’t get back to it for hours.  Treated with methylphenidate, the non-relevant stimuli of an email pop up or phone call is now recognized but the dopamine working on the D1 receptor keeps that signal strength low, and the norepinephrine targeting the α2A receptor keeps the signal strength high for the report in front of him/her that needs to be finished.  This is referred to as “sculpting” or “spatial tuning” as the signal to noise ratio is kept appropriately calibrated to the task in front of the person that needs to be completed. This flow of dynamic signaling management is one of the hallmarks of executive function that can be so affected by ADHD.

Returning to the theme that greater understanding leads to better treatment, appreciation of the two component nature of attentional “sculpting” or “spatial tuning” enhances our ability to fine tune the treatment of our patient’s ADHD.   Clarifying whether our patient is having trouble with target signal emphasis and/or reducing distractor stimuli enables us to customize and more precisely adjust our medication interventions.  This insight is also useful for patients to better understand their specific challenges with this disorder.

We will continue to stay on top of advances like these in our practice areas of specialization so that we can better educate ourselves and you.

 

IPSRT as monotherapy in bipolar II disorder: can psychotherapy be more than an ‘adjunct’ in the treatment of bipolar disorder?

Clinicians who work with patients suffering from bipolar disorder have known this for quite some time: medication alone, while helpful in controlling many of the acute symptoms of bipolar disorder, is not enough to help patients manage this complex illness.   Patients often feel overwhelmed by the diagnosis and need support to adjust to the realities of fluctuating mood states, which frequently result in interpersonal and occupational dysfunction.   For these and other reasons, psychotherapy is an important component of bipolar disorder treatment.

In recent years, multiple studies have been published which support this view, including randomized, controlled trials.  Taken together, they indicate that various psychotherapeutic approaches, such as individual and group CBT (cognitive behavioral therapy), family focused therapy, psychoeducation, and IPSRT (interpersonal and social rhythm therapy), can be helpful adjuncts in the management of bipolar disorder (1,2).   While these studies vary widely in terms of interventions given, patients selected and controls utilized, what they have in common is the idea that psychotherapy is effective as an “add-on,” to pharmacotherapy.  There is little, if any, indication that such treatments can be used as monotherapy in any phase of bipolar disorder.

This may be changing.

We happened to take notice of a small pilot study by Holly Swartz, M.D. and Ellen Frank, Ph.D. and their group in Pittsburgh (3).  Published in 2009, this study evaluates the effect of psychotherapy as monotherapy in patients with bipolar II depression.  Unmedicated individuals (n=17) meeting DSM-IV criteria for bipolar II depression received weekly IPSRT (interpersonal and social rhythm therapy) for 12 weeks.  After 12 weeks of acute treatment, individuals received an additional 8 weeks of follow-up treatment with continued IPSRT (with supplementary lamotrigine for IPSRT nonresponders).  By week 12, 41% (n=7) of the sample responded to IPSRT monotherapy; 53% (n=9) had responded by week 20 (by this time, one subject was receiving lamotrigine in addition to IPSRT while the other was receiving IPSRT alone).

While small and limited by the lack of a control group, this study is significant in that it demonstrates that psychotherapy – even without medication – can help those who suffer from bipolar II depression.  It puts psychotherapy back on the radar, not as a mere adjunct to treatment, but as THE treatment for this condition. 

Some caveats: the population consisted of bipolar II patients.  Thus, patients with a history of mania were excluded.   Mood stabilizing medication such as lithium, valproic acid, and neuroleptics remain the “gold standard” in managing acute mania.  However, bipolar depression is often resistant to medication treatment.  Antidepressants have been shown to cause worsening of mood cycling.  Not everyone can tolerate side effects.  This population, therefore, of depressed bipolar II patients, might be specifically amenable to psychotherapy as monotherapy.

So what can we conclude from the results?  Obviously, more research is needed, but there are clues that psychotherapy, specifically IPSRT, can play an important role even in bipolar I patients taking medication.  Dr. Frank’s group in 2005 published a randomized trial of IPSRT vs. ICM (intensive clinical management), in which 175 patients were included (4).  This study showed that participants with bipolar I disorder assigned to IPSRT in the acute phase of treatment were able to stay in remission longer (during the maintenance phase) than those assigned to ICM.  This was especially true for individuals without serious medical illnesses or anxiety.

IPSRT is unique for multiple reasons:  it focuses on interpersonal relationships and how closely related these are to mood episodes.    A special emphasis is placed on how bipolar disorder has impacted one’s life, causing role transition, fractured relationships, career derailment and “grief for the lost self.”  In addition, sleep, wake, and social interactions are tracked closely.   Why?   Because of the “social zeitgeber hypothesis”: unstable or disrupted daily routines lead to circadian rhythm and mood instability (4,5).  This is certainly in keeping with our clinical observations that changes in sleep/wake patterns (i.e. pulling an all-nighter) and overstimulation can bring on a manic episode.

We applaud Drs. Frank and Swartz for showing us that psychotherapy can have a powerful effect on a patient’s overall response to treatment.  IPSRT has lent itself well to clinical trials, as it follows a fairly structured and manualized format, and we look forward to larger, controlled studies of IPSRT as monotherapy in bipolar II depression.   A more challenging, but no less important, endeavor would be to examine the efficacy of psychodynamic psychotherapy in the treatment of bipolar disorder.   While manualized treatments (such as IPSRT or CBT, cognitive behavioral therapy) address key symptoms in bipolar disorder, we should not lose sight of the importance of understanding the meaning and overall implications of such symptoms in the context of a person’s life.

 

(1)  Jones S.  Psychotherapy of bipolar disorder: a review.  J Affective Disorders 2004; 80: 101-114.

(2)  Schottle D et. al.  Psychotherapy for bipolar disorder: a review of the most recent studies.  Curr Opin Psychiatry 2011; 24: 549-555.

(3)  Swartz H, E et. al.  Psychotherapy as monotherapy for the treatment of bipolar II depression: a proof of concept studyBipolar Disord 2009; 11: 89-94.

(4)  Frank E, Kupfer DJ et. al.  Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorderArch Gen Psychiatry 2005; 62: 996-1004.

(5)  Frank E.  Treating bipolar disorder.  New York: The Guilford Press, 2005.

New Wonder Drug Remarkably Effective in Bipolar Disorder: Lithium (Yes, Lithium).

The single most important research study in the past year in the area of clinical therapeutics of bipolar disorder was conducted  by Geddes and colleagues at Oxford University in England[1].  Using a randomized open-label design (no placebo control group and subjects knew which medications they were receiving), the BALANCE study sorted 330 subjects with bipolar disorder type I into three treatment groups: lithium alone, valproate (Depakote) alone, or combination treatment with both lithium and valproate.  The outcome measures were time to recurrence of a major mood episode, either mania or depression.  The study design allowed for an extended, two year follow-up on these subjects.  This time frame allows for meaningful assessment of genuine prophylactic effects.  The results found that combination therapy was most effective, marginally more so that lithium alone, but significantly greater than valproate monotherapy.  The interpretation of the data supports the unique efficacy of lithium as the single-most effective mood stabilizer available.

In recognition of the singular importance of this study, the journal Bipolar Disorders devoted an issue for commentaries from major luminaries in the field including  Ross Baldessarini[2], Rasmus Licht[3], and S. Nassir Ghaemi[4] and others.  The commentary by Ghaemi, a researcher and analytic thinker whose work I respect enormously, was forthright, pointed, and compelling.  In this commentary, he challenges the pharmaceutically-inspired practice habits of American psychiatrists and their seduction by the next, newest, sexiest drug brought to market.  His writing deserves to be read by patients and clinicians alike.  I include portions of his commentary below:

Clinical conclusions about lithium

“Clinicians can, and should, draw some conclusions, if we have the courage. We need to avoid being mugwumps, refusing to commit to using lithium out of vague fears, despite clear benefits that outweigh the real risks. With the results of BALANCE, in the setting of forty years of lithium research, it seems to me that one clinical conclusion is hard to avoid: Lithium is, by far, the first-line treatment for bipolar disorder. There should be very good reasons not to give lithium to the majority of patients with bipolar disorder as initial treatment. Patient preference, by itself, is not a good enough reason to avoid lithium; the hassles of being a doctor (checking blood levels, assessing kidney function long term) are not good enough reasons either. Patients need to be educated about the many benefits of lithium, including two other major areas, besides mood prophylaxis: mortality reduction, both by suicide and by cardiovascular death, and neuroprotective effects, especially probable reduction of dementia risk and potential protection against the cognitive impairment that is a long-term consequence of multiple mood episodes (1). The drawbacks of lithium are well known, though exaggerated: long-term chronic renal insufficiency, in the best prospective studies with decades of follow-up, is not more than 5% (8); other kidney effects, like decreased urinary concentration capacity, are more common but reversible and not medically dangerous; hypothyroidism is more common but treatable and reversible; nuisance side effects are less frequent than many believe; weight gain is less than with valproate and much less than most neuroleptics; cognitive side effects are problematic in some, but not most persons, and counteracted by long-term cognitive benefits; toxicity in overdose is a risk but this is the only drug that is proven to prevent suicide by a huge effect size (estimated to be nine-fold decreased risk) (1).

Some people cannot take lithium. But everyone should be offered it, most should try it, and a minority can then stop it if it is intolerable. If we take this approach, we find that many persons tolerate it, do well, and do not need the common current rigamarole of antidepressants plus neuroleptics, which leaves patients partially treated at best, and hardly treated at worst.

Lithium is unique because it actually treats an entire disease—manic-depressive illness. It is not merely a treatment for a symptom—like neuroleptics for mania or antidepressants for depression. Studies indicate that about one-third of patients get completely well long term with lithium monotherapy (10). This figure is not minor, and compares favorably with the long-term remission seen with antidepressants in major depressive disorder in the STAR*D study (11). BALANCE is another source of evidence for the notable benefit of lithium monotherapy in a substantial minority of persons with bipolar disorder. The makers of our DSM-IV nosology have assumed that all our pills are mere symptom treatments; they do not think our diagnoses reflect diseases in any meaningful way, and they do not believe that any of our treatments cure diseases. Hence, the claim that we should only make pragmatic judgments, compensating for the follies of practitioners and the manipulations of pharmaceutical companies. Lithium is their refutation, and BALANCE is a modern proof that, though they are hard to conduct and require a great deal of labor, we can clarify clinical controversies with rigorous studies. We researchers need to do the studies, perpend on their importance, teach clinicians to implement the results in practice, and educate our nosologist colleagues, especially now as DSM-5 is in process, as to what they mean.”

 

We listen in full agreement to this elegant and rigorous analysis.  Lithium really is the closest thing we have to a wonder drug.  It is our first choice for the great majority of bipolar patients that we treat in our practice.

 

1.            BALANCE investigators and collaborators, G.J., Goodwin GM et al, Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. The Lancet, 2010. 375(9712): p. 385-395.

2.            Baldessarini, R.J., Commentary: The Bipolar Affective Disorder: Lithium/Anticonvulsant Evaluation (BALANCE) Study. Bipolar Disorders, 2010. 12(7): p. 669-672.

3.            Licht, R.W., A new BALANCE in bipolar I disorder. The Lancet, 2010. 375(9712): p. 350-352.

4.            Ghaemi, S.N., From BALANCE to DSM-5: taking lithium seriously. Bipolar Disorders, 2010. 12(7): p. 673-677.

 

Acute Antidepressant Effects of Lamotrigine: More and More Disappointing.

In the past several years, two new studies have been published examining the efficacy (in pristine, experimental conditions; rigorous selection criteria, minimal comorbid conditions) and effectiveness (real world variability) of lamotrigine (Lamictal) in the treatment of acute bipolar depression [1, 2].  These and other studies were recently summarized in a review paper by Amann and colleagues in the Journal of Psychopharmacology[3].  Attempting to synthesize disparate findings, Amann concludes that “…the antidepressant effect of LTG in acute bipolar depression, if it exists, is small.

 

These data support our own clinical work with this anticonvulsant, where we consistently find its acute antidepressant effects quite limited.  In our practice, we now reserve lamotrigine for use with residual depressive symptoms, which either fail to respond to primary mood stabilizers or other antidepressant treatment, or that fail to clear with the remission of the depressive episode.  We are less pessimistic but still uncertain about lamotrigine’s efficacy in the long-term prevention of depressive episodes.

 

This emerging profile of lamotrigine as a marginal antidepressant stands in stark contrast to the fanfare announcing its arrival in the late 1990’s when it was viewed as the Holy Grail for the treatment and prevention of bipolar depression.  This recalibration parallels our growing recognition of the limited potential of standard antidepressants, in general, in the therapy of the depressed phase of this illness[4].

 

1.            Calabrese, J.R., et al., Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disorders, 2008. 10(2): p. 323-33.

2.            Geddes, J.R., J.R. Calabrese, and G.M. Goodwin, Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. British Journal of Psychiatry, 2009. 194(1): p. 4-9.

3.            Amann, B., et al., Lamotrigine: when and where does it act in affective disorders? A systematic review, in J Psychopharmacol OnlineFirst 2010. p. 1-6.

4.            Sachs, G.S., et al., Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Depression, in NEJM 2007. p. 1711-1722.

 

Not the SAMe Old Story: New Antidepressant Data on Popular Nutritional Supplement.

May 13th, 2011

Evidence is building for the use of SAMe (S-adenosyl methionine) as adjunctive therapy in major depressive disorder. Just this past August, a landmark study by Papakostas, et al, demonstrated the superior efficacy of SAMe when combined with other antidepressant agents (e.g., fluoxetine, venlafaxine, duloxetine) over antidepressant monotherapy.1 Although SAMe has been reported to induce mania in some case reports, there may be a potential role in treatment for bipolar depression as well.2

Previous to this double-blind, randomized controlled trial, SAMe had been shown to have similar efficacy to tricyclic antidepressants such as imipramine in small trials.3 Based on results from the most recent trial, in a group of patients with an incomplete response to conventional antidepressants, six would need to be treated to experience one response and seven would need to be treated to achieve one remission (also known as number needed to treat).1 On the flip side, few adverse effects were reported. However, caution should be used because of the theoretical risk of serotonin syndrome.

In addition, the study results were only analyzed for patients who took the drug exactly as prescribed, which tends to favor the study medication and does not reflect real-life practice.1 Caution is also warranted because exact percent improvements for each group were not reported and only 73 patients were included in the study. The study participants were only tracked for a period of six weeks, making long-term conclusions impossible.

Typical treatment doses are in the 400-1600 mg/day range.

Recommendation: Because SAMe is an affordable nutritional supplement with few side effects, it is a suitable option for patients with major depressive disorder and suboptimal response to standard antidepressant therapy. The jury is still out on a potential role in bipolar depression.

____________________

1. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry. 2010 Aug;167(8):942-8.

2. Nelson JC. S-adenosyl methionine (SAMe) augmentation in major depressive disorder. Am J Psychiatry. 2010 Aug;167(8):889-91.

3. Delle Chiaie R, Pancheri P, Scapicchio P. Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Am J Clin Nutr. 2002 Nov;76(5):1172S-6S.

Riluzole: Promising Therapy for Treatment-Resistant Mood Disorders.

One 8-week study showed possible response based on significant improvement in Montgomery-Asberg Depression Rating Scale scores in patients treated for acute bipolar depression when riluzole was added to other antidepressants.1 However, the small, non-randomized, non-blinded nature of the trial limits the conclusions that can be drawn. Of note, there were no instances of mania or hypomania in this trial, indicating that riluzole may not have the mood destabilizing effects of many other antidepressants. Trials with larger sample sizes would be necessary to confirm this result.

A recent study of 14 patients with bipolar disorder given 100-200 mg of riluzole per day showed a relative decrease in glutamate in the brain, as demonstrated by imaging studies.2 This suggests that imaging may play a role in determining response to therapy if further trials support the existing evidence.

Riluzole is being looked at with equal interest in the treatment of major depressive disorder. Another trial with a similar design that looked at response in treatment-resistant patients with major depression taking other antidepressants found a response in some.3 A third trial with high doses of 150-200 mg/day (ALS dose: 50 mg/day) found that riluzole could be effective—even when given without other antidepressants—over a 6-week period.4 However, as in the other two trials, this study was open-label and included fewer than 20 patients. Two randomized trials to be completed over the course of the next 2 years should provide additional evidence regarding the relative efficacy of riluzole in treating mood disorders.

From a safety perspective, the most pressing concern is that the medication may cause liver damage, especially in those already at risk or those who drink excessive amounts of alcohol. Coffee and other caffeinated drinks may increase the effect of riluzole, and smoking may speed its elimination from the body, making higher doses necessary. Riluzole also has to be taken 1 hour before or 2 hours after food, which may be inconvenient for many patients.

Recommendation: Based on preliminary study data, riluzole is a promising therapy that may provide an alternate treatment for bipolar depression and/or major depressive disorder, pending positive results in larger randomized, double-blind trails.

1. Zarate CA Jr, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005 Feb 15;57(4):430-432.

2. Brennan BP, Hudson JI, Jensen JE, et al. Rapid enhancement of glutamatergic neurotransmission in bipolar depression following treatment with riluzole. Neuropsychopharmacology. 2010 Feb;35(3):834-846.

3. Sanacora G, Kendell SF, Levin Y, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007 Mar 15;61(6):822-825.

4. Zarate CA Jr, Payne JL, Quiroz J, et al. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004 Jan;161(1):171-174.

N-Acetyl Cysteine for Bipolar Depression: Novel Approach, Limited Data.

Always looking for novel ways to treat bipolar disorder, researchers have turned to an old standby for Tylenol overdose: n-acetyl cysteine (NAC). Among other causes, mood disorders may be a result of oxidative or metabolic imbalances in the brain caused by low levels of the biochemical glutathoine. NAC works to restore these imbalances, which are possibly at the root bipolar depression, by working as an antioxidant.

While its absolute efficacy has not been proven, one randomized controlled trial showed statistically significant improvement in overall depressive symptoms in bipolar patients on long-term therapy with 1g of NAC taken twice daily in a capsule formulation.1 This is a non-FDA approved version, which is only available as a nutritional supplement. Unlike the liquid and injection available by prescription, only a small percentage of the capsule formulation is active because it is broken down so quickly by the body.2

The study results also have to be interpreted with caution because the trial only involved 75 patients. Another limitation is that the time to next mood episode was the same regardless of whether the patient was taking NAC or placebo. On the positive side, the trial took place over a 24-week period and showed moderate improvement in symptoms. Despite the lack of published evidence, some U.S. psychiatrists are finding a useful place for NAC in clinical practice.

Although NAC is typically described as well tolerated, the side effects may be appreciable. Nausea, abdominal pain, vomiting, constipation, and diarrhea are common with oral treatment.

Recommendation: Because of its sparse efficacy data and at times noxious side effects, this nutritional supplement has a limited place in therapy.

1.Berk M, Copolov DL, Dean O, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder: a double blind randomized placebo-controlled trial. Biol Psychiatry. 2008 Sep 15:64(6):468-475.

2.Sjödin K, Nilsson E, Hallberg A, Tunek A. Metabolism of N-acetyl-L-cysteine: some structural requirements for the deacetylation and consequences for the oral bioavailability. Biochem. Pharmacol. 1989 Nov 15;38(22):3981-3985.

 

Do Antiepileptics Increase the Risk of Suicide?

Antiepileptic medications have been a mainstay in the treatment of bipolar illness since the use of valproate in the 1980’s.Since that time other anticonvulsants such as carbamazepine, lamotrigine, and oxcarbazepine have been added to the list that help control the mood fluctuations that occur in bipolar disorder. In January 2008, the FDA issued an alert about patients being treated with antiepileptics:

 

In the FDA’s analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%).  The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs.  Patients who were treated for epilepsy, psychiatric disorders, and other conditions were all at increased risk for suicidality when compared to placebo, and there did not appear to be a specific demographic subgroup of patients to which the increased risk could be attributed. The relative risk for suicidality was higher in the patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions.

The following is a list of antiepileptic drugs included in the analyses:

 

How did the FDA arrive at this conclusion?

According to their documents, the FDA began receiving reports of the increased risk of suicidality with the anticonvulsants and did a preliminary review that confirmed the possibility.So in 2005, the FDA began analyzing 199 placebo controlled trials of eleven different antiepileptic drugs. The conditions studied in these clinical trials included epilepsy, selected psychiatric illnesses, and other indications, including migraine and neuropathic pain syndromes.  The analysis included 27,863 patients in drug treatment groups and 16,029 patients in placebo groups.  Patients included in the analysis were five years of age or older.  There were 4 completed suicides among patients in drug treatment groups and none among the patients in placebo groups.  There were also 105 reports of suicidal symptoms in the drug treatment groups in comparison to 35 reports of suicidal symptoms in the placebo group.

Overall, 0.43% of the patients in drug treatment groups experienced suicidal behavior or ideation versus 0.22% of the patients in placebo groups, corresponding to an estimated 2.1 per 1000 (95% CI: 0.7, 4.2) more patients in the drug treatment groups who experienced suicidal behavior or ideation than in the placebo treatment groups.  In comparison, the overall suicide risk in a treated bipolar population was found to be 3.66% in the STEP-BD study (Marangell, et al. Prospective Predictors of Suicide and Suicide Attempts, Bipolar Disorders 2006, 8: 566-575).In this analysis, the relative risk for suicidal thoughts or behavior was higher for patients with epilepsy compared to those patients with psychiatric or other disorders.  The higher risk for suicidal behavior or suicidal ideation was observed at one week after starting a drug and continued to at least 24 weeks.  The results were generally consistent among the drugs and were seen in all demographic subgroups. Specifically, there was no clear pattern of risk across age groups. (For more information please go to: http://www.fda.gov/cder/drug/InfoSheets/HCP/antiepilepticsHCP.htm)

The Response

The FDA has placed a warning label on all antiepileptic drugs reflecting this increase risk of suicide, but it did not attach the dreaded black box warning.Since then, numerous groups have weighed in on the FDA’s findings.At a December 2008 meeting of the American Epilepsy Society, two researchers presented evidence that the findings are inconsistent and vary greatly by drug, region, and illness.Still other experts felt that this warning will do more harm than good and that it is too early to make such a broad statement without further research to substantiate the FDA’s claims. A noted psychiatrist, Dr. David Kahn of Columbia University, weighed in by commenting that the risk of suicide in bipolar disorder is far higher in an untreated patient than a treated one, and that both doctor and patient should be aware of the risk of suicidality in bipolar disorder.

What should you take from all of this?

It appears that antiepileptic drugs roughly double the risk of suicidality as compared with placebo. However, the absolute risks are small, and the effect appears more likely in patients treated for epilepsy than for patients with psychiatric illness (although the FDA has yet to publish all the data required to compare these two populations). In our daily practice, we as psychiatrists are always closely monitoring patients for any evidence of suicidality, so any signs and symptoms should be detected early and carefully evaluated.If it appears a medication is contributing to the increased suicidality, it should be discontinued.With this close monitoring of a given patient’s mood state and the small absolute risks found in the FDA’s analysis, we believe the risk associated with prescribing anticonvulsants in bipolar illness is extremely small.That being said, these findings should be discussed with any patient prior to initiating treatment with an antiepileptic medication, and more research is needed to understand the possible link between suicidality and antiepileptics.

Atypical Antipsychotics and Sudden Cardiac Death: More Trouble in the Promised Land.

The Background

The second generation of antipsychotic medications was launched by the arrival of clozapine in1990. Subsequent pharmacologic development produced a handful of similar follow-ups including risperidone, olanzapine, zispradone, aripiprazole and quetiapine. Their novel mechanism of action (increased antagonism at certain dopamine and serotonin receptors) combined with their reduction of certain side effects (movement disorders, especially tardive dyskinesia and hyperprolactinemia) gave these new agents a sense of promise and potential advantage. Later findings that several of these new atypicals might be specifically effective in mood disorders, particularly bipolar states, made their glow even stronger.

The bloom is now off the rose. The first corrective was the uncovering of metabolic problems associated with the use of these second generation antipsychotics. We now know that, as a whole, this group of medications can produce weight gain, increased cholesterol and triglycerides, raised blood sugar and associated diabetes. While these effects vary by particular medication and dose, the idea of a newer, cleaner class of antipsychotics without the burden of troublesome side-effects is no longer tenable.

The Story

It is with additional disappointment then that we report on the article by Ray et al in the January 15th (2009) issue of the New England Journal Medicine. In a large, retrospective study of Tennessee Medicaid enrollees, the authors compared the rates of sudden cardiac death (SCD) in three groups: those using conventional antipsychotics, those using atypicals and those using neither. They found significantly increased rates of SCD in those groups using either conventional or atypical antipsychotics relative to non-drug-using controls who were matched (in a questionable and novel manner) on a variety of sociodemographic and illness-related variables. (The validity of the matching method is critical to enable genuine drug-related differences to be discerned from patient variables that might predispose to increased rates of cardiovascular mortality, such as tobacco use, obesity or poverty which are all found in higher frequency in patients with persistent, severe mental illness).

More surprisingly, the rates of SCD were essentially similar in those patients using the conventional and the atypical drugs. So, not only were the 2nd generation agents found to be associated with increased rates of SCD, they did so to a degree comparable to that found with the older, conventional drugs.

Last, the increased risk was found to be dose-dependent with low doses (eg, less than or equal to 75mg/day of quetiapine, or 2 mg/day or risperidone or 7.5 mg/day of aripiprazole) conferring a incidence rate ratio of 1.6, relative to non-users. This incidence rate ratio increased to 2.86 for patients on high doses, which were defined as 3x or more than the maximum lower doses just specified.

Now, what do these numbers mean in real terms? The Ray study found a rate of SCD in the general population of 143 per 100,000 patient years or 0.0014 per year per single person. This rate increased two to three-fold, with higher doses of medication, to between 0.0029 to 0.0033% per year for a given individual. So, if you were to take an atypical medication for a year, you would have a risk of SCD of between 2 to 3.3 per thousand.

Our Reactions

As usual, we are now left trying to give the appropriate interpretation and attention to these new data. Specifically, to what degree should this new information alter our existing clinical practice? After getting over the initial shock and alarm, we have several reactions and suggestions.

First, though the data is worrisome, this is hardly the last word to be written on atypicals and cardiovascular risk. An earlier study by Liperoti in the 2005 Archives of Internal Medicine found no increased risk of ventricular arrhythmias or cardiac arrest in a case-controlled study of nursing home residents taking atypical antipsychotics (they did, however, confirm an approximately two-fold higher rate of risk in those residents taking first-generation medications). We expect that future studies will refine the emerging picture of risk associated with this class of medications.

Second, if the association between atypicals and SCD is replicated and found to hold water, it does not portend the immediate elimination of this class of medications. Even if this risk is verified, the absolute numbers involved are small enough that judicious use with appropriate cautions will enable ongoing use in those patients where the potential benefits outweigh the associated potential for harm.

A third is to sensitize us to predisposing clinical factors that increase cardiovascular risk in our patients and, thus, make them even greater targets for any rhythm-disrupting properties of antipsychotics. A partial list of such factors includes female sex, older age, the presence of dementia, pre-existing cardiovascular disease, a personal history of syncope, a family history of sudden cardiac death before the age of 40, electrolyte abnormalities, and the use of other drugs which can effect cardiac conduction such as stimulants and tricyclic antidepressants. See Zarate and Patel (Archives of General Psychiatry, 2001, 58, pp 1168-1171) and Abdelmalwa and Mitchell (Advances in Psychiatric Treatment 2006, 12(1), pp 35-44) for thorough reviews of this topic.

The Controversy

Having said all this, the bottom-line question remains: Will we now conduct ourselves differently with this new information? This topic has been the subject of several controversial and conflicting commentaries, each weighing in on the Ray et al study. The accompanying editorial in the New England Journal of Medicine advocated for reduced usage in vulnerable populations (the young and the elderly) and EKG monitoring both before and during treatment with these medications. The Carlat Report (www.thecarlatreport.com, a fantastic source of impartial information on psychiatric research) takes a roughly similar stand. An APA report prepared by Lieberman, Merrill and Parameswaran (www.omh.state.ny.us/omhweb/advisories/adult_antipsychotic_use_attachement.html) takes a stance that is more critical and questioning of the original study and argues that routine EKG monitoring may be premature. We refer readers to these commentaries to obtain a more direct picture of this debate.

Conclusion

Whether EKG monitoring becomes a standard of care or not, I am certainly more cognizant and aggressive in my screening for cardiovascular risk factors in patients in whom I am starting or continuing on antipsychotic medications. The Lieberman et al and NEJM editorial both provide guidelines for assessing risk and managing EKG readings (see also, Abdelmalwa and Mitchell, Advances in Psychiatric Treatment, 2006, 12, pp100-109, for a comprehensive review of monitoring and prevention recommendations).

Given the uncertainty of these findings and the relative ease of getting an EKG, I am trending towards routine monitoring.

How does the Ray et al study affect the status of atypicals? Were the promised benefits and claims of greater safety illusory? The answer, I think, pertains both to this class of medication specifically and to the larger issue of drug development and marketing. Because of the phenomenal costs involved in bringing a psychotropic to market, pharmaceutical companies promote new drug launches with marketing and supporting research designed to maximize usage. This is especially true in the post-approval phase. To a certain extent, we all greet new treatment developments with hope and anticipation. When exaggerated, this optimism can become excessive, leading to the type of irrational exuberance seen in the stock market rise prior to last year. When this type of exuberance takes hold and critical analysis is put aside, this almost ensures a subsequent market correction which will bring a product or a stock back to a more realistic place.

The recent studies about the metabolic and cardiac toxicities of 2nd generation antipsychotics are simply bringing these new medications back to the type of more realistic valuation they should have had and maintained from the start. Atypicals will need to take their place with all other psychotropic medications as drugs with distinct risks and potential efficacies. True progress will have been made if, in the future, we are a little more circumspect about the next class of agents that comes our way.

Modafinil in Bipolar Depression: Treatment Advance or Back to the Future?

The search for effective treatments for bipolar depression is fully underway. Driven by epidemiologic prevalence, clinical need and financial profit, academic researchers and Pharma are both developing anda testing new compounds at a furious pace. Modafinil (Provigil) is a recent entrant into this mad race. Approved by the FDA for use in Excessive Daytime Sleepiness (EDS) associated with Narcolepsy, Sleep Apnea and Shift Work Sleep disorder, studies over the past five years have assessed the potential of this new drug in treating conditions that range from ADHD, Cocaine Dependence and Mood Disorders.

Modafinil is usually described as a novel compound that affects a variety of neurotransmitter systems in the brain. The purported novelty of this compound is intended to distinguish it from traditional stimulants, such as amphetamine, with which it shares numerous properties. Articles from the past two years though have more carefully examined the mechanism of action of modafinil and found that it appears to facilitate the release of dopamine and act through dopaminergic receptors in a similar fashion to traditional stimulants. A 2007 study from the European Journal of Pharmacology described it as a psychostimulant that is pharmacologically similar to, but much less potent and efficacious than, amphetamine (Dopheide, MM., et al).

Given this profile, it is no wonder that the antidepressant potential of this compound would attract interest. There is a long history of stimulant trials in the treatment of depression.

There are several, mainly indirect, lines of evidence that suggest that modafinil might be of value in the treatment of bipolar depression. First, as an agent with demonstrated wakefulness-promoting activity (it keeps people awake), it makes sense to think that it might benefit the anergia and hypersomnia that so often characterize the depressed phase of this illness. To date, the evidence on this point is mixed and limited. When used in unipolar depression in patients who had only partially responded to SSRI’s and had residual symptoms of depression, fatigue and tiredness one placebo-controlled, double-blind study showed a statistically significant advantage (Fava M, et al., 2005), another study of similar design failed to show any difference between modafinil and placebo (Dunlop, BW, et al., 2007). A third open-label trial by Ninan and colleagues in 2004 showed significant benefit. Notably, these studies focused on modafinil’s effect on residual fatigue and tiredness. To what extent modafinil would be active against other, core features of depression (feelings of guilt, disturbed sleep and eating, hopelessness) is unknown.

A second, indirect line of evidence bearing on this drug’s potential in bipolar depression is a single study of modafinil monotherapy for atypical depression (a syndrome that shares many symptoms with bipolar depression.) Structured somewhat unusually, patients were first treated in an open-label fashion and then randomized to either placebo or active drug for continuation treatment. Relative advantage for the drug was found in the open-label but not the continuation phase of this study. Not definitive but intriguing.

Last is the single and only direct study of modafinil in bipolar depression. Done by Mark Frye and colleagues at UCLA and published in the American Journal of Psychiatry in 2007, this research tested modafinil augmentation in 85 patients with bipolar depression who were inadequately responsive to a mood stabilizer with or without an antidepressant. Performed over 6 weeks, this placebo-controlled, double-blind study showed a rapid, significant and sustained advantage of modafinil on depressive symptoms. So what conclusions can be drawn on the overall efficacy of modafinil for bipolar depression at this time?

First, with the exception of the one well-controlled study by Frye on patients with bipolar depression, most of the evidence to date comes from open-label, non-blinded studies, often addressing other forms of depression. Second, all of the research has evaluated short-term efficacy; whether longer-term and prophylactic benefit will be demonstrated is anybody’s guess. Third, while modafinil was not associated with any serious side-effects, including hypomanic/manic switching, its long-term safety profile requires documentation. Last, under closer inspection, modafinil appears to have considerable similarity to traditional stimulants. An article by P.J. Carlson in 2004 in the journal Bipolar Disorders showed that methylphenidate (Ritalin) and amphetamine (Adderall or Desoxsyn) effectively treated residual symptoms of depression and fatigue in patients with bipolar depression. How this new drug compares to stimulants and other antidepressant and mood stabilizing drugs used in bipolar depression is unknown. The answers to these questions will help determine whether modafinil represents a truly novel agent with a distinctive mechanism of action or is simply old wine in a new bottle. In the meantime, I’ll use it sparingly and give some reconsideration to old-fashioned stimulants.