Bipolar Disorder: Novel Clinical Trials II

This is the second post reviewing recent novel trials for the treatment of bipolar disorder.

Again, for my sources I am using are clinicaltrials.gov and PubMed.

Clicking on the study title will take you to the clinicaltrials.gov site for more detailed protocol information.

Allopurinol Maintenance Study for Bipolar Disorder

This completed study examined the effect of 300 to 600 mg per day of allopurinol on mania prevention. Allopurinol is a drug used primarily for the treatment of gout or kidney stones. The drug lowers serum levels of uric acid. Uric acid in elevated in mania and potentially has a contribution role in mania. A small international randomized placebo-controlled study of allopurinol found significant improvements in acute mania. 

Quetiapine Alone Versus Quetiapine Plus Lithium for Mania

Physicians have a variety of drug choices in the treatment of the manic phase of bipolar disorder. In this study, manic subjects were randomized to 600 to 800 mg of quetiapine with or without lithium dosed from 500 mg to 2000 mg per day. The study was conducted in China and the results showed that quetiapine alone was as effective as quetiapine plus lithium in reducing symptoms of mania.

Internet-Based Interventions for Bipolar Disorder

This study is currently recruiting subjects between the ages of 21 to 65 years of age with a diagnosis of bipolar I, II or NOS. Subjects are randomized to one of three arms including: 1.) moderated discussion board, 2.) moderated discussion board plus psychoeducation or 3.) moderated discussion board, psychoeducation and interactive psychosocial tools. The study is sponsored by the VA Palo Alto System and primary outcome measures include assessment of depression and mania symptoms.

Bipolar Depression Treatment with Deep Brain Repetitive Transcranial Magnetic Stimulation

This study is currently recruiting subjects in Brazil and is sponsored by the University of Sao Paulo. The study uses a type of coil that is felt to be able to reach deeper areas of the brain felt to be important in mood regulation. Subjects must meet depression criteria at entry and the primary outcome measure is the Hamilton Rating Scale for Depression.

Citations below are provided for more information on the treatments in the above studies. Readers can access abstracts by clicking on the link in the citation.

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Jahangard, L., Soroush, S., Haghighi, M., Ghaleiha, A., Bajoghli, H., Holsboer-Trachsler, E., & Brand, S. (2013). In a double-blind, randomized and placebo-controlled trial, adjuvant allopurinol improved symptoms of mania in in-patients suffering from bipolar disorder Pharmacopsychiatry, 46 (06) DOI: 10.1055/s-0033-1353345

Lauder S, Chester A, Castle D, Dodd S, Gliddon E, Berk L, Chamberlain J, Klein B, Gilbert M, Austin DW, & Berk M (2015). A randomized head to head trial of MoodSwings.net.au: an Internet based self-help program for bipolar disorder. Journal of affective disorders, 171, 13-21 PMID: 25282145

Rapinesi C, Bersani FS, Kotzalidis GD, Imperatori C, Del Casale A, Di Pietro S, Ferri VR, Serata D, Raccah RN, Zangen A, Angeletti G, & Girardi P (2015). Maintenance Deep Transcranial Magnetic Stimulation Sessions are Associated with Reduced Depressive Relapses in Patients with Unipolar or Bipolar Depression. Frontiers in neurology, 6 PMID: 25709596

Bipolar Disorder: Novel Clinical Trials I

To finish out the bipolar disorder topic month I will review some of the novel clinical trials in this condition.

Clinicaltrials.gov is a valuable resource in searching for active and recently completed clinical trials.

Here are some of the rostered trials from this site related to bipolar disorder that caught my attention.

Sensoril for Bipolar Disorder
Sensoril is the trade name for the natural product ashwagandha an herbal extract from the herb Withania somnifera. This trial was sponsored through the University of Pittsburgh. It has been completed and the results were published in 2013. The study targeted some of the cognitive impairment associated with bipolar disorder. The results pointed to some evidence for improvement in working memory, reaction time and social cognition with the drug.

Mindfulness Therapy on Disrupted Sleep in Bipolar Disorder
This trial sponsored by Massachusetts General Hospital is listed as currently recruiting subjects. The study compares a form of mindfulness therapy compared to brief supportive therapy on total sleep time in a group of subjects with bipolar disorder and sleep complaints. Sleep problems including both insomnia and hypersomnia are common in bipolar and new innovative interventions are needed.

N-Acetyl Cysteine and Aspirin as Adjunctive Treatment for Bipolar Disorder
This trial is sponsored by the University of Texas Health Science Center, Houston and is also listed as currently recruiting subjects. Subjects receive aspirin, n-acetyl-cysteine or both in addition to their usual bipolar disorder drug treatment regimen. The study seeks to see if an anti-inflammatory drug or an antioxidant drug can reduce depression symptoms. 

Minocycline and Aspirin in the Treatment of Bipolar Depression
This study is sponsored by the Laureate Institute of Brain Research in Tulsa in collaboration with the Stanley Medical Research Institue and the University of Oklahoma.  Subjects are eligible for enrollment if they have bipolar disorder and are currently depressed. Subjects receive aspirin, minocycline or a combination compared to placebo and are monitored for change in depression scores as measured by the Montgomery-Asberg Depression Rating. Disclosure: I am a participating research psychiatrist in this protocol. 

Readers with more interest in these trials can find more information by going to clinicaltrials.gov and typing in bipolar disorder in the search box. Additionally, specific trial information can be access by clicking on the link in the headings for this post.

I have listed some of the relevant citations related to these trials below.

In the next post I will look at four more novel trials in bipolar disorder.

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Chengappa KN, Bowie CR, Schlicht PJ, Fleet D, Brar JS, & Jindal R (2013). Randomized placebo-controlled adjunctive study of an extract of withania somnifera for cognitive dysfunction in bipolar disorder. The Journal of clinical psychiatry, 74 (11), 1076-83 PMID: 24330893

Deckersbach T, Hölzel BK, Eisner LR, Stange JP, Peckham AD, Dougherty DD, Rauch SL, Lazar S, & Nierenberg AA (2012). Mindfulness-based cognitive therapy for nonremitted patients with bipolar disorder. CNS neuroscience & therapeutics, 18 (2), 133-41 PMID: 22070469

Savitz J, Preskorn S, Teague TK, Drevets D, Yates W, & Drevets W (2012). Minocycline and aspirin in the treatment of bipolar depression: a protocol for a proof-of-concept, randomised, double-blind, placebo-controlled, 2x2 clinical trial. BMJ open, 2 (1) PMID: 22357572

Neuroscience Videos: Alzheimer's, OCD, Charcot-Marie-Tooth

Alzheimer's Association:  This 3 minute video examines the importance of clinical trials to study the effect of new medications for Alzheimer's disease.  Better treatments are desperately needed.  There are not enough clinical trial subjects with Alzheimer's disease.  In this video, the Alzheimer's Association presents information about the trialmatch program.  This program makes it easy for finding local clinical trials.

Seth Rogen and Fiancee Interview:  Seth Rogen and his fiancee discuss her mother's diagnosis of Alzheimer's disease.  In this 3 minute video,  Larry King asks whether Rogen's fiancee has been tested  for the illness.  She responds appropriately that since there is not yet an effective treatment, there is little support for testing relatives of those with Alzheimer's disease.



Charcot-Marie-Tooth:  In this excellent New York Times series titled "Patient Voices" patients with Charcot-Marie-Tooth described the effect of the illness on their life.  Charcot-Marie-Tooth (or CMT) is a neurological disorder that effects the peripheral nerves in the legs, hands and feet.

The link to slide show video on CMT is here.

A good summary of the genetics of CMT is here at Wikipedia.

Obsessive Compulsive Disorder: Another Patient Voices slide show focussed on obsessive compulsive disorder.  This video highlights the variability of symptoms found in OCD.  This video also describes some of the benefit of behavior therapy in the treatment of OCD.

The link to the OCD slide video is here. 

Childhood ADHD and Food "Sensitivity"

I admit that I am a skeptic about the effect of diet on ADHD and most mental disorders.  No one can argue that a healthy diet should not be routinely advised for all individuals with or without an emotional disorder.   However, I am open to looking at research studies and data--I'm willing to change my opinion if the research supports such a change.

A group of Dutch researchers recently published a study of diet and ADHD symptoms in a small sample of children with ADHD between the ages of 4 and 8 years. This study was published in Lancet, a highly regarded scientific journal.  In the study one hundred children were assigned to an experimental group (elimination diet) or a control group (healthy diet education).  ADHD as well as oppositional defiant symptoms were monitored during the experimental phase by a single pediatrician (blinded to diet assignment), parents (not blinded to assignment) and teachers (not blinded to assignment).  The authors noted that it was impossible to blind parents and teachers due to the food restrictions required in the elimination diet group.

The elimination diet was a diet called few foods diet: rice, meat, vegetables and pears.  Strangely, parents were allowed to add potatoes, fruits and "wheats".  If there was no improvement after two weeks of this modified few foods diet, the diet was then restricted to the rice, meat, vegetables and pears diet.  Here were the key findings reported in the study:

• 32 of 41 (78%) children on the elimination diet had at least a 40% reduction in the ADHD Rating Scale (defined as response)--I was unable to find the response rate in the education group although the mean rating on this measure did not change pre- to post
• Improvement was noted by both parents and teachers on ADHD rating scales
• Ratings of severity of oppositional defiant disorder also improved along with ADHD symptoms
• After the initial phase, ADHD responders to the elimination diet were re-challenged with food and the majority (63%) "relapsed" when re-challenged with non-elimination diet foods.  This occurred in those re-challenged with either foods considered high or low risk for sensitivity based on individualized food-specific immune globulin G assays.

There are several things of note about this study.  First, this team previously reported a similar finding in a smaller sample--so this is not an independent replication. Second, the primary outcome ratings in the study were made by a single pediatrician that was "masked".  I would have liked to have seen consistent results from several blinded raters.  Additionally, the pediatrician ADHD ratings were scheduled at nine weeks in the elimination diet sample and 13 weeks in the control sample so this had the potential to void blinding in some cases.  The parents were not blinded to intervention but were instructed to not reveal their diet assignment to the pediatrician.  The fidelity of this instruction is not addressed.

One other issue here is biological plausibility.  The authors propose a food sensitivity mechanism-- not a distinct food allergy mechanism.  Serum IgE levels can be markers of allergy to food and non-food antigens.  The elimination diet "responders" did not have higher rates of elevated IgE compared to the non-responders. Exactly how a non-allergic food sensitivity could cause persistent attention, motor and behavior problems is unclear to me. 

I was surprised this study was published in a top-notch research journal.  Maybe it will be replicated by an independent group using a better design.  I wouldn't hold my breath on this or make treatment decisions based on the results of this small study.

I guess if I had a child with severe ADHD, I would not make a dietary change based on this study.  I would continue evidence-based treatments and continue to keep abreast of research advances in the diagnosis and treatment of this disorder.


Photo of African Lion Courtesy of Sarah Yates

Pelsser, L., Frankena, K., Toorman, J., Savelkoul, H., Dubois, A., Pereira, R., Haagen, T., Rommelse, N., & Buitelaar, J. (2011). Effects of a restricted elimination diet on the behaviour of children with attention-deficit hyperactivity disorder (INCA study): a randomised controlled trial The Lancet, 377 (9764), 494-503 DOI: 10.1016/S0140-6736(10)62227-1

Why Is Anorexia Nervosa Neglected for Drug Development?

Atypical Antipsychotic Olanzapine

Eating disorders have been a neglected area for high-quality psychopharmacologic research.  There are probably several reasons for this.  The classic eating disorder anorexia nervosa is relatively rare and identifying 500 to 1000 subjects for a clinical trial would likely be a significant (but not impossible) research challenge.   There are currently no FDA approved drugs indicated for the treatment of anorexia nervosa.

One drug in the U.S. has FDA approval for bulimia nervosa, the antidepressant fluoxetine.  But this approval occurred in the late 1980’s meaning we are approaching twenty-five years without a new drug approval for bulimia nervosa.  Pharmaceutical company interest in bulimia may be tempered somewhat by the experience of a trial using the drug bupropion.  Bupropion appeared effective in reducing binge eating in bulimia nervosa but a the clinical trial participants on bupropion had an increased risk of seizures during the trial.  The electrolyte disruption seen in bulimia (from bingeing and purging behaviors) may contribute to an increased risk of seizure—particularly for drugs with a known risk of reducing seizure thresholds.

So is anorexia nervosa neglected because there just are no potential candidates?  There is some evidence of the potential for the atypical antipsychotic medications in anorexia nervosa.  This evidence comes from outside the FDA approval process and typically involves small numbers of subjects.  McKnight and Park from the Department of Psychiatry at the University of Oxford recently summarized the research knowledge base in this area.

Why should atypical antipsychotics be considered for an eating disorder?  McKnight and Park propose three reasons:

• Atypicals reduce agitation and anxiety—common hindrances in refeeding underweight patients with anorexia nervosa
• Atypical often cause weight gain
• Some features of anorexia nervosa resemble psychosis—persistent belief of being overweight despite starvation and weight loss

Only three double-blind trials have been published according to this review.  All involve olanzapine versus placebo.  Two of these studies found and increase in BMI (weight) with the drug.  All of the these studies found some favorable effect on anxiety, depression or eating disorder psychological symptoms.

One single blind study compared the atypical antipsychotic drug amisulpride to fluoxetine and placebo.  Amisulpride produced a significant weight gain compared to the other two treatment arms. 

Four open label non-blinded studies suggest the potential for quetiapine to have a favorable effect on weight gain and/or reduction in eating disorders psychological variables.

Evidence for the use of other atypical agents (i.e. risperidone, aripiprazole) is limited to a few case reports, but these have generally been favorable.  One case report noted development of hyperglycemia in adult with anorexia receiving 15 mg of olanzapine daily.

I searched the ClinicalTrials.gov website for anorexia nervosa and found only two active clinical trials recruiting subjects:

• Olanzapine versus placebo for outpatients with anorexia nervosa (an NIMH-sponsored study) conducted by Cornell, University of Pittsburgh, Johns Hopkins and the University of Toronto with a targeted enrollment of 160
• Aripiprazole versus placebo—a phase III study being conducted at the University of Barcelona in Spain with a targeted enrollment of 60

So the history of neglecting anorexia nervosa for drug development seems to be continuing.  What will it take for more research attention to this important disorder so that clinicians will have more to offer the patients and their families?

Image of Chemical Structure of Olanzapine provided in the public domain by author Ben Mills.

McKnight RF, & Park RJ (2010). Atypical antipsychotics and anorexia nervosa: a review. European eating disorders review : the journal of the Eating Disorders Association, 18 (1), 10-21 PMID: 20054875