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 Guidelines: NICE Update

Clinicians treating bipolar disorder and patients with a bipolar disorder diagnosis are aided by the availability of expert opinion guidelines.

In the last post, I reviewed a study that found decreased rates of suicidal behavior in bipolar patients treated with antidepressant drugs.

This review prompted me to look for a recent consensus update on assessment and treatment of bipolar. One recent update came from the UK National Institute for Health and Care Excellence or NICE. This guideline is freely available and I will post a link at the end of this blog post.

I will focus on psychopharmacology in my review but the reader is encouraged to take a look at these excellent guidelines for other details.

The recommendations from the guideline for general maintenance treatment of bipolar disorder in adults in specialty care:

• Do not use gabapentin or topiramate
• Antipsychotic drugs
• Lithium therapy
• Valproate therapy
• Lamotrigine therapy

Recommendations for treatment of mania in specialty care:

• If manic bipolar patient is taking antidepressant consider stopping it
• Electroconvulsive therapy is an intervention that should be considered in those with severe and prolonged mania
• The further treatment of mania follows the maintenance list as above: antipsychotics (haldol, olanzapine, quetiapine or risperidon), lithium, valproate and lamotrigine

Recommendations for treatment of bipolar depression in specialty care:

• Make sure full psychological services are used as a base in treatment
• Add fluoxetine plus olanzapine or quetiapine on it's own
• If no response to initial antidepressant treatment consider a trial with lamotrigine

As you can see from these depression guidelines, the use of standard antidepressants in bipolar depression is not recommended. The exception to this is the use of fluoxetine (covered with olanzapine).

The full pdf guideline from NICE is 59 pages and I would encourage interested reader to go to the website and download the full guide. You can do that by clicking HERE .

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Kendall T, Morriss R, Mayo-Wilson E, Marcus E, & Guideline Development Group of the National Institute for Health and Care Excellence (2014). Assessment and management of bipolar disorder: summary of updated NICE guidance. BMJ (Clinical research ed.), 349 PMID: 25258392

Alzheimer's: Challenges in the Newly Diagnosed

Alois Alzheimer

Memory loss is a cardinal feature in the presentation and diagnosis of new patients with Alzheimer’s disease(AD).  However, the accompanying neurological and psychiatric problems seen in this population can be significant challenges.  Spalletta and colleagues have recently published a comprehensive assessment of the prevalence and types of problems families and clinicians face. 

Between 2003 and 2005, five Italian outpatient memory clinics studied a series of 1015 patients newly diagnosed with Alzheimer’s disease.  The subjects received a comprehensive assessment that including psychiatric, neurological and behavioral domains.  Men with newly diagnosed AD were contrasted with women newly diagnosed with AD to see if there were any specific gender effects in the findings.   Of interest, despite the new (recent) diagnosis, 40% of men and 47% of women already met criteria for severe dementia.  The authors note that there is significant variability in the timing of presentation for specialty evaluation and assessment.  Some find their way quickly, some only after dementia has progressed to a significant level.

The research team used a structured behavioral inventory called the Neuropsychiatric Inventory (NPI).  A factor analysis of the NPI showed 5 key factors that could be rated as absent, mild or clinically significant.  Here are the factors and prevalence rates in the sample for each of the domains men (women), (*-indicates statistical difference between men and women):

• Psychosis--8% (9%)
• Affective (Depression)--23% (32%)
• Mania- 2% (6%)*
• Psychomotor (agitation/irritability/aberrant motor behavior)—12% (11%)
• Apathy-37% (39%)
• At least one of the five syndromes—56% (61%)

The authors then examined how the prevalence for these neuropsychiatric problems correlated with the severity of dementia.  They found that severity increased four of the problem domains with most severe dementia raising risk from 70% for apathy to raising risk 420% for psychomotor problems.  Of note, depressive symptoms did not increase with severity of dementia. 

The authors note their study highlights the importance of assessing for apathy in this population.  The make it the most prevalent of the neuropsychiatric syndromes in the newly diagnosed with AD.   Apathy has been linked to neuropathological involvement in the medial frontal cortex and the anterior cingulate cortex in AD.

The authors note that their findings support looking for clusters of individual symptoms that make up these key five domains.  It would be helpful for future intervention studies (i.e. pharmacological/behavioral studies) to examine response over these domains.   We are seeing some recent clinical trials break out response of specific behavioral domains for drugs targeting AD.  A recent open label naturalistic study of the drug rivastigmine found apathy measures were more likely to improve than worsen over a 6 to 12 month follow up period.

Wikipedia Commons photo of Dr. Alois Alzheimer, Bavarian physician instrumental in describing the clinical features of dementia and discovering the histological brain changes characteristic of the illness.  Image estimated to be from about 1915 and is in the public domain due to expiration of any copyright.

Spalletta G, Musicco M, Padovani A, Rozzini L, Perri R, Fadda L, Canonico V, Trequattrini A, Pettenati C, Caltagirone C, & Palmer K (2010). Neuropsychiatric symptoms and syndromes in a large cohort of newly diagnosed, untreated patients with Alzheimer disease. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, 18 (11), 1026-35 PMID: 20808086


Gauthier S, Juby A, Dalziel W, Réhel B, Schecter R, & EXPLORE investigators (2010). Effects of rivastigmine on common symptomatology of Alzheimer's disease (EXPLORE). Current medical research and opinion, 26 (5), 1149-60 PMID: 20230208