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 .

Photo of baseball player Albert Pujols in spring training is from the author's files.

Follow the author on Twitter @WRY999

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

Antidepressants Linked to Lower Suicide in Bipolar Disorder

Bipolar disorder is known to have a marked increased lifetime risk for suicide.

There has been limited study of the effect of specific interventions in the risk of suicidal behavior and completed suicide.

A recent study has added to our understanding of this topic using data from the Collaborative Depression Study or CDS.

The CDS is a large longitudinal stud funded by the NIMH that enrolled a large sample of subjects with bipolar I disorder, bipolar II disorder and unipolar depression.

Subject were followed intensely after a research diagnostic assessment every six months. Follow up interviews including information about antidepressant treatment, mood state, suicidal ideation and suicidal behaviors.  

This was a significantly ill cohort. Twenty-four subjects committed suicide during the five year period of follow up.

Subjects receiving drug treatment with bipolar disorder had statistically lower suicidal behavior (but not in the unipolar group). The estimated level of reduction of suicidal behavior by diagnosis group was:

• Bipolar I disorder: 54% reduction (95% confidence interval 31% to 69
• %)
• Bipolar II disorder: 35% reduction (95% confidence interval 1% to 57%)
• Unipolar disorder: 12% reduction (95% confidence interval 36% reduction to 22% increase)

The authors note some clinicians are less likely to use antidepressants in bipolar depression due to concern about inducing mania or more rapid cycling. They note their study supports a link between antidepressant use and reduced suicidality in bipolar disorder.

Many clinicians recommend chronic use of mood stabilizers with intermittent antidepressant use in bipolar disorder during depressive episode only. This may reduce potential risk for the use of antidepressants in bipolar disorder. The authors note some previous studies support a specific role for the mood stabilizing drug lithium to reduce suicide risk in bipolar disorder.

The psychopharmacologic treatment of bipolar disorder is a complicated process that needs to be customized to individual patient comorbidity, tolerance, medical comorbidity and past treatment response. Patients with bipolar disorder are best managed in a setting of expert medical care, family support and longitudinal monitoring. Patients are best served when they make decisions about drug treatment options in this type of setting.

The CDS cohort study was done prior to the evolution of the use of the novel antidepressant drug treatment lamotrigine in bipolar disorder.  Lamotrigine is an antiepileptic drug that is increasing used in bipolar disorder and is an FDA approved drug for maintenance therapy. The FDA also has approved aripiprazole and the combination of olanzapine plus fluoxetine for the treatment of depression in bipolar disorder.

Readers with more interest in the above study can access the free full-text manuscript by clicking on the PMID link in the citation below.

Slide showing symptoms in the manic phase of bipolar disorder is an original slide from the author's files. 

Follow the author on Twitter: @WRY999

Leon AC, Fiedorowicz JG, Solomon DA, Li C, Coryell WH, Endicott J, Fawcett J, & Keller MB (2014). Risk of suicidal behavior with antidepressants in bipolar and unipolar disorders. The Journal of clinical psychiatry, 75 (7), 720-7 PMID: 25093469

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