Dextromethorphan for Alzheimer's Disease Agitation

In my last post I summarized a review of the pharmacology of the drug dextromethorphan.

This drug is receiving significant attention for disorders in neuroscience medicine. 

A phase 2 clinical trial of dextromethorphan-quinidine (DM-Q) was published last fall in JAMA.

Here are the key design and results from this study:

Subjects: 220 subjects with a diagnosis of probable Alzheimer's disease with clinically significant agitation.
Randomization Design: This was a five week trial of 3:4 randomization to received DM-Q or placebo. Placebo subjects were re-randomized and enrolled in a 1:1 DM-Q versus placebo trial
Drug Dose Design: DM-Q 20mg-10mg daily for one week, then 20-10 twice daily for two weeks then 30mg-10mg twice daily for remainder of study.
Outcome: The primary outcome score was the agitation/aggression subscale score from the Neuropsychiatric Inventory. Active drug assignment reduced this score more than placebo (7.1 to 3.8 versus 7.0 to 5.3).
Adverse effects: Serious adverse effects were more common in active drug groups 7.9% versus 4.7% and included higher rates for falls, diarrhea and urinary tract infections. 

The authors note in the discussion that the higher rate of falls may have been due to an imbalance of fall risk at randomization.

This is an important study of a novel treatment approach to agitation in the elderly with Alzheimer's disease. Current drug treatment approaches are limited and linked to significant side effects.

Phase 3 studies of this drug combination are recruiting at the present time.

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Readers can access the free full-text manuscript by clicking on the PMID link below.

Figure of dextromethorphan comes from a Wikipedia Creative Commons file authored by Benjah-bmm27.

Cummings JL, Lyketsos CG, Peskind ER, Porsteinsson AP, Mintzer JE, Scharre DW, De La Gandara JE, Agronin M, Davis CS, Nguyen U, Shin P, Tariot PN, & Siffert J (2015). Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA, 314 (12), 1242-54 PMID: 26393847

How Brain Cancer Can Produce Psychopathology

Working in consultation psychiatry you become familiar with how brain diseases, like brain cancer can produce a variety of psychopathology. It is important to not search for psychological explanations in these situations but accurate diagnosis and treatment of the underlying brain disorder is key.

The New York Times has a very evocative and informative piece by a neuroscientist who experienced metatstatic melanoma to the brain. Her account is an excellent summary of some of the types of psychopathology found in brain cancer. I counted these signs and symptoms of psychopathology but there are probably more in her account:
*blindness in a partial visual field (homonymous hemianopsia)
*psychomotor agitation
*personality change
*amnesia
*loss of personal GPS
*behavioral disinhibition
*agnosia
*hypergraphia
*grandiosity
*paranoia

Read the New York Times story HERE.

Osprey in flight is an original pic from the authors' files.

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Nicotine Replacement in Schizophrenia

Inpatient psychiatric hospitals increasingly prohibit smoking by patients, staff and family in their units.  Although the public health benefits of smoking restrictions are undeniable, there may be some situations where smoking restrictions have unintended consequences.  One area is the emergency management of patients with serious psychiatric illnesses such as schizophrenia and bipolar affective disorder.

Rates of smoking have been documented to be higher in both schizophrenia and bipolar affective disorder.  The likelihood is high that acute psychiatric emergencies in schizophrenia and bipolar will be accompanied by nicotine dependence.  Clinicians are left making a decision on how to manage nicotine dependence in the context of psychotic decompensation.

Michael Allen and colleagues recently conducted a small study of nicotine dependence management in forty subjects with schizophrenia admitted to a psychiatric emergency service.  Subjects were required to be smokers at the time of admission.  Severity of smoking dependence was assessed using the Fagerstrom scale.  Subjects received standard antipsychotic therapy without restriction but they were randomized to receive either nicotine replacement therapy (21 mg nicotine patch per day) or placebo patch.

Here is a summary of the results of the study:

• Nicotine replacement reduced a measure of agitation by 33% in the first four hours and 23% at 24 hours
• This reduction was statistically significantly more than with antipsychotic alone and placebo
• Subjects with lower nicotine dependence scores tended to show the most response compared to placebo
• The size of the effect of nicotine replacement on agitation reduction approached the level seen with standard antipsychotic therapy

So the beneficial effects of replacing nicotine in the short term in this population is pretty dramatic and of signifcant magnitude.  The authors note that it is possible the 21 mg nicotine patch is insufficient to address nicotine withdrawal in schizophrenics with more severe nicotine dependence.  Since the nicotine patch typically takes several hours to provide significant blood levels, the authors suggest a combination of nicotine gum (with rapid onset) and a patch may be the best strategy.

Encouraging patients with psychotic disorders and mood disorders to quit smoking is an important general health strategy.  However, this study suggests that attempting this during an acute psychotic break is probably counter productive and may be inhumane.  Acute nicotinie withdrawal may exacerbate the agitation of psychosis.  Nicotine withdrawal attempts in this population is probably better suited for periods where psychotic symptoms are under control.  It also makes sense to monitor patients with schizophrenia closely during attempts to stop smoking.  This period may be one of increased risk of psychiatric decompensation.

Photo of Nicotine Patch Courtesy of Wikipedia Creative Commons by RegBarc

Allen MH, Debanné M, Lazignac C, Adam E, Dickinson LM, & Damsa C (2011). Effect of nicotine replacement therapy on agitation in smokers with schizophrenia: a double-blind, randomized, placebo-controlled study. The American journal of psychiatry, 168 (4), 395-9 PMID: 21245085