The risk of death in dementia patients utilizing antipsychotics varies rather widely, depending on the agent employed, according to a study published online in the British Medical Journal in late February, 2012. The study examined 75,000 nursing home patients (large sample size) with dementia for risk of possible death within six months of the initiation of antipsychotic medication. The study looked at Haldol, Seroquel and Risperdal, in particular.

Patients placed on Haldol demonstrated a doubling in their risk of mortality compared with those placed on Risperdal – while Seroquel users were significantly less likely to expire compared to the Risperdal users.

Seroquel, although seemingly safer than others in this sample, didn’t work as well in dementia patients. This finding comes as no surprise to me.

I’ve taught that Risperdal is the agent of choice within the 2^nd generation antipsychotic group for years now in my Psychopharmacology seminars. It is satisfying to know that the aforementioned study seems to agree from both a safety and efficacy standpoint. This does not mean that Risperdal is void of risk, but at low dose (less than 1 or 2 mg per day) the drug has minimal side effects; whereas Haldol is prone to cause extrapyramidal symptoms, thereby exacerbating agitation and disruptive behavioral sequences in these patients.

Nondrug intervention strategies should always be utilized first in elderly dementia patients.

According to this FDA warning, reported signs and symptoms include anaphylaxis, angioedema (swelling below the surface of the skin), hypotension, tachycardia, swollen tongue, difficulty breathing and rash. The FDA also indicates that the drug’s label has been modified to include information about this risk.

My concern with these atypical antipsychotics is what will unfold from an adverse event standpoint as more and more prescriptions for these agents are generated. As I noted in a previous blog, this antipsychotic class has become its own cottage industry, generating $15 billion in sales annually. The first shoe to drop with these drugs was their propensity for causing obesity. This then led to the subsequent emergence of metabolic syndrome (elevated blood sugar, lipids, cholesterol) in susceptible users. Then along came a black-box warning regarding their use in dementia.

I predict that the warning issued about Saphris is only the tip of the iceberg and that increasingly these atypical antipsychotics will be defined by a widening and expanding array of side effects as opposed to their therapeutic benefits. Another issue with potentially long-term adverse event implications is that their use in children and adolescents is exploding. There are too many of them now and recent releases (I’m thinking Saphris and Latuda here) earn me-too status at best.

Stay tuned.

Atypical antipsychotics have clawed their way along to $15 billion in sales per year despite the fact that much of the prescribing is unsupported by scientific evidence, lacks clear rationale and is bringing obesity and its attendant risks more to the problematic forefront.

As alarming as the potential consequences of overuse may be, it is not really surprising. A few supposed psychiatric “thought leaders” have been working in concert with pharmaceutical companies to promote off-label use of these agents for years now. And they’re succeeding because the cavalier use of these drugs is indicative of the lack of caution that now permeates everyday prescribing practices.

This is not an indictment of this psychotropic medication class. Used appropriately, antipsychotics are a godsend to the management of the psychotic spectrum disorders. In fact, acute psychotic features could not be managed effectively without them. But nothing can justify the fact that objective sales data indicate they have become best-sellers.

There are now 10 second-generation antipsychotics on the U. S. drug market. Bulleted below are the latest updates on the advantages and disadvantages of each:

Clozaril (clozapine)

• Truly a miracle agent for some
• Not a first-line treatment – can cause potentially serious agranulocytosis
• FDA approved for the management of recurrent suicidal behavior in schizophrenics
• Because of the agranulocytosis risk, blood count monitoring is necessary – weekly for 6 months, followed by every 2 weeks for 6 months, then monthly.
• Significant weight gain and very sedating
• High risk for the development of metabolic syndrome

Risperdal (risperidone)

• Well accepted for the treatment of agitation and aggression in dementia, in spite of carrying a black-box warning
• Few side effects at low dose
• Above 6mg/day – extrapyramidal symptoms – dystonia, parkinsons, akathisia
• Available in a long-acting Consta® formulation

Zyprexa (olanzapine)

• Rapid calming action for agitation
• Sedating, and produces the most weight gain among the SGAs
• Like Clozaril, significant risk for the development of metabolic syndrome
• Lowest discontinuation rate among the SGAs
• Available in a long-acting injection – Relprevv

Seroquel (quetiapine)

• Some efficacy in bipolar depression
• Seroquel XR is FDA approved as an augmenting agent to traditional antidepressants in the management of treatment-resistant unipolar depression
• Has taken off in the U.S as the new sleeping pill
• Don’t count on its antipsychotic efficacy as a monotherapy treatment

Geodon (ziprasidone)

• Least likely of the SGAs to cause weight gain
• Cardiac safety is a concern, though not as serious as previously thought
• Available as an IM injection

Abilify (aripiprazole)

• Like Seroquel XR, Abilify is approved as an augmenting agent to traditional antidepressants in the management of treatment-resistant unipolar depression
• Few side effects
• Not sedating enough in acute agitation
• Stand-alone antipsychotic efficacy questionable

Invega (paliperidone)

• Active metabolite of risperidone, extended-release action
• Kidney metabolized, fewer drug interactions compared to risperidone
• Available as a long-acting IM preparation: Sustenna®
• More expensive than risperidone for too little benefit

Saphris (asenapine)

• Available only as a sublingual tablet
• Elevated level of EPS – comparable to that of some FGAs
• Associated with weight gain, oral numbness, and it’s sedating

Fanapt (iloperidone)

• Twice-a-day dosing a disadvantage
• The rights to the drug were handed off among several companies
• Took at least 15 years to gain FDA approval
• Linked to possible heart rhythm problems
• No distinct advantages

Latuda (lurasidone)

• No distinct advantages or disadvantages, a “me-too” SGA

In association with the approval of Zyprexa and Seroquel, the FDA also stated it wants to know more about the risk of weight gain and diabetes in youth taking these drugs and other antipsychotics as well.

It has been clear for years that weight gain and other endocrine risks are associated with these medications, and their warning labels say so. Some evidence however, suggests that these issues are even more paramount in kids.

A study published in the November, 2009 issue of JAMA ( Journal of the American Medical Association) found that children and adolescents using antipsychotics gained significantly more weight over an 11-week period than comparable kids who weren’t taking the drugs. Those on Zyprexa demonstrated the most weight gain – 19 pounds – although weight gain was also associated with several others of these antipsychotics.

Zyprexa labeling does warn that youth are not only likely to gain weight, but are prone to gain more weight compared to adults taking the drug. But the labels for the other antipsychotics the FDA is investigating – Risperdal, Abilify, Geodon and Seroquel – don’t state whether children and teens are at higher risk than adults for weight gain. Frankly, I believe the reason for this is that Zyprexa clearly produces the most weight gain – regardless of age.

The safety conundrum associated with second-generation antipsychotic use in the treatment of schizophrenia and bipolar disorder in youth will linger until a new, safer generation of compounds is developed. These safer agents aren’t coming soon, as some big Pharma companies are planning to cut billions of dollars in annual research and development spending. When it comes to treating psychotic and bipolar disorders in children, I staunchly agree that the balance needs to favor minimizing risks. However, for children with serious and potentially dangerous behavioral problems such as severe aggression, violent outbursts and out-of-control tantrums, what other viable options are there outside of the use of these drugs? Mood stabilizers such as lithium and Depakote carry similar risks of marked weight gain, in addition to other debilitating side effects. Benzodiazepines are not approved for use in the pediatric population period, and carry the risk of potential abuse and dependence. Lastly, with many states experiencing severe cutbacks in mental health care services, there is a paucity of well trained, experienced behavioral specialists with the requisite skills for managing the above-mentioned behaviors in youth. And even if very capable behaviorists were in adequate supply, how on earth could the management of out-of-control behavior be successfully or even adequately facilitated in the absence of medication augmentation?

The bottom line is this: Don’t look for prescribers of these medications to change their prescription-writing habits anytime soon. Why? Because for children with serious and potentially dangerous behavioral problems associated with schizophrenia, bipolar disorder or other associated syndromes, physicians as a whole continue to conclude that the benefits of medication use typically outweigh the risks.

The manufacturer, Schering-Plough, is promoting the drug on the premise that it’s more effective at improving the negative and cognitive symptoms of schizophrenia compared to other atypical antipsychotics, and that Saphris (asenapine) has a better safety profile.

The safety profile issue has been used over and over before. While the drug demonstrated less weight gain compared to Risperdal ( risperidone) or Zyprexa (olanzapine), it has an elevated level (18%) of extrapyramidal symptoms (EPS) – comparable to first generation antipsychotics.

Schering-Plough’s specialty sales force is handling the detailing of Saphris (asenapine) – as opposed to its primary cast of sales representatives – targeting psychiatrists to prescribe this new antipsychotic.