This is a topic that gets scant attention leaving the consuming public largely in the dark. Even though I work in the field, I've not hear this information except from my own reading. Fortunately, SSRIs are not as susceptible to problems crossing from brands to generics or between generics. But buproprion in other forms may not be as good as Wellbutrin.

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Antidepressant and antipsychotic drugs have become blockbusters for the firms that developed them, making them hot markets for generic competition. Moreover, the effectiveness of these drugs is measured in the same way as anticonvulsants -- either they work or they don't.

Consequently, psychiatry is another specialty that has had to think about how to handle the variability in potency among generics.

Michael Thase, MD, of the University of Pennsylvania in Philadelphia, said that when problems do arise, it's usually when patients switch between different generic versions of a drug.

"There are multiple generics," Thase said, noting that broad bioavailability confidence intervals allow for substantial variation between different generics.

"If the pharmacy changes generics frequently, which often they do because it's a highly competitive business ... you might have some series of 40% fluctuations," he said. "Every few months there might be such a large fluctuation."

But for antidepressants, clinical problems resulting from these fluctuations are not that common, he said.

The dose-response relationships with SSRIs are not rigid, and, therefore, patients generally don't see big changes in drug effects, he said.

"You might have an increase in side effects with the change, or you might feel you've lost a bit of the therapeutic effect."

But some non-SSRI antidepressants aren't so forgiving, said Jeffrey Lieberman, MD, a psychiatrist at Columbia University in New York City.

He mentioned the tricyclic drug nortriptyline and bupropion (Wellbutrin) as more susceptible than most antidepressants to dosage variations.

In the case of bupropion, he said, seizure risk is relatively sensitive to dosage.

Thase acknowledged that cases do occur when patients suffer serious problems following switches to or between generics. But he said those cases tend to have an outsized influence on perceptions.

"You don't hear about all the times [problems] don't happen," he pointed out. "We may think it's a bigger problem than it is."

Lieberman said the common antipsychotics generally posed few problems with generics.

He said anecdotal reports of problems tended to focus on clozapine. "[It] seems to be a particular compound that suffers from this kind of experience," Lieberman said.

But he cautioned that these reports may result from "the kind of selective memory Michael [Thase] was talking about."

Lieberman noted that it was hard to pin down the potential for problems because -- as is the case with the antiepileptics -- systematic, controlled trials to compare different generic formulations and the branded original are generally lacking.

There is an important new research study on treatment of schizophrenia. They have found delayed or interrupted treatment is associated with permanent lost brain function and less success in recovery. That is indeed my clinical experience with schizophrenia and bipolar disorder. Any kind of chronic brain dysfunction makes permanent changes to brain structures and functioning. PTSD has been associated with permenent changes in emotion intensity and increased difficulty in emotion regulation. Chemical abuse has been associated with brain changes as well.

When the brain is involved, respond quickly, ask for help and persist to be sure the treatment is effective. Anything less will cost you in brain function. This applies to any serious mental health or neurological problem.

Psychiatric Weekly

In summary, it appears that there are benefits to be gained by identifying psychotic exacerbations early and bringing effective treatment to bear quickly (Table).11 If patients do not respond within the first 2 weeks to the initially prescribed antipsychotic, consider switching antipsychotics until you find something that works. When patients respond, our work is not finished. Optimize the response. Try to reduce psychopathology to a minimum. Attend to side effects; think of this task in terms of how you would feel if you had to take a medication every day for the rest of your life. Repeatedly inquire about patients' judgments as to their need for medication and the value of the medications they are presently taking. Treat their viewpoints with respect, express your point of view on these issues with clarity and persistence, and make it clear that their feeling better is the goal for both of you.

Anti-psychotic medication has gotten very expensive, especially when compared to long standing generics. Now research is finding the generics work just as well as the new "atypicals". But the fact is, medication has to be subscribed one client at a time. While on average, some of the generics work as well with low side effects, some individuals have extreme side effects from the generics or don't benefit from them any where near as effectively as the new "atypicals". In particular, the worse permanent side effect, tardive dyskinesia appears less likely with new atypicals in individuals prone to that problem.

So when we have journal articles pointing out the excesses of the pharmeceutical industry, we need to be sure we don't eliminate the best option for the minority of persons who need the new "atypical" anti-psychotic medications.

Archives of General Psychiatry

In people with schizophrenia whose medication is changed for clinical reasons, there is no disadvantage across 1 year in terms of quality of life, symptoms, or associated costs of care in using FGAs rather than nonclozapine SGAs. Neither inadequate power nor patterns of drug discontinuation accounted for the result.

Here is a NAMI.org press release supporting my position.

“For Medicare, Medicaid, and the Department of Veterans Affairs, it would be a grave mistake to use the study to restrict access to newer medications, based on general findings that older medications seem to work as well as the newest generation,” Duckworth said. “General findings cannot be substituted for specific choices made in treating individuals with schizophrenia. One size does not fit all. It is critical that the study’s limitations be recognized.”

For one, the British study relies heavily on an older drug, sulpiride that has never been approved by the Food & Drug Administration (FDA) and is unavailable in the United States. In addition, the study’s comparisons are limited to classes of drugs, rather than specific medications. The study does not include comparison of doses of drugs, either between classes or specific medications.

Although longer than clinical trials required for FDA approval of specific drugs, the study’s one-year test period is still largely inadequate for evaluating treatment outcomes over time.

Some of you might remember the report released last year saying that an older medication Trilafon was just as effective as the new MUCH more expensive medications. Even though NIMH commented later that the research did not support that belief, many Medicaid programs wrote the new medications out of their formularies.

A follow-up to this research has reinforced the fact that most psychiatrists already know. Each person's body chemistry responds uniquely to each medication. The full range of medicaitons are required to find an effective choice. Besides, the side effect profile is much better for the newer medications. The permanent neurological damage evidenced by tardive dyskinesia too often caused by the older medications were often an unacceptable consequence of appropriate treatment. People shouldn't have to choose one scourge for another, especially if it's not necessary.

NAMI

Phase II of CATIE strongly reinforces the individualized nature of treatment for schizophrenia. There are a multitude of clinical factors that impact on specific medications that should be prescribed to specific individuals. Most importantly, access to a range of antipsychotic medications must be protected. When it comes to the treatment of schizophrenia, there is no one size that fits all.

The results in Phase II also illustrate the critical need for a new generation of research to find medications for schizophrenia that are both more effective and have fewer side effects. Although existing medications clearly benefit many people, there are also many who continue to struggle with symptoms despite taking medications and others who experience side effects so serious that they ultimately choose to stop treatment.

I will keep my eyes open for the release of the report on the NIMH website. If anyone else finds it, let me know.

NIMH has published a press release on initial results of an important new study of anti-psychotic medications. The study compares the newer medications with an older medication thought to have a lower incidence of movement disorders.

NIMH: NIMH Study To Guide Treatment Choices for Schizophrenia

In the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) trial, researchers directly compared an older medication (perphenazine), available since the 1950s, to four newer medications (olanzapine, quetiapine, risperidone, and ziprasidone), introduced in the 1990s. The purpose of the study was to learn whether there are differences among the newer medications and whether the newer medications hold significant advantages over the older medications; these newer medications known as atypical antipsychotics, cost roughly 10 times as much as the older medications.

The size and scope of the trial, with more than 1,400 participants at 57 sites around the country, its 18-month duration, and its inclusion of a wide range of patients in a variety of treatment settings ensure that the findings are reliable and relevant to the 3.2 million Americans suffering from schizophrenia.

At the beginning of the study, patients were randomly assigned to receive one of the five medications. Almost three quarters of patients switched from their first medication to a different medication. The patients started on olanzapine were less likely to be hospitalized for a psychotic relapse and tended to stay on the medication longer than patients taking other medications. However, patients on olanzapine also experienced substantially more weight gain and metabolic changes associated with an increased risk of diabetes than those study participants taking the other drugs.

Contrary to expectations, movement side effects (rigidity, stiff movements, tremor, and muscle restlessness) primarily associated with the older medications, were not seen more frequently with perphenazine (the drug used to represent the class of older medications) than with the newer drugs. The older medication was as well tolerated as the newer drugs and was equally effective as three of the newer medications. The advantages of olanzapine — in symptom reduction and duration of treatment — over the older medication were modest and must be weighed against the increased side effects of olanzapine.

Thus, taken as a whole, the newer medications have no substantial advantage over the older medication used in this study. An important issue still to be considered is individual differences in patient response to these drugs.

NIMH: CATIE Schizophrenia Q&As for Media

...the primary measure of treatment success in the CATIE study was how long a patient benefited from and thus stayed on a medication before they or their doctor decided that it had to be changed. Investigators also recorded why a patient stopped a medication: if the medication did not control symptoms, or if the side effects were not tolerable, or if the patient chose to stop treatment for some other reason. In addition to this primary outcome, the study also examined medication effects on the symptoms of schizophrenia, as well as other important outcomes such as overall level of function.
[...]
This study provides the largest, longest, and most comprehensive independent trial ever conducted to study existing therapies for this disease. It will provide valuable information to help physicians and patients choose the most appropriate medication for them. There is considerable variation among individuals; what works for one does not necessarily work for another. It is important to have a variety of treatment options. The CATIE study provides specific information, on therapeutic effects as well as side effects, about those options.
[...]
The investigators will continue to study other important outcomes, including cost-effectiveness, quality of life, and predictors of response. As additional results from CATIE are analyzed, disseminated, and put into context, the hope is that the cumulative findings will yield a more complete picture of the interaction between patient characteristics, medication, environment, and outcomes.

The complete study is available September 22nd:

Lieberman, J.A., Stroup, T.S., McEvoy, J.P., Swartz, M.S., Rosenheck, R.A., Perkins, D.O., Keefe, R.S.E., Davis, S.M., Davis, C.E., Lebowitz, B.D., Severe, J., Hsiao, J.K. (2005). Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. New England Journal of Medicine, (353), p.1209-1223.

These first published results offer some interesting outcomes, perhaps a low cost alternative to the high priced newer medications. Perphenazine is better known by it's brand name Trilafon. Its important to note that a positive outcome was defined rather narrowly in this study. More detailed data is said to be forthcoming.

I think the most important issue in using anti-psychotic medications is the long-term side effects, in particular tardive dyskinesia and diabetes. The new medications promised fewer movement disorders. So far, these promises seem to hold true. But the emerging concerns about diabetes has clouded the future of the newer anti-psychotic medications. Doctors are currently advised to watch for metabolic changes as well as the development of movement disorders.

The definitive answers for these two concerns can't be obtained in the 18 months the study followed patients. I would hope someone has discovered this problem and is tracking down those who participated, some as long as five years ago, to gather new data about these critical issues.

Meanwhile, I'll be particularly interested in seeing results related to quality of life and the even more exciting studies of the interaction between patient characteristics, medication, environment, and outcomes. Ultimately, the study may have a significant impact on patient care and understanding the dynamics of recovery.

Anti-psychotic drug warning for seniors with dementia

U.S. health officials Monday advised physicians not to give elderly patients with dementia anti-psychotic drugs approved for other medical conditions. The Food and Drug Administration said the drugs included in the warning were Abilify (aripiparozole), Zyprexa (olanzapine), Seroquel (quetiapine), Risperdal (risperidone), Clozaril (clozapine) and Geodon (ziprasidone). All are approved for treatment of schizophrenia and mania but are associated with a higher death rate when given to elderly patients with dementia for behavioral problems. Symbyax, approved for depression linked to biopolar disorder, also was included in the advisory.

Manufacturers of these drugs must add a boxed warning to their labels, FDA said, describing the risk and noting the drugs are not approved for treatment of behavioral symptoms in elderly patients with dementia.

An analysis of 17 placebo-controlled studies of four drugs in this class found the death rate for elderly patients with dementia was about 1.6 to 1.7 times that of placebo. Causes of death were varied but most seemed to be either heart-related or stem from infections.

This is a very important move by the FDA. There are thousands of seniors in nursing homes on anti-psychotics to control behavior disorders such as combativeness in seniors with dementia and alzheimers disease. With the FDA warning, many will have a resurgence of their behavior problems without alternative treatments. This is particularly a signficant change for nursing homes who already have a problem retaining staff who are frequently assaulted by their patients. Doctors will be trying alternative medications to attempt to manage these problematic behaviors.

Doctors should Monitor Metabolic Side Effects of Anti-Psychotics

Psychiatrists are doing a "modest" job of monitoring for weight gain, diabetes and other metabolic problems that may result from use of the newer antipsychotics for schizophrenia, researchers say. Nearly all of the 258 members of the American Psychiatric Association in Georgia, Ohio and Iowa responding to a survey said they considered metabolic side effects serious or very serious, said researchers from the Medical College of Georgia, University of Iowa and Northcoast Behavioral Healthcare in Ohio. However, monitoring for these problems - including getting baseline data on personal and family health history as well as baseline and regular checks of height and body weight, waist circumference, blood pressure, fasting blood glucose and lipid levels - largely goes undone, researchers said of findings presented during the 10th International Congress on Schizophrenia Research in Savannah, Georgia.

If you or someone you know are taking anti-psychotic medications, make sure your doctor checks for metabolic side-effects. Like all the new information in medicine, it takes a while for physicians to adjust their practice. The same is true for psychiatrists. Read the article linked above and talk to your doctor about your anti-psychotic medications.

You, the consumer, need to be directing your care with the expert advice of your physician and therapist.