Dr. Sussman is editor of Primary Psychiatry as well as Associate Dean for Post-Graduate Programs and professor of psychiatry at the New York University School of Medicine in New York City.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please e-mail questions or comments for Dr. Sussman to ns@mblcommunications.com.


 

In general, I have been a skeptic about the continued use of brand name psychotropics once the generic form of that drug becomes available. In most cases the generic version is significantly less costly to my patients. It also means that I do not have to get into a sometimes time-consuming fax war with a pharmacy benefits management firm asking me to justify the use of the branded drug. Having said that, my clinical experience and some recent articles have made me think again about whether the use of generic formulations of medications, which are presumed to be therapeutically equivalent to their branded counterparts, are in fact equivalent. I have seen patients who experience a return of symptoms when switched from the brand name drug—which in many cases had kept them well for years—to a generic medication.

 

Howard C. Margolese, MD, and colleagues,1 recently published a report on three patients who experienced clinical deterioration after switching to the generic formulation of the brand name psychotropic medication they had been using. In one case, a schizophrenic patient stable on risperidone long-acting injection 75 mg every 2 weeks—branded divalproex sodium 1,500 mg/day, procyclidine 12.5 mg/day, and olanzapine 5 mg/day—became depressed with vague suicidal thoughts 3 weeks after his pharmacy had switched his original prescription of branded divalproex sodium to a generic formulation. He restarted original divalproex sodium and his depressive symptoms and vague suicidal thoughts improved within 9 days. Twenty-four months later, the patient remained stable.

In a second case, a 53-year-old woman with recurrent major depressive disorder (MDD) had been treated for 3 years with fluoxetine up to 80 mg/day, trazodone 50 mg QPM, and weekly psychodynamic psychotherapy. At 2 years of treatment, several months after her pharmacist substituted branded fluoxetine, she experienced moderate depressive symptoms with suicidal thoughts. Four weeks after reinstituting original fluoxetine she reported improved mood, energy, and concentration, as well as absence of suicidal ideation. She remained stable for the next 12 months.

In the third case, a 47-year-old woman with MDD and obsessive-compulsive disorder was stable on mirtazapine 60 mg/day, bupropion sustained release 150 mg/day, imipramine 175 mg/day, and diazepam 13 mg/day. After her pharmacist switched her from original mirtazapine to a generic, her symptoms returned. The patient was restarted on original mirtazapine and reported a 90% improvement in all mood symptoms within 8 days. Four weeks later, her mood and obsessive-compulsive symptoms greatly improved and remained stable since then.

These cases are similar to many other reports in the literature. They bring up a number of real world issues. One of these is that prescribing physicians are often unaware that a pharmacy may have substituted a generic for a brand. A second issue is whether the Food and Drug Administration’s standards for approving and monitoring generic medications reflects the true pharmacologic-clinical impact of these standards.

Margolese and colleagues1 note that generic drugs “are not required to undergo efficacy and safety studies before being marketed. A generic is approved if the manufacturer shows an ‘essential similarity’ to the original medication through identical routes of administration, and type and quantity of active compound as shown by bioequivalence studies.”Something that cannot be tested for, they also point out, is, the “delicate balance” that is often achieved when combination therapy is used to good clinical effect. Change in a formulation can “disrupt” treatment response by affecting how medications are metabolized by the liver.

In another recent article on the subject of generics, Ellingrod2 discusses how differences among generics might affect a patient’s response. She describes the case of a 47-year-old male with MDD who received brand-name fluoxetine 20 mg/day. His mood improved after 4 weeks but he experienced delayed ejaculation, which resolved spontaneously after 12 weeks of treatment. Because the patient had recently lost his job and health insurance, his fluoxetine was changed  to a generic formulation. After 9 months on the generic, he reported experiencing delayed ejaculation again. He had no changes in medical history and had not started any new medications. He also had been compliant with his medication, although he mentioned that the fluoxetine tablets looked different when he last refilled his prescription. A call to the pharmacy confirmed that they started dispensing generic fluoxetine from a different manufacturer around the time he refilled his prescription. After receiving the previous generic formulation, his sexual dysfunction resolved within 2 weeks.

Ellingrod, in discussing the implications of switching to and among generics, notes that “pharmaceutical manufacturers developing a generic drug must create a product that will deliver the same amount of medication at the same rate and in the same form (ie, tablet, capsule, suspension, etc.) as the brand-name product.” While the FDA requires that bioequivalence studies be conducted, they “usually include fewer than 40 healthy individuals.” A new generic formulation does not have to be tested against other generic formulations, rather, only against the brand-name drug. Therefore, two generic formulations may differ substantially in terms of their pharmacokinetics. Generic drugs are also not required to contain identical inactive ingredients, possibly leading to unwanted clinical effects if therapy is switched from the branded product to the generic version, or even to an alternative generic formulation. Although FDA regulations assume that because two formulations are bioequivalent they also are similarly safe and effective, this is not always the case. There are more aspects to this problem than can be addressed in a brief editorial. The literature on the subject, which includes an abundance of case reports, is also too big to summarize. In the future, Primary Psychiatry will devote an entire issue to the actual and theoretical consequences of switching from brand to generic and generic to another generic drug.

I want to thank the guest editor for this issue, Leslie Zun, MD, for her update on behavioral emergencies. In addition to the theme-based articles, Donna Antonucci, MD, and colleagues present data on patient experience and satisfaction with lisdexamfetamine  dimesylate in adults with attention-deficit/hyperactivity disorder. Kim S. Griswold, MD, MPH, and colleagues discuss access to primary care and whether mental health peers are effective in  helping patients after a psychiatric emergency. Finally, there is a letter to the editor responding to a recent case report about a presumed pharmacokinetic interaction between modafinil and quetiapine that may have led to psychotic relapse.  PP

 

References

1. Margolese HC, Wolf Y, Desmarais JE, Beauclaira L. Loss of response after switching from brand name to generic formulations: three cases and a discussion of key clinical considerations when switching. Int Clin Psychopharmacol. 2010; 25(3):180-182.
2. Ellingrod VL. How differences among generics might affect your patient’s response. Current Psychiatry. 2010;9(5). Available at: www.currentpsychiatry.com/article_pages.asp?aid=8627&UID=. Accessed May 14, 2010.