New Developments in CNS Drugs

October 30, 2008 - November 2, 2008, San Diego, California

Norra Macready


December 03, 2008

Second-generation antipsychotic agents may not compare as well to first-generation agents as previously thought, according to a new analysis presented at this year's US Psychiatric and Mental Health Congress.

In a second look at data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), advantages of the second-generation antipsychotics (SGAs) that emerged from the initial analysis became less robust, Stanley N. Caroff, MD, said in a presentation on central nervous system drugs and movement disorders.

A New Look at CATIE

Psychiatrists still regularly see patients in whom extrapyramidal syndrome (EPS) and tardive dyskinesia (TD) develop, explained Dr. Caroff, Professor of Psychiatry at the Veterans Affairs Medical Center in Philadelphia. In fact, EPS and TD were, in part, what drove the development of the SGAs. The mechanism of TD has never been satisfactorily identified, but it may be related to the drugs' mechanisms of action, and not the physiology of the psychoses themselves, as some investigators had thought.

Designed to examine the long-term clinical efficacy and safety of SGAs, CATIE was a randomized, double-blind study that initially enrolled 1460 patients, who received either an SGA (olanzapine, quetiapine, risperidone, or ziprasidone) or the first-generation antipsychotic perphenazine. The initial CATIE analysis suggested that the SGAs did, in general, match perphenazine therapeutically, but with a milder side effect profile.[1,2]

However, at the Congress, Dr. Caroff presented still-unpublished data from a second analysis in which he and his colleagues re-examined the CATIE data using more rigorous criteria (Miller DD, et al. EPS side effects of antipsychotics in a randomized trial: findings from the CATIE schizophrenia trial; submitted for publication).

All in all, a total of 213 CATIE patients discontinued their medication due to intolerable side effects, with EPS among the top 4 reasons for all the drugs. As expected, perphenazine led the way, with 22 of 261 patients (8.4%) on that agent discontinuing due to EPS.[1] Dr. Caroff made the following points regarding movement disorders associated with these drugs that became clear from the second analysis:

  • Dystonia: Only 6 patients (0.4%) discontinued their medication due to dystonia, including 2 of 3 patients taking ziprasidone, and 1 patient each in the perphenazine, quetiapine, and risperidone groups. These differences were not statistically significant (Miller DD, et al. EPS side effects of antipsychotics in a randomized trial: findings from the CATIE schizophrenia trial; submitted for publication).

  • Parkinsonism: This afflicts at least 10% to 15% of patients in everyday practice, so the rate of 6% to 8% reported in the initial CATIE analysis was very encouraging. In CATIE, parkinsonism was defined as a mean Simspon-Angus score (SAS) of ≥ 1 in patients who had ≤ 1 at baseline. However, in the second analysis, Dr. Caroff and his colleagues included only patients who had no parkinsonism at baseline and did not meet SAS criteria. By that standard, an average of 32.6% of patients developed any parkinsonism event, ranging from a low of 29.4% among people on quetiapine to a high of 37.2% in the risperidone group. These differences were not statistically significant. Four percent of the patients, on average, required medications for symptom control, ranging from 1% (quetiapine) to 6.7% (risperidone), and although no one taking either quetiapine or ziprasidone discontinued treatment due to parkinsonism, 3.7%, 3%, and 1.9% of patients taking olanzapine, perphenazine, and risperidone did, respectively (Miller DD et al. EPS side effects of antipsychotics in a randomized trial: findings from the CATIE schizophrenia trial; submitted for publication).

  • Akathisia: The first CATIE analysis showed akathisia, defined as a score > 3 on the Barnes Akathisia Scale (BAS), occurring in anywhere from 5% of patients on olanzapine to 9% of those taking ziprasidone, with the other agents falling somewhere in between. In the second analysis, Dr. Caroff and his colleagues once again studied akathisia events only in patients who had not had the condition at baseline and were not taking medication for Parkinsonism. They defined "any akathisia event" as meeting Barnes global assessment criteria, discontinuing due to akathisia, or adding medications to control akathisia. By those criteria, the incidence of akathisia ranged from 17% (quetiapine) to 25% (perphenazine, risperidone). Of those patients, an average of 4.6% required medication for symptom control, including 8% in the perphenazine group.

Based on these findings, Dr. Caroff said the SGAs appear less advantageous than they initially did, especially if they are compared to a first-generation agent that is less potent than haloperidol.

The findings from the new analysis regarding tardive dyskinesia (TD) were more encouraging. With first-generation antipsychotics, the prevalence of TD ranges from 20% to 25% to as much as 50% to 60% if the patients are elderly.[3,4] Diagnosis is tricky, with differential diagnoses including disparate conditions such as Huntington's disease, Tourette's syndrome, hyperthyroidism, and toxicity from antidepressants or antihistamines, to name just a few. Many studies of TD have methodologic flaws or inconsistencies, making them hard to compare, Dr. Caroff warned. He also noted that TD often occurs spontaneously in people with schizophrenia, especially as they age, and the condition may fluctuate. In fact, antipsychotic agents may suppress spontaneous TD, so it is not unusual to see a rebound when the drugs are discontinued.[5]

At baseline, 212 of the CATIE patients (14.5%) met modified Schooler-Kane criteria for probable TD, and 1098 had no history of TD and no Abnormal Involuntary Movement Scale (AIMS) score rated higher than 1. The remaining 150 patients had either mild symptoms on the AIMS or a history of TD, which put them in an indeterminate category, so they were excluded from the initial analysis. Patients with TD were significantly older, had been on antipsychotics longer, and were more likely to have used a first-generation agent. They also were more likely to have a history of substance abuse and to have higher scores on the Positive and Negative Symptom Scale, especially in the negative symptom and overall psychopathology components.[6,7]

For the second analysis, Dr. Caroff and his coauthors included only patients with no TD at baseline, for a total of 1066. An average of 2.9% of those patients met Schooler-Kane TD criteria on at least 2 subsequent assessments, ranging from 1.1% of patients taking olanzapine, to 4.5% of those on quetiapine. Another 9.5% met modified Schooler-Kane criteria on 1 assessment. However, only 1% of the patients in the perphenazine group and < 1% in the quetiapine group had to discontinue their medication due to TD symptoms, and only 1% in the risperidone group and < 1% in the olanzapine and quetiapine groups required medication for their symptoms.[8,9]

All in all, he drew the following conclusions from the second CATIE analysis:

  • In general, perphenazine was as well tolerated as the SGAs and as effective as 3 of them. In moderate doses, it was not associated with more EPS or TD symptoms than the newer drugs;

  • The advantages of the SGAs over haloperidol fade when the SGAs are compared to modest doses of a low- or mid-potency first-generation agent such as perphenazine; and

  • Drug-induced movement disorders remain a significant concern because they can be irreversible or cause life-threatening symptoms such as pharyngeal dystonia or neuroleptic malignant syndrome.

New Uses for Psychedelic Drugs

Psychedelic drugs have elicited new interest for potential therapeutic benefits, Walter A. Brown, MD, said in another presentation at the Congress.

Ketamine has psychedelic properties such as dissociation and perceptual alteration, but is also used legitimately as an anesthetic and analgesic. Work going back to 2000 suggests that it also is "a uniquely rapid acting and effective antidepressant," said Dr. Brown, Clinical Professor of Psychiatry at Brown University School of Medicine. In a small, double-blinded placebo-controlled study published that year, Berman and colleagues found that intravenous ketamine infusion significantly improved scores on the Hamilton Depression Rating Scale in 4 of 8 patients with major depressive disorder.[10] The effects lasted several days, much longer than any "psychedelic" or dissociative side effects, Dr. Brown said. He cited another study, presented by Sanjay Mathew, MD, and colleagues at the 2008 meeting of the New Clinical Drug Evaluation Unit of the National Institute of Mental Health, held last May, in which 20 treatment-resistant patients who were on either lamotrigine or a placebo were followed after receiving a 40-minute infusion of ketamine.[11] The dissociative symptoms lasted about 90 minutes, but 24 hours after the infusion, the patients' scores on the Montgomery-Asberg Depression Rating Scale (MADRS) had improved. Patients in both the lamotrigine and the placebo groups showed striking benefits in individual MADRS components, including concentration, sadness, suicidal and pessimistic thoughts, and sleep and appetite difficulties. Patients required infusions 3 times a week to maintain this effect, but they became tolerant of the dissociative symptoms over time.

Another agent, psilocybin, is a tryptamine alkaloid found in the "psychedelic" mushrooms. In a few small studies, psilocybin has emerged as a potential treatment for obsessive-compulsive disorder (in a modified, double-blind study in which patients received varying doses)[12] and cluster headaches (based on clinical interviews with headache sufferers describing the effects of their psilocybin use).[13] And in a study that truly evokes the spirit of the 1960s, psilocybin also was shown to enhance and prolong spiritual experiences and deepen their meaning for people open to such events.[14] Dr. Brown reported that a study is now under way under the direction of Charles Grob, MD, at Harbor-UCLA Medical Center to examine the drug's ability to relieve the pain and anguish of terminal cancer.


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