APA Annual Meeting Highlights New Research

A recent study assessed the effectiveness and tolerability of the atypical agent quetiapine(Drug information on quetiapine) (Seroquel) in patients with Parkinson's disease (PD) and psychosis who are particularly susceptible to the extrapyramidal symptoms (EPS) and anticholinergic side effects associated with other atypical antipsychotic agents.

In a 24-week, open-label trial, 29 patients (mean age 73 years) received quetiapine up to 400 mg/day. According to the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression (CGI) Severity of Illness Scale and Neuropsychiatric Inventory (NPI), patients responded well, with scores decreasing significantly. Scores on the Unified Parkinson's Disease Rating Scale (UPDRS) remained stable. No important effects were observed on mean vital signs, weight gain, laboratory tests or electrocardiograms. The results showed that quetiapine is effective and well-tolerated in patients with PD. (Juncos JL et al., NR687).

This study was conducted to determine whether bupropion SR would be beneficial for patients with MDD who failed to respond to fluoxetine(Drug information on fluoxetine). In this trial, 28 subjects who were resistant to fluoxetine were switched to bupropion SR 150 mg bid without a washout period. Because of adverse effects, 21% of the 28 subjects dropped out of the study. Of these 28 patients, 35% were considered responders and six were considered partial responders. (Responders were those with a 50% decrease in baseline HAM-D score.)

Despite the adverse effects experienced by some of the subjects, preliminary results suggested that bupropion SR treatment is well-tolerated in fluoxetine nonresponders without a washout and may be effective for some SSRI nonresponders. Of the 22 patients who completed eight weeks of therapy, 45% of them were considered responders and 27% were considered partial responders (McGrath PJ et al., NR707).

Because patients with psychosis and acute agitation often need treatment with intramuscular (IM) conventional neuroleptics such as haloperidol(Drug information on haloperidol) (Haldol) and sedatives, they experience debilitating side effects, such as EPS and profound sedation. Ziprasidone (Zeldox) IM, however, has a unique receptor profile, making it effective in relieving the symptoms of agitation in patients with an acute exacerbation of schizophrenia. It is the first novel antipsychotic to enter late-stage clinical development as a rapid-acting IM formulation.

To further assess the efficacy of ziprasidone, several clinical trials were conducted. Two, 24-hour, randomized, double-blind trials compared ziprasidone IM 10 mg and 20 mg to respective 2 mg dose groups with acute agitation and psychosis. Then there were two open-label, seven-day trials with fixed- and flexible-dose ziprasidone IM and haloperidol IM.

Researchers concluded that ziprasidone IM is a considerable advancement in therapy for the acute control of agitated patients. It acts rapidly and is effective in reducing acute agitation. In addition, it offers tolerability advantages over haloperidol IM, particularly with regard to movement disorders. Doses of 5 mg, 10 mg and 20 mg up to qid for <3 days were well-tolerated (Zimbroff DL et al., NR365).

The 21 drugs currently marketed in the United States for the treatment of depression can be divided into four categories based upon their acute pharmacologic actions: 1) selective enhancers of noradrenergic transmission (e.g., desipramine [Norpramin], reboxetine [Vestra]); 2) selective enhancers of serotonergic transmission (e.g., fluoxetine, citalopram(Drug information on citalopram)); 3) nonselective enhancers of both noradrenergic and serotonergic transmission (e.g., phenelzine(Drug information on phenelzine) [Nardil], amitriptyline(Drug information on amitriptyline), mirtazapine); and 4) no known potent pharmacologic effects to enhance either noradrenergic or serotonergic function (e.g., bupropion, nefazodone(Drug information on nefazodone)). Keep in mind that the third category is not homogeneous, as drugs may be efficacious by inhibiting monamine oxidase, by inhibiting the reuptake of both norepinephrine(Drug information on norepinephrine) and serotonin, or by being antagonists of a-adrenoceptors.

In nonselected depressed patients, there does not seem to be any difference in efficacy among drugs with different mechanisms of action. This may not be true for different subgroups of depressed patients. As doctors consider the best drug for a depressed patient, they should also consider the side-effect profiles, which vary greatly among these drugs (Frazer A, Symposium 18A).

Depression and anxiety occur together more than they occur individually. While this may be because both disorders are prevalent in the general population, there is also evidence that a number of neurobiologic abnormalities may be common denominators for mixed anxiety and depression. For example, early life stress can cause permanent neurobiological changes-one of which is an increase in the activity of systems mediated by corticotropin-releasing factor (CRF). Elevated in humans diagnosed with depression and several anxiety disorders, CRF both influences and is regulated by the serotonin (5-HT) and noradrenergic neurotransmitter systems.

So what medications should be used to treat the co-occurrence of anxiety and depression? It appears that medications which downregulate the activity of the brain's main noradrenergic center and locus ceruleus and increase overall brain 5-HT activity, may decrease fear-induced increases in CRF release also. Therefore, drugs that modulate either serotonergic or noradrenergic systems, or both, are the best treatments for this comorbid situation (Gorman JM, Symposium 18b).

The safety and efficacy of bupropion SR for the long-term treatment of depression were evaluated in approximately 800 subjects with moderate recurrent depression. They were treated with bupropion SR (300 mg/day) during an eight-week, open-label phase trial. Of these subjects, 52% responded to the treatment (CGI Scale of Improvement of 1 or 2 for the three weeks prior to randomization), thus qualifying them to enter a 44-week, randomized, placebo-controlled, double-blind phase.

The results indicated that long-term treatment with bupropion SR is well-tolerated. Adverse events accounted for 9% and 2% of discontinuation from the open-label and double-blind phases, respectively (Weihs KL et al., NR507).

Sexual dysfunction affects 60% of patients taking SSRIs. In this randomized, double-blind, placebo-controlled study, 30 euthymic patients experiencing sexual dysfunction, as determined by the Arizona Sexual Experience Scale (ASEX), were randomized to either bupropion SR 150 mg/day or placebo for three weeks.

The outcome showed that there were no significant differences between the bupropion SR and placebo groups, as measured by side effects or change in ASEX or HAM-D scores (Ashton AK et al., NR684).