APA Annual Meeting Highlights New Research

(The following are highlights of new research presented at the 2000 American Psychiatric Association Annual Meeting. Additional highlights can be found in "APA Meeting Highlights New Research," in the February issue of Psychiatric Times, p23-Ed.)

Bupropion Sustained Release in the Treatment of Dysthymic Disorder

This study was conducted to evaluate the efficacy of bupropion (Wellbutrin) sustained release (SR) in treating dysthymic disorder. Subjects meeting DSM-IV criteria for dysthymic disorder were enrolled in this eight-week, open-label study. Bupropion SR was initiated with 150 qd and increased to a maximum of 200 mg bid for 21 patients.

Of the 21 subjects, 15 were treatment responders, with response defined as 50% drop in Hamilton Rating Scale for Depression (HAM-D) score. Patients with a diagnosis of past alcohol or chemical abuse were significantly less likely to respond to bupropion SR. Minor side effects were reported. Neither sexual dysfunction nor weight gain was reported. The findings suggested that bupropion SR was not only effective in treating dysthymic disorder but also highly tolerable among patients (Hellerstein DJ et al., NR702).

Prevalence and Assessment of Antidepressant-Induced Sexual Dysfunction

Antidepressant-induced sexual dysfunction (AISD) has become an important clinical side effect since the advent of selective serotonin reuptake inhibitors and the newer generation of antidepressants. Each of the major classes of antidepressants is associated with variable rates of sexual dysfunction. The early data in package inserts regarding AISD's prevalence are grossly underestimated because studies used-by default-a "don't ask, don't tell" methodology. In head-to-head studies using established rating scales to measure sexual functioning before and after treatment, findings indicated that bupropion, nefazodone (Serzone) and mirtazapine (Remeron) are associated with the least incidence of AISD. On the other hand, fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa) (the SSRIs) and venlafaxine (Effexor) are associated with substantial rates of AISD. Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) have a long history of AISD as well, but the rates are less clear because of methodological limitations (Nierenburg AA, Symposium 2B).

Smoking, Smoking Cessation and Antidepressants

Researchers have reported that smokers with a history of depression who succeed in smoking cessation are at risk for new episodes of depression. As one might assume, this has serious ramifications for patients who smoke. New episodes occur not only in the immediate withdrawal period but also for months after cessation.

Antidepressants, bupropion in particular, have effectively aided smoking cessation, whether or not the patient is depressed. There is also evidence that the TCA nortriptyline (Pamelor) may be useful. No study has shown SSRIs to be beneficial (Glassman AH, Symposium 6B).

Weight Changes Associated With Long-Term Antidepressant Therapy

Short-term effects of antidepressant drugs on body weight may be different from those seen during chronic therapy. Early in treatment, SSRIs typically produce weight loss, but during ongoing therapy some patients gain substantial weight. This is a common occurrence according to anecdotal and non-placebo-controlled studies. Mirtazapine causes significant weight gain early in treatment, but patients lose the added weight over time. Nefazodone appears to be weight neutral, and bupropion can actually cause weight loss (Sussman N, Symposium 14B).

Sexual Dysfunction Associated With Treatment of Major Depression

Both depression and pharmacologic treatment of depression are associated with sexual dysfunction. Most patients (70% to 80%) with major depressive disorder (MDD) experience decreased libido. To improve their quality of life, several strategies are available to manage the medication-induced sexual dysfunction. One such strategy is switching to an antidepressant with minimal effects on sexual functioning, such as bupropion, mirtazapine or nefazodone. In fact, substituting an SSRI with bupropion SR is an effective alternative in at least 55% of patients. Other strategies include waiting for spontaneous remission, decreasing the antidepressant dose, prescribing drug holidays and adding a pharmacologic antidote for sexual dysfunction (Clayton ALH et al., Symposium 14A).

Targeted Treatment of Depression

While there are currently no reliable methods for determining which antidepressant is most likely to benefit an individual depressed patient, there are some inferences that offer helpful guidelines: 1) serotonergics may be more beneficial in anxious, angry, irritable and impulsive (demodulated) states; 2) catecholaminergics may be more effective in apathetic and fatigued (deactivated) states; and 3) dual-mechanism medications may be more efficacious in melancholic and other mixed states.

To test such targeted treatment and improve results in practice, for the past decade, private outpatients suffering from MDD have been managed by giving SSRIs to patients in demodulated states, catecholaminergics (such as bupropion) to those in deactivated states, and venlafaxine or dual-mechanism combinations (such as fluoxetine and bupropion) to patients in mixed states. In comparing the randomly selected charts of 100 recent targeted-treatment cases with those of a similar group in the 1980s whose treatment was not targeted in this way, researchers found that 95% of patients globally improved in the targeted group compared to 65% in the non-targeted group (Metzner RJ, Symposium 35D).

Quetiapine in Psychotic Patients With Parkinson's Disease

A recent study assessed the effectiveness and tolerability of the atypical agent 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).

Bupropion SR for SSRI-Resistant Major Depression

This study was conducted to determine whether bupropion SR would be beneficial for patients with MDD who failed to respond to 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).

An Overview of the Efficacy and Safety of Rapid-Acting Intramuscular Ziprasidone

Because patients with psychosis and acute agitation often need treatment with intramuscular (IM) conventional neuroleptics such as 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).

Antidepressants: Mechanism of Action and Clinical Response

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); 3) nonselective enhancers of both noradrenergic and serotonergic transmission (e.g., phenelzine [Nardil], amitriptyline, mirtazapine); and 4) no known potent pharmacologic effects to enhance either noradrenergic or serotonergic function (e.g., bupropion, 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 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).

Co-Occurrent Anxiety and Depression: Pharmacotherapy

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).

Long-Term Treatment of Depression With Bupropion SR

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).

Bupropion SR for SSRI-Induced Sexual Dysfunction

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).