Bupropion re-kindles interest in dopamine strategy for major depression

Main Category: Depression
Article Date: 12 Nov 2005 - 18:00 PDT

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Dopamine is one of the brain's 'feel good' chemicals. Alcohol boosts levels of dopamine, hence the popularity of social drinking. No surprise then, that for the treatment of depression, interest is growing in dopamine as a therapeutic target - at least according to presentations at 'Beyond Serotonin - The Science of Neurotransmitters' a workshop held at the recent European College of Neuropsychopharmacology (ECNP) congress held in Amsterdam.

"Dopamine is the neurotransmitter associated with the 'pleasure system' of the brain. It provides feelings of enjoyment and reinforcement to motivate us to continue certain activities," said Professor Stuart A Montgomery, Emeritus Professor of Psychiatry, Imperial College School of Medicine, London.

"Dopamine was originally known as the 'reward chemical' because it is released during rewarding activities such as food and sex - this neurotransmitter is primarily involved in regulation of attention, motivation, pleasure, and reward. Lack of dopamine is associated with decreased ability for experience pleasure, decreased motivation, decreased attention and cognitive slowing," he added.

According to Dr George Papakostas, Assistant Professor of Psychiatry, Harvard Medical School, USA, dopamine has largely been ignored as a target for pharmacotherapy in major depressive disorder, a situation he finds surprising.

"Very few agents with dopamine activity have been developed to date. Pro-dopaminergic agents represent a potential for treatment breakthrough for major depressive disorder," said Professor Papakostas. "Furthermore," he added, "Agents with prodopaminergic activity may possess efficacy and tolerability advantages over traditional 5HT-selective agents."

New trials

One of the few dopaminergic agents to be developed, the noradrenaline-dopamine reuptake inhibitor (NDRI) bupropion hydrochloride has been available in United States (but not Europe) for major depressive disorder since 1989. GlaxoSmithKline is currently conducting clinical trials with the extended release formation (Bupropion XL) and is planning to file an application in Europe to market bupropion XL for major depressive disorder.

According to Dr Papakostas, clinical studies reported at the ECNP indicate that bupropion XL given once-daily could be an important option for the treatment of patients with moderate to severe major depressive disorder.

The studies show that bupropion XL is effective and well tolerated for depressed patients who present with core symptoms of decreased pleasure, energy and interest. Additional data presented at the meeting also show bupropion XL has similar efficacy to escitalopram, a newer-generation selective serotonin reuptake inhibitor (SSRI), in treating adults with major depressive disorder, also known as depression.

"Furthermore, while shown to be as effective as the SSRI escitalopram, treatment with bupropion XL does not appear to be associated with sexual side effects or sedation that patients often experience during treatment with the SSRIs," said Dr Papakostas.

"Such adverse effects often have a significant and negative impact on patient's quality of life, psychosocial functioning, as well as long-term compliance with treatment."

In a randomised, double-blind, placebo-controlled study, investigators evaluated the efficacy of bupropion XL 300 to 450 mg per day in 274 adult outpatients with major depression characterised by loss of pleasure, interest and energy for eight weeks.

Patients were enrolled in the study with a Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) diagnosis of major depression and Inventory of Depressive Symptomatology (IDS) score of seven on the general interest, energy, pleasure, sexual interest and physical energy items. Investigators used IDS-Self Report (IDS-SR) and IDS-Clinician Rated (IDS-C) questionnaires to assess each subject's change in depressive symptoms during the study.

Patients taking bupropion XL (n=135) had a statistically significantly greater improvement in both the IDS-SR and IDS-C total score compared to patients on placebo (n=139) at week 8 (p=.018 and p<.001, respectively).

Patients treated with bupropion XL reported significant improvement at the end of the first week of treatment. Patients in the bupropion XL arm had a 41 percent remission rate, or subsiding of depressive symptoms, compared to a 27 percent remission rate for patients on placebo (p=.01, bupropion versus placebo).

"Low energy, lack of interest or poor interest, and the inability to experience pleasure are core symptoms of depression that are not always completely alleviated by existing treatments and; thus, can continue to impair patients' functioning, and prolong patient suffering," said Dr. Papakostas. "The data presented demonstrate that bupropion XL is well tolerated and effective in alleviating these particular depressive symptoms."

Two classes compared

The efficacy of two antidepressants from different classes - bupropion XL, an NDRI that acts on noradrenaline and dopamine, and escitalopram, an SSRI that affects serotonin - was examined in patients with moderate to severe major depressive disorder in a double-blind, placebo-controlled study. Investigators randomised 424 adult outpatients to receive either bupropion XL 300-450 mg per day, escitalopram 10-20 mg per day or placebo for eight weeks.

Over the study period, efficacy was evaluated on a weekly or biweekly basis using the investigator-rated Hamilton Depression Rating Scale (HAMD-17) and the Hospital Anxiety and Depression Scale (HADS), which is a self-evaluation completed by study participants.

Patients treated with bupropion XL (n=138) and escitalopram (n=149) achieved a mean difference from baseline HAMD-17 score (Week 8) of 0.94 (95% CI -0.7, 2.6) demonstrating comparable efficacy between the two treatments. On the HADS, bupropion XL and escitalopram patients showed similar total score mean improvements from baseline(-11.0 versus -11.5, respectively).

Patient response to treatment (responder rate), subsiding of their depressive symptoms (remission rate) and mean change in severity of their depression scores (global severity scores) were similar for patients on bupropion XL and escitalopram. With the exception of escitalopram's negative impact on sexual function, both bupropion XL and escitalopram were well tolerated.

Written by:
Ian Mason
ianmason@ntlworld.com