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PRIORITY PRESS - 59th Annual Conference of the Canadian Psychiatric Association

St. John’s, Newfoundland / August 27-30, 2009

A wide variety of antidepressants have been approved for the treatment of Major Depressive Disorder (MDD). When effective, “The lives of many patients have been wonderfully improved,” according to Dr. Roger McIntyre, Associate Professor of Psychiatry and Pharmacology, University of Toronto, Ontario. Unfortunately many, if not most, patients fail to achieve remission with their first antidepressant trial. With each subsequent antidepressant course, the prospect of remission becomes substantially minimized. This reality was reflected by the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study.

Funded by the National Institute of Mental Health, 3671 patients, almost two-thirds of whom had a concurrent psychiatric disorder, were initially treated with citalopram followed by up to four sequential treatments of currently available antidepressants (Rush et al. Am J Psychiatry 2006;163(11):1905-17). Approximately one-third remitted after initial therapy while 30.6% remitted after step 2. However, among patients who required a third and fourth therapeutic course, remission rates were approximately 13% for each step. As the likelihood of remission dropped with each successive treatment, relapse rates ascended. Among patients achieving remission, relapse rates were 33.5%, 47.4%, 42.9% and 50% for each of the four treatment steps, respectively, and relapse rates were higher in patients who improved on treatment but who did not achieve remission (59% to 83%).

In the STAR*D cohort, which was representative of patients seen in clinical practice, the cumulative sustained recovery rate after four different treatments, taking relapse rates into account, was 43%, as pointed out by Dr. Craig T. Nelson, University of California, San Francisco, in his editorial on this study (Am J Psychiatry 2006;163:1864-6).

“Even in an ideal situation with optimal therapy, the vast majority of patients are not achieving remission,” Dr. McIntyre observed, “and this unmet medical need provides us with a clinical rationale for using the atypical antipsychotics [AAPs] in MDD.”

Neurobiology of Depression

In dissecting the neurobiology of depression, Dr. Glenda MacQueen, Professor of Psychiatry, University of Calgary, Alberta, provided insight into why response to antidepressants is so variable and why that response may be improved with select AAPs. “There is almost nothing the brain does that is not affected by depression,” Dr. MacQueen observed. Indeed, depression is “fascinating,” she added, because it affects among the most primitive of human drives—appetite, sexuality and aggression—as well as the most highly evolved domains of cognition, motivation and emotion.

The cingulate cortex, the amygdala and the hippocampus are three key anatomical areas that are clearly implicated in the pathophysiology of depression, as they govern functions that are disregulated in depression. “Multiple neurotransmitters must also be involved because of the array of depressive symptoms,” Dr. MacQueen added. For example, reduced serotonergic turnover has been identified as one of the main neurochemical abnormalities in depression. It therefore makes sense that medications that increase the availability of serotonin in the synapse may modulate that particular neurochemical dysfunction, she indicated. “Similarly, we have some evidence there is a reduction in central noradrenergic activity when patients are depressed, so increasing noradrenalin at the synapse with medications with a noradrenergic component may also be what we are changing,” Dr. MacQueen told delegates.

The role of dopamine has been more difficult to characterize in depression but it is believed that low levels of dopaminergic neurotransmission may be related to depression and that inhibition of dopamine reuptake may in turn modulate abnormalities in the neurotransmitter as well.

As do traditional antidepressants, the AAPs also target serotonin and norepinephrine systems and thus provide a mechanistic rationale for their use in MDD. In addition, neuroprotective molecules, including BDNF, are important for neuronal survival and growth. Any treatment that increases the production of BDNF, as chronic administration of quetiapine has been shown to do, has neuroprotective potential.

By modulating chemical neurotransmission, several AAPs, including olanzapine, clozapine and quetiapine, influence a variety of functions that regulate neuronal resilience and viability, Dr. MacQueen added, and they may also potentiate neuroprotection by inhibiting reactive oxygen species. “We know that multiple anatomic regions are involved in most of our [mental] illnesses and that communication between them is really important,” she commented. “In the same way that there is a lot of clinical overlap between illnesses, we would expect there to be a lot of biochemical overlap as well.”

New Treatment Guidelines

New treatment guidelines for MDD which have just been completed and published will discuss the role of the AAPs in MDD in detail. In the meantime, Dr. Raymond Lam, Professor and Head of Psychiatry, University of British Columbia, Vancouver, noted that there are several therapeutic options available when patients fail an initial antidepressant course. One is an “add-on” strategy with proven agents such as lithium and the AAPs. A second attractive alternative is to switch patients to a different monotherapy agents; to this end, quetiapine extended release (XR) is the only AAP which has been approved for use as monotherapy in MDD.

Approval was based on results from a number of studies (six studies, n<u>></u>1700), one of which included patients with MDD who had been treated with quetiapine XR 150 or 300 mg, duloxetine 60 mg or placebo for six weeks. At the end of six weeks, approximately 55% of patients on both of the two XR doses of the AAP had achieved a response, as had 50% of those receiving duloxetine and 36% of placebo controls. Some 26% of the 150-mg group and 32% of the 300-mg recipients had also gone into remission, as had 32% of duloxetine patients and 20% of placebo controls. “Quetiapine XR also worked on all core symptoms of depression, so it is a true monotherapy antidepressant. We saw effects as soon as one week after treatment was initiated,” Dr. Lam emphasized.

Given that the real goal of depression management is to “get patients well and keep them well,” investigators sought to determine whether the same XR compound would remain effective as maintenance monotherapy and prevent recurrences over a longer follow-up. The maintenance trial consisted of a four- to eight-week open-label treatment interval during which 787 patients were randomized to receive quetiapine XR 50 mg, 150 mg or 300 mg.

The study consisted of three phases. The first was an open label lead-in phase of a four- to eight-week duration. If patients responded to treatment during the open-label phase, they continued on therapy during a stabilization interval of 12 to 18 weeks, at the end of which phase 787 patients were randomized for up to 52 weeks to continue on active therapy or placebo (same dose as taken at the last study visit in the open-label stabilization treatment period). During the randomization treatment period, AAP XR could have been adjusted to 50 mg, 150 mg, or 300 mg/day based on the clinical judgement of the investigator. The primary end point was time to recurrence of a depressive event.

During the randomization phase approximately 14% of patients randomized to AAP XR had experienced a recurrent episode vs. 34% of placebo controls, for a 66% reduction in the risk of recurrence in favour of the extended release AAP (P<0.001). “This is as good as or better than most maintenance studies using traditional antidepressants, and it shows that quetiapine XR is effective for maintenance treatment of depression,” Dr. Lam told delegates.

The most common adverse event reported by patients during the randomized treatment phase was weight gain, which occurred in 9.7% of patients receiving active therapy and 1.6% of placebo patients. However, significant weight gain (<u>></u>7% increase) was not much more likely to occur in the active therapy arm at 5.4% vs. 2.9% among placebo controls. Weight gain with quetiapine XR was less than is often seen with long-term antidepressant use, Dr. Lam observed.

No other significant metabolic effects, including changes in lipids or glucose levels, were noted over the course of the maintenance trial. According to Dr. Lam, this may indicate that the lower doses needed to treat MDD either acutely or as maintenance monotherapy with an AAP may be associated with a lower risk of metabolic and other adverse events such as extrapyramidal effects associated with higher doses.

Summary

MDD tends to be chronic, as even when patients achieve remission with antidepressant therapy, they frequently relapse. A number of strategies may be deployed following treatment failure, one of which is to switch patients to an alternative monotherapy within a different class of agents.