Therapy Analysis - Depression
What progress has been made?
SSRIs, while making up the bulk of treatment options, are not the only class of antidepressants available to patients. Companies are constantly developing therapeutics with other mechanisms of action, many of which have also reached the market. Obvious examples are Takeda's alprazolam, a benzodiazepine originally used as an anxiolytic and hypnotic, and Sanofi-Aventis' amisulpride, a dopamine D2 and D3 antagonist. The analeptic carbamazepine, a sodium channel antagonist, is also used to control bipolar disorder.
The success already shown with label extensions for existing non-SSRI drugs appear to be encouraging for companies aiming to produce antidepressants with novel pharmacologies. There are currently 73 drug candidates undergoing clinical trials for the treatment of depressive disorders, and 60 of these are non-SSRI-based therapies (Graph 2). A further 59 projects with alternative pharmacologies are in preclinical development, so in the coming months and years there should be a wealth of data to accompany the multitude of theories of depression.
Amongst the non-SSRIs in development is Irish company Amarin's phospholipase A2 inhibitor Miraxion. Phospholipids are important in maintaining the structure of neurons, synapses in particular, and have an important role in signal transduction in response to dopamine, 5-HT, acetylcholine and glutamate. Abnormalities in phospholipid structure suggest a role for these cellular components in depression. Miraxion is currently in Phase III trials for both Huntington's disease and depression, and has already shown efficacy in four Phase II trials. In 70 patients with treatment non-responsive depression, Miraxion at a dose of 1g/day produced improvements in symptoms of depression, including anxiety, sleep disturbances and loss of libido. The Phase III trial programme for Miraxion began in 2006, and it will be interesting to see how the drug fares in this larger-scale trial.
As reprofiling becomes increasingly popular, companies are testing old drugs or their mechanisms in new indications. Aspirin was once hailed as a wonder drug, being successfully used as an analgesic, an antipyretic, and for the prophylaxis of blood clots, heart attacks and strokes. Unfortunately, sideeffects, particularly gastrointestinal damage, have slightly curbed this enthusiasm. However, its mechanism of action is now being applied in the field of depression due to the idea that activation of pro-inflammatory cytokines in the brain may be responsible for depression. Cimicoxib, for example, is a cyclooxygenase-2 (COX-2) inhibitor, currently under development by Affectis Pharmaceuticals, under license from Palau Pharma, for the treatment of pain and depression. Phase I trials showed it to be well tolerated, and it is currently in Phase II trials in depressed patients.
The path for cimicoxib to the market may not be a straightforward one. In 2005, the European Medicines Evaluation Agency recommended that the marketing authorization for valdecoxib (Bextra) be suspended, due to the risk of potentially fatal skin reactions as well as cardiovascular risks seen with Merck & Co's much publicized rofecoxib (Vioxx). Contraindications and label warnings were also added to other COX-2 inhibitors, including celecoxib, etoricoxib, lumiracoxib and parecoxib. While there are still a number of COX-2 inhibitors in development for various indications, particularly inflammatory disorders, cimicoxib is the only one currently in clinical trials for depression. Perhaps if Affectis has success with this approach, other companies will be encouraged to follow suit.
AstraZeneca is taking an interesting approach with its Phase II drug AZD-2327, which targets the delta-opioid receptor. Delta-opioid receptor agonists have already shown antidepressant activity in animal models of the forced swim test, and AZD-2327 is currently being assessed in 80 patients with anxious major depressive disorder. Some delta agonists can produce seizures at high doses, so determining the sideeffect profile for this drug will be paramount.
Sanofi-Aventis, along with a number of other companies, is assessing neurokinin-2 antagonists for their antidepressant activity. In multiple Phase III trials, the drug saredutant was well tolerated; however, results in terms of efficacy were not astounding. In 2/4 trials, it showed no benefit over placebo in terms of improvement of depressive symptoms. Later, a pooled analysis of Phase III data showed a positive short-term benefit for MDD patients as measured by Hamilton-D scores. Sanofi-Aventis is now assessing this drug as a combination therapy with SSRIs.
The neurokinin route has proved less than straightforward for other companies too, including Merck & Co, which discontinued its drug aprepitant, a neurokinin-1 antagonist for the treatment of depression, following a failure to demonstrate efficacy at Phase III. This drug is launched for chemotherapy-induced nausea and vomiting, and is currently in preclinical development for the treatment of HIV/AIDS infection.
It seems that the most successful candidates are still those which directly affect the level of monoamines in the synapse, whether it is by inhibiting the reuptake of these neurotransmitters, or by inhibiting their breakdown. Another popular approach has been to antagonize the inhibitory autoreceptors on the presynaptic membrane that usually slow the release of monoamines in a negative feedback loop. These drugs are variations on a tried and tested theme, and it is worthwhile finding newer alternatives with improved side-effect profiles and specificities. But it seems that finding a truly novel approach to treating depression is still in the early stages, with the majority of compounds being at the preclinical stage, and those in early clinical trials providing mixed results.
