(Laurie Barclay, MD, February 2003)

Depressive disorders, including major depression, dysthymia, and bipolar disorder, affect 9.5% of the population annually, or about 18.8 million American adults. One in five individuals suffers from a mood disorder during their lifetime, and women experience depression about twice as often as men.

These disabling conditions can disrupt relationships, careers, and all aspects of daily and family life. If untreated, they often end in suicide, which is now the second leading cause of death among children and adolescents.

In the U.S. alone, costs for depression in 1990 were estimated at over $44 billion. According to the World Health Organization, major depression is the fourth most important cause worldwide of loss in disability-adjusted life years, and will be the second most important cause by 2020.

Symptoms of depression include feelings of sadness, hopelessness, anxiety, or worthlessness; recurrent thoughts of death or suicide; loss of energy and interest; anhedonia; sleep disorders including insomnia and hypersomnia; anorexia or increased appetite; difficulty concentrating, indecisiveness, or forgetfulness; and slowed or unclear thinking.

Depressive illness may result from inherited predisposition, as in the case of bipolar disorder, or from environmental situations, such as stress, mourning, or other loss. Often the interaction of genes and environment may be important. In women, hormonal factors may play a key role. Medical illnesses including stroke, myocardial infarction, and cancer can trigger depressive illness, either because of physiological changes or secondary stress. Whatever the cause, depression is typically linked to imbalances in brain neurochemistry offering an attractive target for drug treatment.

Fortunately, more than 80% of depressed individuals respond to available medications, either alone or in conjunction with psychotherapy or behavioral interventions. These medications include cyclic antidepressants, monoamine oxidase (MAO) inhibitors (MAOIs), and newer "third generation" medications including selective serotonin reuptake inhibitors (SSRIs).

However, adverse effects associated with many of these drugs, late onset of action, and lack of efficacy in some patients have prompted ongoing research into better drug treatments. CenterWatch has identified a pipeline of 30 drugs in various stages of clinical development for depression.

Eli Lilly has received an FDA-approvable letter for Cymbalta (duloxetine hydrochloride), a dual reuptake inhibitor that increases neurotransmitter levels of serotonin and norepinephrine. Data presented at the 15th Annual U.S. Psychiatric and Mental Health Congress in Las Vegas, NV in October 2002 showed that depressed patients taking Cymbalta, 60mg once daily had significantly greater improvement in mood and anxiety measures than did placebo-treated patients by the end of the first week of therapy. These early and rapid improvements were also sustained throughout treatment.

In an open-label trial, 79% of patients achieved response and 69% of patients achieved symptom remission after one year of therapy with Cymbalta 80 mg or 120 mg daily, with good tolerability, few adverse effects, and discontinuation due to adverse events in 17%.

DOV Pharmaceutical is in phase Ib testing of DOV 216,303, a triple uptake inhibitor affecting norepinephrine, serotonin and dopamine. Sepracor's phase II testing of an (R)-sibutramine metabolite is on hold due to budgetary constraints. This isomer of an active metabolite of Abbott’s Meridia is an inhibitor of norepinephrine, dopamine and serotonin reuptake. SLV 308, in phase II testing by Solvay Pharmaceuticals, also affects multiple neurotransmitters including norepinephrine, dopamine, and 5-hydroxytryptamine.

Although Organon has submitted an NDA for Gepirone-ER, formerly Ariza, additional phase III trials are ongoing to address the FDA's response to their submission. This drug is a partial agonist of 5-hydroxytryptamine-1A (5-HT1A), and it was found to be effective and well tolerated for the short-term treatment of major depressive disorder.

In an intention-to-treat population of 204 adults, mean improvement and percentage of responders was significantly greater for Gepirone-ER than for placebo at weeks three and eight. Discontinuation for adverse events occurred in 9.8% of patients in the Gepirone-ER group and in 2.8% in the placebo group. Most adverse events were mild, including dizziness, headache, and gastrointestinal symptoms. There was no reported weight gain, sedation, sexual dysfunction, or serious adverse events.

Eli Lilly has submitted a NDA and corresponding EU paperwork for Zyprexa (olanzapine) for bipolar maintenance. The mechanism of action of this antipsychotic agent may be to inhibit receptors for several CNS neurotransmitters, including dopamine and serotonin type 2 (5-HT2). At the May 2002 American Psychiatric Association meeting, data presented from a randomized, 18-week trial of 58 bipolar patients suggested that relapse into depression following initial therapy occurred in nearly 40% of patients who received a placebo with Depakote or lithium, compared with 23.3% in patients who received Zyprexa in addition to mood stabilizers.

At the same meeting, speakers suggested that augmenting an antidepressant with another drug may help achieve remission more rapidly, avoid discontinuation, and control breakthrough symptoms. Accordingly, Eli Lilly has also submitted an NDA for Zyprexa/Prozac (olanzapine/fluoxetine). In a double-blind, randomized study of more than 800 patients with bipolar depression, efficacy at week one was better in patients receiving Zyprexa alone and in those receiving Zyprexa plus Prozac than in those receiving placebo. After eight weeks, Zyprexa was superior to placebo, and Zyprexa/Prozac was superior to both the placebo and to Zyprexa alone. Induction into mania occurred in about 6% in all groups.

Paxil (paroxetine), an SSRI which has long been a mainstay of antidepressant therapy, is now in phase III testing by GlaxoSmithKline (GSK) as a dispersable tablet formulation. Other SSRIs in phase II testing include Otsuka America Pharmaceutical's OPC-14523, and GSK's Vilazodone (SB 659746A), which also acts as a 5-hydroxytryptamine 1A (5-HT1A) receptor partial agonist.

ORG-12962, Organon's phase II product, is a selective 5-HT2C receptor agonist. Conversely, robalzotan (NAD-299), in phase II testing by AstraZeneca, acts as a 5-HT1A antagonist, and AR-A2, a phase I AstraZeneca product, acts as a 5-HT1B antagonist.

MAOIs in the pipeline include Aurorix (moclobemide), an MAO-A inhibitor in phase II testing by Dainippon Pharmaceutical. Somerset Pharmaceuticals has received an FDA non-approval letter for Emsam (selegiline), an irreversible MAO inhibitor. GW 650250, in phase II by GSK, is a mixed monoamine reuptake inhibitor.

Although most antidepressants to date act on specific neurotransmitters, INN-00835 (netamiftide), in phase III testing by Innapharma, is in a new class of synthetic peptide antidepressants. Unlike earlier generation antidepressants which may not be fully effective for several weeks, the peptide antidepressants appear to have a rapid onset of action within three to five days, and peak effect between seven and 14 days. INN-00835 is available in both subcutaneous and sublingual formulations, and it appears to have an excellent safety profile.

In a study of 55 patients with major depression given netamiftide subcutaneously at 18 mg/day, there was a significant pharmacodynamic correlation between plasma drug concentrations and treatment response, and there were no significant adverse effects. Onset of action was within 48 hours, peak effect was at one week, and efficacy was maintained during four-week follow-up.

An alternative appproach to treating depression is to block the substance P receptor. In phase III testing by Merck, MK-869 appeared promising and was initially thought to be as effective as Paxil, but results were less clear in subsequent studies. Merck, Pfizer and Eli Lilly and Co. are now working on other substance P blockers which may be more potent.

Neurokinin 1 (NK1) antagonists in the pipeline include CP-122.721, in phase II testing by Pfizer; TAK-637, in phase II testing by Takeda Chemical Industries; and GW 597599, in phase I testing by GSK. Corticotropin releasing factor (CRF) receptor antagonists in phase I testing include NBI-34041 by Neurocrine Biosciences, and GSK products SB723620, NBI-37582.

Although 80% of depressed patients respond to currently available treatment, therapeutic issues addressed by this pipeline include more rapid onset of action and fewer adverse effects, which should encourage compliance. Improvements in these areas could result in fewer suicides and less disability for depressed patients, and higher quality of life for both patients and their families.