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DOV announces second Phase I trial for depression drug

By Wai Lang Chu , 20-Dec-2005

DOV Pharmaceutical has announced the initiation of a Phase Ib clinical trial, which investigates the potential of its triple reuptake inhibitor candidate for treating depression. The drug's mechanism of action inhibits three separate neurotransmitters serotonin, norepinephrine and dopamine.

This novel combination of properties in a single antidepressant could provide a breakthrough in the treatment of depression. Based upon preclinical studies, triple reuptake inhibitors such as DOV 21,947 have potential utility in treating a wide variety of central nervous system disorders including depression and obesity.

Co-administrating drugs that in combination inhibit reuptake of the three neurotransmitters most closely linked to depression - serotonin, norepinephrine and dopamine - can produce greater overall efficacy than current antidepressants.

 

The trial is a double-blind, randomised, placebo-controlled study conducted in 28 normal volunteers. Subjects in the trial will receive single or multiple doses of DOV 21,947 or placebo for one week.

 

Safety is being measured by adverse reaction occurrences, vital signs, ECGs, clinical lab tests and other measures.

 

DOV said complete dosing would finish by the end of the first quarter of 2006 and results would be forthcoming in the second quarter of 2006.

 

The trial is also set to determine the upper limit dose to be used in the Phase II evaluation of efficacy and safety in depressed outpatients, which commences in the third quarter of 2006.

 

A prior Phase Ib study in normal volunteers conducted by DOV evaluated the safety and pharmacokinetics of repeat doses of DOV 21,947. That trial indicated DOV 21,947 was well-tolerated and no dose-limiting side effects were seen.

 

Norepinephrine, serotonin and dopamine are neurotransmitters that regulate numerous functions in the central nervous system, and imbalances in them have been linked to a number of psychiatric disorders, including depression.

 

Specific transport proteins that remove them from synapses in the brain terminate the actions of these neurotransmitters.

 

Antidepressants are thought to produce their therapeutic effects by inhibiting the uptake activity of one or more of these transport proteins, effectively increasing the concentration of these neurotransmitters at their receptors.

 

DOV 21,947 is structurally related to DOV Pharmaceutical's other depression treatment, 216,303. DOV recently announced efficacy results from a Phase II clinical trial with DOV 216,303.

 

In that trial, patients who completed two weeks of treatment in both the DOV 216,303 and citalopram groups demonstrated reductions from baseline (p<0.0001) in the total HAM-D scores. In both groups, the reductions from baseline in the HAM-D scores were greater than 40 per cent.

 

Currently, the major classes of antidepressant medication are the selective serotonin re-uptake inhibitors (SSRIs), the tricyclic antidepressants (TCAs), the monoamine oxidase inhibitors (MAOIs), and the atypical antidepressants.

 

SSRI medications affect levels of serotonin in the brain. For many people, these medications are the first choice and include Fluoxetine (Prozac), Sertraline (Zoloft), Paroxetine (Paxil) and Citalopram (Celexa).

 

TCAs are often prescribed in severe cases of depression or when SSRI medications don't work. These drugs are not as well known as SSRIs. TCA's include Amitriptyline (Elavil), Clomipramine (Anafranil) and Desipramine (Norpramin).

 

The MAOIs are not used as often since the introduction of the SSRIs. These medications are often used to treat elderly people because their side effects are relatively mild.

 

Because of interactions, the MAOIs may not be taken with many other types of medicines, and some types of foods that are high in tyramine must be avoided as well. The two best-known MAOI's are Phenelzine (Nardil) and Tranylcypromine (Parnate)

 

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