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Psychotropic Drug Update The FDA Approval Process: Why rats in a maze are good screeners for anxiolytics

Vol. 1, No. 1 / January 2002

When you want information about a psychotropic drug not yet approved for a specific treatment, where can you turn? This information is not widely available until the drug gets final approval and the details of the package insert or the drug’s labeling have been agreed upon between the pharmaceutical manufacturer and the Food and Drug Administration (FDA).

Pharmaceutical sales representatives are a major source of drug information. Under federal regulations, however, they are not permitted to discuss unapproved products.

This policy holds not only for investigational drugs but also for the “off-label” use of approved drugs. Many medications approved by the FDA for treatment of various mental illnesses are also used “off-label” for other psychiatric disease states. For example, the mood stabilizer divalproex sodium, which is approved for treating mania associated with bipolar disorder, is also commonly used “off-label” to treat behavioral agitation associated with dementia.

The focus of this column will be to provide you with information about new drugs in the pipeline that might one day be on the market. We will focus on drugs that are being developed for a particular psychiatric indication or that are being used “off label” for non-approved indications. We will provide information about a drug’s stage of development, sponsoring company, mechanism of action, and additional therapeutic areas being explored.

For this first column, let’s look at preclinical research—the first of six phases of clinical testing. Each phase involves various methods of experimentation to ultimately determine the drug’s safety and efficacy in humans. (See “How drugs move from the lab to your prescription pad,” below.) It takes approximately 15 years for a drug to advance from preclinical studies to FDA approval, with research and development costs ranging anywhere from $400 million to $500 million depending upon the indication.1

How drugs move from the lab to your prescription pad3

Preclinical studies [4-5 years]

Evaluate safety in both laboratory and animals

Phase I [1-2 years]

  • Recruit 20-80 healthy volunteers
  • Evaluate the drug’s safety
  • Determine a safe dosage range
  • Evaluate the drug’s structure-activity relationships, mechanism of action, and how it metabolizes
  • Identify side effects

Phase II [2 years]

  • Follow 100-300 patients with the indicated disease
  • Evaluate the drug’s effectiveness
  • Evaluate its safety

Phase III [3-4 years]

  • Follow 750-2,000 patients with the indicated disease
  • Confirm the drug’s effectiveness
  • Monitor side effects
  • Compare it to commonly used treatments
  • Collect information that will allow it to be used safely

FDA evaluation [1-2 years]

Phase IV [after approval]

  • Collect information about effectiveness in various populations and any side effects associated with long-term use

Of 5,000 potential drug candidates in preclinical testing, only five will reach the clinical trial stage and of those five agents, only one will eventually be approved. 2

More than 200 drugs for treatment of mental illnesses are being tested in clinical trials worldwide. These include agents for treating dementia, panic disorder, schizophrenia, bipolar disorder, anxiety, posttraumatic stress disorder, depression, eating disorders, drug addiction, and attention deficit disorder.

Preclinical research uses animal models of behavior. Response to the drug in animal models of human illness is important to the screening process, as is measuring its pharmacological mechanism of action.

One commonly used animal model is the elevated plus maze, in which rats explore open and closed ends of a T maze. This is a good screening tool for anxiolytic drugs. Drugs that are likely to be anxiolytic in humans have been shown to reduce the time rats spend in the closed arms and increase their time in the open arms. This reaction has its roots in the natural tendency of rodents in the wild to prefer dark regions in order to avoid predators.

Interestingly, pharmaceutical companies employ this rodent trait to screen compounds to treat anxiety disorders in humans. In this way, newer agents with novel pharmacologic actions could be discovered.

For instance, drugs for treating psychosis have the common property of dopamine 2 receptor antagonism. Certain compounds in the brain interact with and regulate the neurons that possess dopamine 2 receptors. Pharmacologic agents directed towards these compounds might treat psychosis with improved efficacy, such as more rapid onset of action or greater likelihood of response in a larger proportion of individuals. Even more important, novel medications may have better side effect profiles than the currently used agents.

Next time, we will outline drugs in development for treatment of major depression.

Drug brand names

  • Divalproex sodium • Depakote


1. DiMasi JA. Trends in drug development costs, times, and risks. Drug Info J. 1995;29:375-384.

2. Pharmaceutical Research and Manufacturers of America.

3. US Food and Drug Administration Center for Drug Evaluation and Research Handbook.

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