Addendum (January 2007)

This addendum to the booklet Medications for Mental Illness (2005) was prepared to provide updated information on medications in the booklet and results of recent research on medications. This addendum also applies to the Medications Web page document.

Antidepressant Medications

Nefazodone — brand name Serzone

The manufacturer discontinued sales of the antidepressant in the U.S. effective June 14, 2004.

FDA Warnings and Antidepressant Medications

Despite the relative safety and popularity of SSRIs and other antidepressants, some studies have suggested that they may have unintentional effects on some people, especially adolescents and young adults. In 2004, the Food and Drug Administration (FDA) conducted a thorough review of published and unpublished controlled clinical trials of antidepressants that involved nearly 4,400 children and adolescents. The review revealed that 4% of those taking antidepressants thought about or attempted suicide (although no suicides occurred), compared to 2% of those receiving placebos.

This information prompted the FDA, in 2005, to adopt a "black box" warning label on all antidepressant medications to alert the public about the potential increased risk of suicidal thinking or attempts in children and adolescents taking antidepressants. In 2007, the FDA proposed that makers of all antidepressant medications extend the warning to include young adults up through age 24. A "black box" warning is the most serious type of warning on prescription drug labeling.

The warning emphasizes that patients of all ages taking antidepressants should be closely monitored, especially during the initial weeks of treatment. Possible side effects to look for are worsening depression, suicidal thinking or behavior, or any unusual changes in behavior such as sleeplessness, agitation, or withdrawal from normal social situations. The warning adds that families and caregivers should also be told of the need for close monitoring and report any changes to the physician. The latest information from the FDA can be found on their Web site at www.fda.gov.

Results of a comprehensive review of pediatric trials conducted between 1988 and 2006 suggested that the benefits of antidepressant medications likely outweigh their risks to children and adolescents with major depression and anxiety disorders.²⁸ The study was funded in part by the National Institute of Mental Health.

Also, the FDA issued a warning that combining an SSRI or SNRI antidepressant with one of the commonly-used "triptan" medications for migraine headache could cause a life-threatening "serotonin syndrome," marked by agitation, hallucinations, elevated body temperature, and rapid changes in blood pressure. Although most dramatic in the case of the MAOIs, newer antidepressants may also be associated with potentially dangerous interactions with other medications.

Antipsychotic Medications

Below are further details concerning side effects of antipsychotic medications found on pages 5 and 6 in the original Medications for Mental Illness booklet. The medications discussed below are primarily used to treat schizophrenia or other psychotic disorders.

The typical (conventional) antipsychotic medications include chlorpromazine (Thorazine®), haloperidol (Haldol®), perphenazine (Etrafon, Trilafon®), and fluphenzine (Prolixin®). The typical medications can cause extrapyramidal side effects, such as rigidity, persistent muscle spasms, tremors, and restlessness.

In the 1990s, atypical (second generation) antipsychotics were developed that are less likely to produce these side effects. The first of these was clozapine (Clozaril®, Prolixin®), introduced in 1990. It treats psychotic symptoms effectively even in people who do not respond to other medications. However, it can produce a serious but rare problem called agranulocytosis, a loss of the white blood cells that fight infection. Therefore, patients who take clozapine must have their white blood cell counts monitored every week or two. The inconvenience and cost of both the blood tests and the medication itself has made treatment with clozapine difficult for many people, but it is the drug of choice for those whose symptoms do not respond to other typical and atypical antipsychotic medications.

After clozapine was introduced, other atypical antipsychotics were developed, such as risperidone (Risperdal®), olanzapine (Zyprexa®), quietiapine (Seroquel®) and ziprasidone (Geodon®). The newest atypicals include aripiprazole (Abilify®) and paliperidone (Invega®). All are effective and are less likely to produce extrapyramidal symptoms or agranulocytosis. However, they can cause weight gain, which may result in an increased risk of diabetes and high cholesterol level.^1,2

The FDA has determined that the treatment of behavioral disorders in elderly patients with atypical (second generation) antipsychotic medications is associated with increased mortality. These medications are not approved by the FDA for the treatment of behavioral disorders in patients with dementia.

Children and Medications

In October 2006, the FDA approved risperidone (Risperdal®) for the symptomatic treatment of irritability in autistic children and adolescents ages 5 to 16. The approval is the first for the use of a drug to treat behaviors associated with autism in children. These behaviors are included under the general heading of irritability, and include aggression, deliberate self-injury and temper tantrums.

Fluoxetine (Prozac®) and sertraline (Zoloft®) are approved by the FDA for children age 7 and older with obsessive-compulsive disorder. Fluoxetine is also approved for children age 8 and older for the treatment of depression. Fluoxetine and sertraline are selective serotonin reuptake inhibitors (SSRIs). See above for the (FDA) warning concerning SSRIs and other antidepressants.

Research on Medications

In recent years, NIMH has conducted large scale clinical trials to identify effective treatments for schizophrenia, depression, and bipolar disorder. Researchers also wanted to determine the long- term success of different treatments and provide options for patients and clinicians that are based on sound research. The studies were held in many sites across the country to reflect the diversity of real world clinical settings. Details about these studies can be found by clicking on the links below. As additional information about the results of these studies becomes available, updates will be added to the NIMH Web site.

Clinical Antipsychotic Trials of Intervention Effectiveness Study (CATIE)
CATIE compared the effectiveness of typical antipsychotic medications (first available in the 1950s) and atypical antipsychotic medications (available since the 1990s) used to treat schizophrenia.

Sequenced Treatment Alternatives to Relieve Depression (STAR*D)
The main goal of STAR*D was to identify the best “next steps” for people with depression who need to try more than one treatment when the first does not work.

Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)
STEP-BD aimed to obtain long-term data on the chronic, recurrent course of bipolar disorder; identify the best treatments for those with the disorder; obtain data for predicting recurrence of a manic or depressive episode; and study whether adding any one of three medications improved the outcomes for patients with treatment-resistant bipolar disorder.

Treatments for Adolescents with Depression Study (TADS)
TADS compared the use of cognitive-behavioral therapy (CBT) alone, medication (fluoxetine) alone, or a combination of both treatments in adolescents with depression.

These studies provide answers to many, but not all questions about treatment options and help further the understanding of these disorders. NIMH will continue to investigate various approaches to understanding these and other disorders, as well as identify treatments that meet the individual needs of patients.

List of Antidepressant Medications

List of drugs receiving a “black box” warning, other product labeling changes, and a Medication Guide pertaining to pediatric suicidality:

• Anafranil (clomipramine)
• Asendin (amoxapine)
• Aventyl (nortriptyline)
• Celexa (citalopram hydrobromide)
• Cymbalta (duloxetine)
• Desyrel (trazodone HCl)
• Effexor (venlafaxine HCl)
• Elavil (amitriptyline)
• Etrafon (perphenazine/amitriptyline)
• fluvoxamine maleate
• Lexapro (escitalopram hydrobromide)
• Limbitrol (chlordiazepoxide/amitriptyline)
• Ludiomil (maprotiline)
• Marplan (isocarboxazid)
• Nardil (phenelzine sulfate)
• Norpramin (desipramine HCl)
• Pamelor (nortriptyline)
• Parnate (tranylcypromine sulfate)
• Paxil (paroxetine HCl)
• Pexeva (paroxetine mesylate)
• Prozac (fluoxetine HCl)
• Remeron (mirtazapine)
• Sarafem (fluoxetine HCl)
• Serzone (nefazodone HCl)
• Sinequan (doxepin)
• Surmontil (trimipramine)
• Symbyax (olanzapine/fluoxetine)
• Tofranil (imipramine)
• Tofranil-PM (imipramine pamoate)
• Triavil (perphenazine/amitriptyline)
• Vivactil (protriptyline)
• Wellbutrin (bupropion HCl)
• Zoloft (sertraline HCl)
• Zyban (bupropion HCl)

Addendum References

¹Marder SR, Essock SM, Miller AL, et al. Physical Health Monitoring of Patients With Schizophrenia. Am J Psychiatry. August 2004;161(8):1334-1349.

²Newcomer JW. Clinical considerations in selecting and using atypical antipsychotics. CNS Spect. Aug 2005;10(8 Suppl 8):12-20.