Bipolar disorder is characterized by episodes of mania, hypomania, and depression. Recurrences of manic or (more frequently) depressive symptoms are common. About 15-20% of patients with bipolar disorder die by suicide.

In our article on Drugs for Depression, we should have included tardive dyskinesia (TD) in our list of adverse effects of second-generation antipsychotic (SGA) drugs. TD, which is more commonly associated with first-generation- antipsychotics, can also occur in patients taking an SGA, especially with prolonged use. A metaanalysis found that the annualized incidence of TD was 2.6% in SGA users (M Carbon et al. World Psychiatry 2018; 17:330). Older adults are at increased risk.

The FDA has approved the oral GABA_A receptor modulator zuranolone (Zurzuvae – Sage Therapeutics/Biogen) for treatment of postpartum depression (PPD). Zuranolone is the second drug to be approved for this indication; brexanolone (Zulresso), another GABA_A receptor modulator, was approved for IV treatment of PPD in 2019.

A selective serotonin reuptake inhibitor (SSRI) is generally used for initial treatment of major depressive disorder (MDD). A serotonin-norepinephrine reuptake inhibitor (SNRI), bupropion (Wellbutrin SR, and others), and mirtazapine (Remeron, and others) are reasonable alternatives. Improvement in symptoms can occur within the first two weeks of treatment with these drugs, but a substantial benefit may not be achieved for 4-8 weeks.

The FDA has approved the second-generation antipsychotic drug cariprazine (Vraylar — Abbvie) for adjunctive treatment of major depressive disorder (MDD) in adults. Cariprazine was previously approved for treatment of schizophrenia and bipolar depression, and for acute treatment of manic or mixed episodes associated with bipolar I disorder.

The FDA has approved an extended-release fixed-dose combination of dextromethorphan and bupropion (Auvelity – Axsome) for treatment of major depressive disorder (MDD) in adults.

The oral second-generation antipsychotic drug lumateperone (Caplyta – Intra-Cellular Therapies), which was approved by the FDA in 2020 for treatment of schizophrenia, is now approved for use as monotherapy or as an adjunct to lithium or valproate for treatment of depressive episodes associated with bipolar I or II disorder in adults.

The motor symptoms of Parkinson's disease (PD) are caused primarily by degeneration of dopaminergic neurons in the substantia nigra. The nonmotor symptoms of the disease are thought to be caused by degeneration of other neurotransmitter systems. No disease-modifying drugs are available for treatment of PD.

Esketamine (Spravato – Janssen), an intranasal N-methyl-D-aspartate (NMDA) receptor antagonist that was previously approved by the FDA for treatmentresistant depression,1 has now been approved for treatment of depressive symptoms in adults with major depressive disorder (MDD) and acute suicidal ideation or behavior. Esketamine is the S-enantiomer of the anesthetic ketamine (Ketalar, and generics). It is the first drug to be approved for this indication. Most clinical trials of antidepressants have excluded patients with acute suicidal ideation.

Complete remission of symptoms is the goal of treatment for major depressive disorder; a partial response is associated with an increased risk of relapse. Improvement in symptoms can occur within the first two weeks of treatment with an antidepressant, but it may take 4-8 weeks to achieve a substantial benefit. Following successful treatment of a first major depressive episode, antidepressant treatment should be continued at the same dose for at least 4-9 months to consolidate recovery. In patients with recurrent depressive episodes, long-term maintenance treatment can reduce the risk of relapse.

Cannabis (marijuana) contains more than 60 pharmacologically active cannabinoids; delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best known. THC is the main psychoactive constituent of cannabis. CBD, unlike THC, does not produce intoxication or euphoria.

Turmeric is a spice derived from the Curcuma longa plant. Dietary supplements and foods containing turmeric are widely promoted for relief of pain and to improve joint mobility, immunity, digestion, cardiovascular health, depression, anxiety, memory, and cognition.

The FDA has approved the GABA_A receptor modulator brexanolone (Zulresso – Sage Therapeutics) for IV treatment of postpartum depression (PPD). Brexanolone is the first drug to be approved by the FDA for this indication.

The FDA has approved esketamine (Spravato – Janssen), an N-methyl-D-aspartate (NMDA) receptor antagonist, for intranasal treatment (in conjunction with an oral antidepressant) of adults with treatment-resistant depression (TRD). This is the first FDA approval for esketamine, which is the S-enantiomer of the intravenous anesthetic ketamine (Ketalar, and generics). In recent years, IV ketamine has been increasingly used (off-label) for treatment of TRD.

Monitoring adherence of psychiatric patients to oral medication may be especially difficult. The FDA has approved Abilify MyCite (Otsuka/Proteus), an aripiprazole tablet with an embedded sensor that tracks when patients take the medication. It is indicated for treatment of adults with schizophrenia, bipolar disorder, or major depressive disorder. Abilify MyCite is the first drug with a digital ingestion tracking system to be approved in the US.

Bipolar disorder is characterized by intermittent episodes of mania and/or depression. Even with maintenance treatment, recurrences of manic or (more frequently) depressive episodes are common. Some of the drugs and dosages recommended here have not been approved by the FDA for use in bipolar disorder.

Complete remission of symptoms is the goal of antidepressant therapy; partial response is associated with an increased risk of relapse. Improvement can occur within the first two weeks of drug therapy, but it may take 4-8 weeks to achieve a substantial benefit. Fewer than 50% of patients with depression respond to first-line pharmacotherapy, and the rate of response decreases with each subsequent drug trial. Following remission after a first episode of depression, many experts recommend continuing antidepressant treatment at the same dose for at least 6-12 months to consolidate recovery. For patients with recurrent depressive episodes, long-term maintenance therapy can reduce the risk of recurrence.

The FDA has approved the oral, once-daily, second-generation antipsychotic brexpiprazole (Rexulti – Otsuka/Lundbeck) for treatment of schizophrenia and as an adjunct to antidepressants for treatment of major depressive disorder (MDD). Aripiprazole (Abilify), a structurally similar second-generation antipsychotic also comarketed by Otsuka (with BMS), recently became available generically.

The FDA has approved the marketing of another extended-release brand-name formulation of the serotonin and norepinephrine reuptake inhibitor (SNRI) desvenlafaxine (Khedezla – Par/Osmotica) for treatment of depression. It is the third extended-release formulation of desvenlafaxine to become available in the US. Khedezla was approved using a 505(b)(2) application, a new drug application (NDA) that relies upon the FDA's findings of safety and/or effectiveness for a previously approved drug.

Khedezla does not appear to offer any advantage over the other extended-release formulations of desvenlafaxine. There is no evidence that any formulation of desvenlafaxine is more effective for treatment of depression than other SNRIs or any SSRI, which are available in less expensive generic formulations.1

1. Drugs for psychiatric disorders. Treat Guidel Med Lett 2013; 11:53.

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The FDA has approved vortioxetine (vor" tye ox' e teen; Trintellix – Takeda/Lundbeck), a new serotonergic drug, for treatment of major depressive disorder. Like vilazodone (Viibryd), another serotonergic antidepressant, it has been claimed to have a low incidence of sexual side effects and no significant effect on weight.

The motor symptoms of Parkinson's disease (PD) are caused primarily by progressive degeneration of dopaminergic neurons in the substantia nigra. The non-motor symptoms of the disease are thought to be caused by degeneration of other neurotransmitter systems.

The FDA has approved a low-dose formulation of the selective serotonin reuptake inhibitor (SSRI) paroxetine mesylate (Brisdelle – Noven Therapeutics) for treatment of moderate-to-severe vasomotor symptoms associated with menopause. It is the first non-hormonal therapy to be approved for this indication. Paroxetine mesylate (Pexeva) and paroxetine hydrochloride (Paxil, and generics) are marketed in higher doses for treatment of depression and other psychiatric disorders.

In 2011, the FDA asked the manufacturers of the selective serotonin reuptake inhibitor (SSRI) citalopram (Celexa, and generics) to lower the maximum daily dosage of the drug because of a dose-related increase in the QT interval. Since then, some of our readers have asked whether escitalopram (Lexapro, and generics), the active enantiomer of citalopram, could have the same effect.

Drugs are not the only treatment for psychiatric illness. Psychotherapy remains an important component in the management of these disorders, and cognitive behavioral therapy (CBT) can be used for many of them as well. Electroconvulsive therapy (ECT) has a long history of efficacy and safety when drugs are ineffective or cannot be used.

The FDA has asked Impax Laboratories/Teva Pharmaceuticals to stop production and distribution of Budeprion XL 300 mg, a generic extended-release formulation of the antidepressant bupropion (Wellbutrin XL), because it has found that Budeprion XL 300 mg releases bupropion more rapidly than Wellbutrin XL 300 mg, the original brand name product. Patients switched from the brand name to the generic formulation have complained for years that the generic was less effective and caused more side effects than the original formulation. In 2007, ConsumerLab.com, an independent laboratory, conducted dissolution testing of Budeprion XL, which uses a matrix for slow release, and Wellbutrin XL, which uses a membrane. According to the test results, the Budeprion XL matrix released more bupropion in the first 4 hours than the Wellbutrin XL membrane did.1 The FDA decided to conduct its own studies of Budeprion XL 300 mg and arrived at a similar conclusion. The original approval of the generic formulation was based on pharmacokinetic tests conducted on 150-mg tablets of the Impax/Teva formulation, with results extrapolated to the 300-mg tablet.

Bupropion is often used as an alternative to a selective serotonin reuptake inhibitor (SSRI) or another antidepressant because it does not cause sexual dysfunction, sedation, or weight gain.2 It is also used as an aid in smoking cessation.3 It is contraindicated in patients at increased risk of seizures (including patients with a history of an eating disorder). Other 300-mg formulations of generic extended-release bupropion have not been associated with post-marketing complaints and continue to be available.

1. Wellbutrin versus generic bupropion. Med Lett Drugs Ther 2008; 50:54.

2. Drugs for depression and bipolar disorder. Treat Guidel Med Lett 2010; 8:35.

3. Drugs for tobacco dependence. Treat Guidel Med Lett 2008; 6:61.

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A Medical Letter reader asked about the use of the nutritional supplement 5-hydroxytryptophan (5-HTP) for treatment of depression. It is sold in health food stores, pharmacies and on-line for many indications including depression, mood enhancement, emotional well being, and promotion of normal sleep.

5-HTP is the intermediate metabolite in the biosynthesis of serotonin from L-tryptophan.1 Many small studies in the 1970’s and 1980’s found 5-HTP helpful in the treatment of depression, but a Cochrane Review of 108 studies in patients with depression or dysthymia using 5-HTP or L-tryptophan found that the quality of the data was insufficient to establish the efficacy or safety of these products.2

In 1989, contaminated L-tryptophan supplements were implicated as the causative agent in an outbreak of eosinophilia-myalgia syndrome (EMS), which was associated with some deaths. There is no evidence that 5-HTP could cause the syndrome.

There is no acceptable evidence that 5-HTP or L-tryptophan offers any advantage over a selective-serotonin reuptake inhibitor (SSRI) for treatment of depression. Taking 5-HTP or L-tryptophan in addition to an SSRI could cause serotonin syndrome.

There is no good reason to take 5-HTP or L-tryptophan.

1. N Iovieno et al. Second-tier natural antidepressants: review and critique. J Affect Disord 2010; 130:343.

2. K Shaw et al. Tryptophan and 5-hydroxytryptophan for depression. Cochrane Database Syst Rev 2002; (1): CD003198.

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Augmentation with a second-generation (atypical) antipsychotic is a treatment option for patients with major depressive disorder (MDD) whose symptoms persist following antidepressant monotherapy. Aripiprazole (Abilify), olanzapine in a fixed-dose combination with fluoxetine (Symbyax), and extended-release quetiapine (Seroquel XR) have been approved by the FDA for such use.

Vilazodone (Viibryd – Forest), a selective serotonin reuptake inhibitor (SSRI) and partial 5-HT_1A receptor agonist, has been approved by the FDA for treatment of depression. It has been claimed to have no sexual side effects and not to cause weight gain.

Parkinson’s disease (PD) is caused primarily by progressive degeneration of dopamine-containing neurons in the substantia nigra. Dopamine itself cannot be used to treat PD because it does not cross the blood-brain barrier.

The FDA has approved the marketing of an extended-release formulation of trazodone (Oleptro – Angelini Labopharm) for treatment of major depressive disorder in adults. Immediate-release trazodone has been available for treatment of depression for many years, but is used mostly in low doses for its sedating effects.

The antipsychotic drugs listed in Table 1 on the next page are more effective for treating the “positive symptoms” of schizophrenia (hallucinations and delusions) than the “negative symptoms” (apathy, social withdrawal, and blunted affect). Some symptoms of schizophrenia and acute psychoses may improve rapidly after treatment with antipsychotic drugs, but chronic schizophrenia improves slowly over many weeks and some patients may continue to improve for months. Most patients with chronic schizophrenia require prolonged maintenance therapy, but the risk of tardive dyskinesia and adverse metabolic effects must be kept in mind.

Drugs are not the only treatment for mood disorders. Psychotherapy remains an important component in the management of these disorders, and electroconvulsive therapy (ECT) has a long history of efficacy and safety when drugs are ineffective, poorly tolerated or cannot be used. Some drugs are recommended here for indications that have not been approved by the FDA.

L-methylfolate (Deplin — Pamlab) is a “medical food” marketed for adjunctive use in depression or schizophrenia in patients with suboptimal folate levels. It is available only by prescription.

Use of a selective serotonin reuptake inhibitor (SSRI) is common in women taking tamoxifen (Nolvadex, and others) for breast cancer, both to treat depression and to decrease hot flashes. However, tamoxifen must be metabolized by CYP2D6 to become pharmacologically fully active (MJ Higgins et al. J Natl Compr Canc Netw 2009; 7:203), and the SSRIs fluoxetine (Prozac, and others) and paroxetine (Paxil, and others) are strong inhibitors of CYP2D6. Sertraline (Zoloft, and others) inhibits CYP2D6 to a lesser extent. Citalopram (Celexa, and others) and escitalopram (Lexapro), the 2 other SSRIs approved for treatment of depression, are only weak inhibitors of CYP2D6.

Two observational studies presented at a recent meeting of the American Society of Clinical Oncology (45th annual meeting, May 29-June 2, 2009, Orlando, FL abstracts CRA508, CRA509) examined the effect of strong inhibitors of CYP2D6 on the success rate of tamoxifen in preventing recurrence of breast cancer. One found that women who took fluoxetine, paroxetine or sertraline (or bupropion, duloxetine, terbinafine, quinidine or long-term diphenhydramine) with tamoxifen had a higher 2-year recurrence rate (13.9% vs. 7.5%). The other study found no association between cancer recurrence and use of a CYP2D6 inhibitor.

There is no good evidence that any one SSRI is more effective than any other for treatment of depression. For women who are taking tamoxifen and need to begin treatment with an SSRI to treat depression, citalopram or escitalopram might be the safest choice (Treat Guidel Med Lett 2006; 4:35). Use of an SSRI to treat hot flashes in women taking tamoxifen should probably be reconsidered.

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The FDA has cleared a new device for treatment of major depressive disorder (MDD) resistant to antidepressant medication. The NeuroStar TMS System (Neuronetics) produces pulsed magnetic fields that can induce electrical currents in the brain. Unlike electroconvulsive therapy (ECT), it does not require anesthesia or induction of seizures. Other similar devices are under development.

No truly new drugs have been approved for treatment of asthma since omalizumab (Xolair) in 2003, but some randomized controlled trials of older drugs have been published, and new guidelines have become available.

Depression occurs in up to 20% of pregnant women, and the use of selective serotonin reuptake inhibitors (SSRIs) in these women has been increasing. Maternal depression has itself been associated with intrauterine growth problems and low birth weight, so the risks of exposure to antidepressants during pregnancy must be weighed against the risks of untreated depression, which also include self-harm, poor bonding and poor parenting. SSRIs available in the US for treatment of depression include citalopram (Celexa, and others), escitalopram (Lexapro), fluoxetine (Prozac, and others), paroxetine (Paxil, and others) and sertraline (Zoloft).

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The FDA has approved the marketing of desvenlafaxine (Pristiq - Wyeth), the main active metabolite of venlafaxine (Effexor, and others - Wyeth), for treatment of major depressive disorder. Venlafaxine, a norepinephrine and serotonin reuptake inhibitor (SNRI), is available generically as an immediate-release tablet. Venlafaxine extended-release capsules (Effexor XR) are scheduled to go off-patent in 2010.

Drugs are not the only treatment for psychiatric illness. Psychotherapy remains an important component in the management of these disorders, and cognitive behavioral therapy (CBT) is used for many of them as well. Electroconvulsive therapy (ECT) has a long history of efficacy and safety when drugs are ineffective or cannot be used.

The FDA recently approved the monoamine oxidase inhibitor (MAOI) selegiline in a transdermal (patch) formulation (Emsam - Bristol-Myers Squibb/Somerset) for treatment of major depressive disorder. Selegiline is also available in an oral formulation (Eldepryl, and others) for treatment of Parkinson's disease.

A device that stimulates the vagus nerve was approved by the FDA in July 1997 for treatment of refractory epilepsy and is now considered "approvable" for treatment-resistant depression.

Dehydroepiandrosterone (DHEA), an endogenous adrenal steroid, is marketed as a dietary supplement in the US. It is widely promoted to reverse the effects of aging (loss of muscle, memory and libido) and has been used by athletes as a substitute for anabolic steroids. DHEA is banned by the International Olympic Committee, National Collegiate Athletic Association, National Football League and other sports organizations, but it was specifically exempted from becoming a controlled substance in the Anabolic Steroid Control Act of 2004.

An extended-release formulation of carbamazepine, available since 1997 for treatment of epilepsy, has now been approved under a new name, Equetro, for acute mania and mixed episodes of bipolar disorder. Although the drug was effective in some patients for up to 6 months, it has not been approved for maintenance treatment. Carbamazepine has not been shown to be more effective than lithium or valproate, and it can cause serious adverse effects.

Duloxetine hydrochloride (Cymbalta - Lilly), a selective serotonin and norepinephrine reuptake inhibitor (SNRI), has been approved by the FDA for treatment of major depressive disorder in adults, and more recently for diabetic peripheral neuropathy as well. The Medical Letter will review its role in diabetic neuropathy in a future issue.

Gabapentin (Neurontin - Pfizer), which has been available in the US since 1994, is approved by the FDA only for treatment of partial epilepsy and postherpetic neuralgia, but is widely used off-label for a number of other indications, especially neuropathic pain syndromes. According to one report, among Medicaid recipients in Florida receiving gabapentin, 71% of prescriptions were for chronic pain and 8% for seizures and neuralgia ("The Pink Sheet" February 2, 2004; 66:30).

Venlafaxine (Effexor, Effexor XR - Wyeth), an antidepressant that inhibits both norepinephrine and serotonin reuptake, was first approved by the FDA in 1993. It has been used mainly as a second-line agent for patients who have not responded to a selective serotonin reuptake inhibitor (SSRI). Some Medical Letter consultants have had the clinical impression that venlafaxine is more effective than an SSRI, particularly for patients with severe, classic depression (melancholia), and believe it should be considered a first-line drug (Treatment Guidelines from the Medical Letter 2003, 1:69). Is venlafaxine more effective than an SSRI for treatment of depression?

Five different selective serotonin reuptake inhibitors (SSRIs) are promoted for treatment of depression and a sixth (fluvoxamine) for use in obsessive compulsive disorder. Which one should we prescribe for our patients?

A "Dear Colleague" letter from the UK's Committee on Safety of Medicines advised physicians, on the basis of unpublished data, not to use paroxetine (Paxil in the US; Seroxat in the UK) to treat children and adolescents with depression because of possible increased risk of suicidal behavior. This review describes the efficacy and safety of SSRIs in children.

The number of drugs marketed for psychiatric indications has increased sharply in recent years. The recommendations in this article are based on the results of controlled trials and on the experience and opinions of Medical Letter consultants. Interactions with other drugs can be found in The Medical Letter Handbook of Adverse Drug Interactions, 2003.

Escitalopram (Lexapro - Forest), the active S-enantiomer of racemic citalopram (Celexa - Forest), a selective serotonin reuptake inhibitor (SSRI), was recently approved by the FDA for treatment of depression. The manufacturer plans to stop promoting Celexa in favor of Lexapro; Celexa will continue to be available for patients already taking it.

The FDA has approved a new formulation of fluoxetine for once-weekly maintenance treatment of depression in patients who have responded to daily fluoxetine (Prozac).

The number of drugs marketed for treatment of depression has increased in recent years. Antidepressants are generally also effective for treatment of anxiety.

Many readers have asked the Medical Letter to evaluate St. John's wort, an herbal extract now widely sold in health food stores and pharmacies, for its effectiveness and safety in the treatment of depression. St. John's wort is licensed in Germany for treatment of anxiety, depression and insomnia. In the USA, it is considered a dietary supplement and has not been evaluated by the FDA.

The number of new drugs marketed for psychiatric indications has increased sharply in recent years. The recommendations in this article are based on the results of controlled trials and on the experience and opinions of Medical Letter consultants. Interactions with other drugs can be found in The Medical Letter Handbook of Adverse Drug Interactions, 1997.

Mirtazapine (mir taz a peen; Remeron - Organon) has been approved by the US Food and Drug Administration for treatment of depression. A tetracyclic piperazinoazepine, it is an analog of mianserin, an antidepressant available in Europe, but is structurally unrelated to antidepressants previously available in the USA.

Nefazodone (Serzone - Bristol-Myers Squibb) was recently approved by the US Food and Drug Administration for treatment of depression. A phenylpiperazine, nefazodone is chemically related to trazodone (Desyrel, and others).

Venlafaxine hydrochloride (Effexor - Wyeth-Ayerst) was recently approved by the US Food and Drug Administration for treatment of depression. An aminomethyl-benzyl- cyclohexanol, it is chemically related to bupropion (Wellbutrin).

Paroxetine (Paxil - SmithKline Beecham), a new selective serotonin reuptake inhibitor (SSRI), is now available in the USA. Two other SSRIs, fluoxetine (Prozac - Medical Letter, 30:45, 1988; 32:83, 1990) and sertraline (Zoloft - Medical Letter, 34:47, 1992), were approved previously.

Since the introduction of fluoxetine (Prozac - Medical Letter, 30:45, 1988), bupropion (Wellbutrin - Medical Letter, 31:97, 1989), sertraline (Zoloft - Medical Letter, 34:47, 1992) and paroxetine (Paxil - this issue), the choice of an antidepressant has become more difficult. Should these widely prescribed new drugs replace tricyclic antidepressants such as amitriptyline (Elavil, and others), imipramine (Tofranil, and others), or nortriptyline (Aventyl, and others) for treatment of most patients with depression?

Sertraline (Zoloft - Roerig), a serotonin reuptake inhibitor, was recently approved for marketing by the US Food and Drug Administration for treatment of depression. Another serotonin reuptake inhibitor, fluoxetine (Prozac), is prescribed more frequently in the USA than any other antidepressant (Medical Letter, 32:83, 1990).

In the short time since fluoxetine (Prozac - Lilly) first became available in the USA (Medical Letter, 30:45, 1988), it has become the most frequently prescribed of all antidepressants. Some recent reports, however, have questioned its safety.

The 1990 labeling for Norpramin, the Merrell Dow brand of the tricyclic antidepressant desipramine, reports the occurrence of sudden death in an eight-year-old child treated with the drug. Desipramine is also available as Pertofrane (Rorer) and generically.

Bupropion (Wellbutrin - Burroughs Wellcome) was recently marketed in the USA for treatment of depression. First approved by the Food and Drug Administration in late 1985, the drug was withdrawn from the market in early 1986 because of a high incidence of seizures in one study.

Patients with Parkinson's disease have a deficiency of the neurotransmitter dopamine, a catecholamine. Dpamine itself cannot be used to treat the disease because it does not cross the blood-brain barrier, but its metabolic precursor, levodopa, does cross into the brain and is converted to dopamine by a decarboxylase present both in the brain and in the intestinal tract (JM Cedarbaum, Clin Pharmacokinet, 13:141, 1987).

Clomipramine (Anafranil - Ciba-Geigy), a tricyclic antidepressant, is now available for treatment of obsessive compulsive disorder (OCD) in accordance with the new US Food and Drug Administration (FDA) procedure for promising investigational drugs (FE Young et al, JAMA, 259:2267, 1988). In other countries, clomipramine has been widely used for many years for treatment of depression.

Fluoxetine (Prozac - Dista), a phenylpropylamide, is the first serotonin-reuptake blocker introduced in the USA for treatment of . It is being promoted as causing fewer adverse effects than other antidepressants. Claims of greater safety and patient tolerability have often been made for new non-tricyclic antidepressants in recent years, but unpredicted adverse effects have emerged with widespread use, including priapism with trazodone (Desyrel - Medical Letter, 26:35, 1984) and fatal hemolytic anemia with nomifensine (Merital - Medical Letter, 27:73, 1985).