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Journal of Clinical Psychopharmacology
February 2008 – Volume 28 – Issue 1 – p 101-102
To the Editors:
On May 2, 2007, the US Food and Drug Administration expanded black box warnings of all antidepressant medications to include information about an increased risk of suicidality in young adults aged 18 to 24 years. The advisory committee made this decision after evaluating the results of meta-analyses of participants enrolled in 372 randomized antidepressant trials over the past 20 years.
A differential risk of antidepressant induced suicidality among various age groups has previously been reported in the literature. Martinez et al1 found an increased risk of suicidality with selective serotonin reuptake inhibitors (SSRIs) compared with tricyclic antidepressants in patients 18 years and younger.
Another case-control study found that severely depressed patients aged 6 to 18 years treated with antidepressants were at a significantly higher risk of suicide attempts and completed suicides compared with adults.2 Elderly patients have been found to have nearly 5-fold higher risk of completed suicide during the first month of therapy with SSRIs.3
The study also reported consistent results when venlafaxine was included in the analyses with SSRIs. Venlafaxine (which inhibits reuptake of 5-hydroxytryptamine [5-HT] and norepinephrine [NE] at higher doses) shares a similar proposed mechanism of action as duloxetine.4
Duloxetine has been shown to have 100-fold higher affinity for human 5-HT transporters and at least 300-fold higher affinity for NE transporters in vitro compared with venlafaxine.5 It is unknown whether more potent 5-HT and NE blockade correlates with increased suicidal ideation during initial antidepressant treatment.
Mr A is a 37-year-old married white man admitted for a major depressive episode after his wife discovered that he bought equipment to poison himself with carbon monoxide. Two months before admission, the patient started treatment with duloxetine for chronic back pain. The dose was later increased to 60 mg/d for additional pain relief. Two weeks before admission, duloxetine was increased again to 90 mg/d. Seven days later, the patient reported having thoughts of suicide and was admitted to the University of Kansas Medical Center psychiatry unit in August 2005.
Mr A had no previous psychiatric hospitalization or any outpatient psychiatric care. Before taking duloxetine, Mr A had never taken any psychotropic medications. He did not have prior suicidal attempts or suicidal ideations. No signs of character pathology or poor impulse control were elicited. The patient did have 3 first-degree relatives with an affective disorder but no family history of suicide.
Upon admission to inpatient psychiatry, Mr A appeared severely distressed. He continuously repeated the phrase: B My wife deserves better.[ Apparently, the patient developed a romantic interest with a woman at work. He denied any infidelity but started having guilt about the thoughts. Mr A’ s target symptoms also included anxiety, insomnia, and irritability. The patient was unable to state exactly why he wanted to commit suicide. Mr A reported that he did not feel sad and could think of no reason for him to wish to die. He described a loving and supportive marriage.
Mr A was steadily employed with no recent additional social stressors.
On Day 1 of hospitalization, duloxetine was tapered off, and escitalopram was started. The patient was also started on risperidone 1 mg at bedtime for psychic agitation. Within days of discontinuing duloxetine, Mr A reported decreased anxiety and no thoughts of suicide. After 3 days, he was discharged home on escitalopram and risperidone.
Mr B is a 63-year-old well-educated married white man admitted to the University of Kansas Medical Center psychiatry unit in August 2005. The patient presented with a chief complaint of B I started having thoughts of suicide.[ Mr B had a previous history of major depressive disorder (MDD) successfully treated with fluoxetine. Four months before admission, the patient did not feel depressed and stopped taking fluoxetine.
Depression reoccurred; 2 weeks before admission, the patient was started on duloxetine at an initial dose of 30 mg/d for mild symptoms of depression (eg, fatigue, insomnia, and sadness). The patient felt no significant improvement, and duloxetine dose was increased to 60 mg/d. During this period, the patient was not taking any other medications. The patient soon started having obsessive thoughts about suicide together with severe anxiety, insomnia, and irritability.
He was unable to explain why he was having thoughts of wanting to die. Mr B then sought the help of an outpatient psychiatrist, and duloxetine was tapered off, and fluoxetine was restarted. Two days later, the patient expressed concern about having the thoughts of suicide, and his psychiatrist recommended inpatient hospitalization.
Upon admission, fluoxetine was increased to 60 mg/d, and mirtazapine was added at bedtime for depression and insomnia.
Five days after stopping duloxetine, the patient reported decreased anxiety and no longer had thoughts of death or suicide.
Mr B did not have a history of a suicide attempt or any thoughts of suicide before treatment with duloxetine. No symptoms suggestive of character pathology or poor impulse control were noted. The patient did have a first-degree relative with a history of suicide. Mr B described having a loving and stable family. The patient did experience a recent increase in workload after a coworker was let go. He did not attribute the depressive symptoms to work related stress.
Ms C is a 39-year-old married white woman with a 20-year history of MDD and chronic fatigue syndrome. She was admitted to inpatient psychiatry after she and her husband became concerned about her worsening depressive symptoms. This was her first psychiatric hospitalization because her depressive symptoms had been well controlled with antidepressant monotherapy, including fluoxetine and escitalopram (discontinued by the patient 10 months before admission). She had attempted suicide by carbon monoxide poisoning 10 years before this admission, escaping from her garage after developing a headache.
Three months before admission, Ms C had been started on duloxetine 30 mg/d. Duloxetine was titrated to 90 mg/d over the next 4 weeks. She reported experiencing almost no change in her depressive symptoms but had noticed an improvement in weakness and pain associated with chronic fatigue syndrome. Duloxetine was increased again to 120 mg/d. At a follow-up visit 6 weeks later, her depressive symptoms had worsened; she felt more hopeless, worried, and isolated, with increased anxiety and poor sleep. Six days later, in February 2006, she was admitted to the University of Kansas Medical Center psychiatry unit.
At the time of admission, she reported having thoughts of suicide and of her children drowning in their swimming pool. She emphatically denied any intentions of killing her children but was filled with fear that if they should drown, she would have lost her remaining reason for wanting to live.
She reported feeling drugged and losing control of her thoughts. Her husband reported that these thoughts were uncharacteristic of his wife and a source of great concern. During treatment with duloxetine, Ms C also developed a significant problem with urinary retention. Duloxetine was tapered over several weeks, resulting in an abatement of the thoughts of suicide and her children drowning and a resolution of urinary retention.
Ms D is a 42-year-old white woman, who was admitted to the Kansas City VA Medical Center after she presented herself to the mental hygiene clinic complaining of increasing suicidal ideation for the previous 5 days. Two weeks before admission, the patient had been switched from fluoxetine 40 mg/d to duloxetine 40 mg/d because of persistent diarrhea. The patient reported thoughts of poisoning herself in an enclosed garage with carbon monoxide and thoughts of overdosing with clonazepam. She reported vivid flashbacks of experiences with her former husband 20 years before when he had threatened to kill himself by holding a gun to his head. Ms D’ s target symptoms also included decreased concentration, decreased sleep, poor appetite, decreased energy, anhedonia, and increased agitation.
Upon admission to inpatient psychiatry, Ms D was quite tearful and reported that this was the first time that she had ever had thoughts of suicide. Ms D had no previous psychiatric hospitalization. Ms D had been diagnosed with MDD and posttraumatic stress disorder in 1995. Previous treatment had included citalopram, fluoxetine, bupropion, gabapentin, and clonazepam. Current medications included duloxetine 40 mg/d, clonazepam, and naproxen. Upon admission, duloxetine was discontinued, and fluoxetine 20 mg/d was restarted. Three days after stopping duloxetine, the patient reported having no thoughts of suicide, no insomnia, and improved appetite. She was noted to be interacting well with peers and staff. She reported that her mood was positive, and she felt 100%[ better after restarting fluoxetine.
Subsequently, Ms D was discharged home on her third hospital day.
The authors present 4 cases that illustrate a close temporal relationship between the development of acute suicidal ideation and duloxetine use. In all 4 cases, suicidal thoughts appeared after increasing duloxetine dosages and subsided after discontinuing use. The patients were medically stable, with laboratory results within normal limits.
None had recent substance abuse or dependence. No extrapyramidal symptoms were noted.
Duloxetine is currently approved by the Food and Drug Administration for treatment of MDD, generalized anxiety disorder, and diabetic peripheral neuropathic pain. Multiple clinical trials have demonstrated efficacy of duloxetine for treatment of stress urinary incontinence and fibromyalgia.6–9
A review of controlled studies of duloxetine for MDD found no difference between duloxetine and placebo in respect to measures of suicidal ideation and behaviors.10 However, it is unclear what exclusion criteria in regard to suicidal ideation or behaviors were applied to patients entering these studies.
It is also unknown whether the results would have been different if non-MDD duloxetine clinical trials were included in the analysis.
To our knowledge, this is the first case series to describe development of suicidal preoccupation in conjunction with duloxetine use. Clinicians should carefully monitor patients for emergence of suicidal ideation when prescribing any antidepressant, with particular scrutiny during periods of initial use and dosage increases.
Aashish R. Parikh, MD, Benjamin T. Thatcher, DO, Ely A. Tamano, MD, Barry I. Liskow, MD Department of Psychiatry and Behavioral Sciences, The University of Kansas Medical Center Kansas City, KS
- Martinez C, Rietbrock S, Wise L, et al. Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study. BMJ . 2005; 330:389–393.
- Olfson M, Marcus SC, Shaffer D. Antidepressant drug therapy and suicide in severely depressed children and adults: a case-control study. Arch Gen Psychiatry. 2006;63:865–872.
- Juurlink DN, Mamdani MM, Kopp A, et al. The risk of suicide with selective serotonin reuptake inhibitors in the elderly. Am J Psychiatry. 2006;163:813–821.
- Tatsumi M, Groshan K, Blakely RD, et al. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997;340: 249–258.
- Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, et al. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology. 2001;25:871–880.
- Norton PA, Zinner NR, Yalcin I, et al. Duloxetine versus placebo in the treatment of stress urinary incontinence. Am J Obstet Gynecol. 2002;187:40–48.
- Dmochowski RR, Miklos JR, Norton PA, et al. Duloxetine versus placebo in the treatment of North American women with stress urinary incontinence. J Urol. 2003;170: 1259–1263.
- van Kerrebroeck P, Abrams P, Lange R, et al. Duloxetine versus placebo in the treatment of European and Canadian women with stress urinary incontinence. BJOG . 2004;111: 249–257.
- Lilly-sponsored duloxetine clinical studies. Available at: http://www.lillytrials.com/results/ by_product/results_cymbalta.html. Accessed May 16, 2007.
- Acharya N, Rosen AS, Polzer JP, et al. Duloxetine: meta-analyses of suicidal behaviors and ideation in clinical trials for major depressive disorder. J Clin Psychopharmacol. 2006;26:587–594.