临床发现大剂量的服用氟西汀可能导致一些患者出现药物性 孤独症。但是停用后症状会消失。
Fluoxetine
Fluoxetine, sold under the brand names Prozac and Sarafem among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.[1] It is used for the treatment of major depressive disorder, obsessive–compulsive disorder (OCD), bulimia nervosa, panic disorder, and premenstrual dysphoric disorder.[1] It may decrease the risk of suicide in those over the age of 65.[1] It has also been used to treat premature ejaculation.[1] Fluoxetine is taken by mouth.[1]
Common side effects include trouble sleeping, sexual dysfunction, loss of appetite, dry mouth, rash, and abnormal dreams.[1] Serious side effects include serotonin syndrome, mania, seizures, an increased risk of suicidal behavior in people under 25 years old, and an increased risk of bleeding.[1] If stopped suddenly, a withdrawal syndrome may occur with anxiety, dizziness, and changes in sensation.[1] It is unclear if it is safe in pregnancy.[5] If already on the medication, it may be reasonable to continue during breastfeeding.[5] Its mechanism of action is not entirely clear but believed to be related to increasing serotonin activity in the brain.[1]
Fluoxetine was discovered by Eli Lilly and Company in 1972, and entered medical use in 1986.[6] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[7] It is available as a generic medication.[1] The wholesale cost in the developing world is between US$0.01 and US$0.04 per day as of 2014.[8] In the United States, it costs about US$0.85 per day.[1] In 2016 it was the 29th most prescribed medication in the United States with more than 23 million prescriptions.[9]
Medical uses
Fluoxetine is frequently used to treat major depressive disorder, obsessive–compulsive disorder (OCD), post-traumatic stress disorder (PTSD), bulimia nervosa, panic disorder, premenstrual dysphoric disorder, and trichotillomania.[10][11][12][13] It has also been used for cataplexy, obesity, and alcohol dependence,[14] as well as binge eating disorder.[15] It has also been tried as a management for autism spectrum disorders with moderate success in adults.[16][17][18][19]
Depression
The effectiveness of fluoxetine and other antidepressants in the treatment of mild-to-moderate depression is controversial. A review of the comparative efficacy of 21 antidepressant drugs found that fluoxetine was among the least effective for treatment of depression.[20] A meta-analysis published by Kirsch in 2008 suggests, in those with mild or moderate symptoms, the efficacy of fluoxetine and other SSRIs is clinically insignificant.[21] A 2009 meta-analysis by Fournier which evaluated patient-level data from six trials of the SSRI paroxetine and the non-SSRI antidepressant imipramine has been further cited as evidence that antidepressants exhibit minimal efficacy in mild to moderate depression.[22] A 2012 meta-analysis using individual patient level-data of fluoxetine for the treatment of depression concluded statistically and clinically significant benefit was seen irrespective of baseline depression severity, and no significant effect was found on baseline severity on observed efficacy.[23] Overall there is no evidence from randomized controlled trials that fluoxetine or other SSRIs decrease the risk of suicide.[24] There is tentative evidence that suggests it may decrease the risk of suicide in those over the age of 65.[1]
A 2009 systematic review by the National Institute of Care and Clinical Excellence(NICE) (which considered the Kirsch, but not the later meta-analyses) concluded strong evidence existed for the efficacy of SSRIs in the treatment of moderate and severe depression, with some evidence for their efficacy in the treatment of mild depression.[25] Both the NICE and the Fournier analyses concluded that greater evidence is seen for the efficacy of antidepressants in the treatment of chronic mild depression (dysthymia) than in recent-onset mild depression.
NICE recommends antidepressant treatment with an SSRI in combination with psychosocial interventions as second-line treatment for short term mild depression, and as a first line treatment for severe and moderate depression, as well as mild depression that is recurrent or long-standing. The American Psychiatric Association includes antidepressant therapy among its first-line options for the treatment of depression, particularly when "a history of prior positive response to antidepressant medications, the presence of moderate to severe symptoms, significant sleep or appetite disturbances, agitation, patient preference, and anticipation of the need for maintenance therapy" exist.[26]
Obsessive–compulsive disorder
The efficacy of fluoxetine in the treatment of obsessive–compulsive disorder(OCD) was demonstrated in two randomized multicenter phase III clinical trials. The pooled results of these trials demonstrated that 47% of completers treated with the highest dose were "much improved" or "very much improved" after 13 weeks of treatment, compared to 11% in the placebo arm of the trial.[3] The American Academy of Child and Adolescent Psychiatry state that SSRIs, including fluoxetine, should be used as first-line therapy in children, along with cognitive behavioral therapy (CBT), for the treatment of moderate to severe OCD.[27]
Panic disorder
The efficacy of fluoxetine in the treatment of panic disorder was demonstrated in two 12-week randomized multicenter phase III clinical trials that enrolled patients diagnosed with panic disorder, with or without agoraphobia. In the first trial, 42% of subjects in the fluoxetine-treated arm were free of panic attacks at the end of the study, vs. 28% in the placebo arm. In the second trial, 62% of fluoxetine treated patients were free of panic attacks at the end of the study, vs. 44% in the placebo arm.[3]
Bulimia nervosa
A 2011 systematic review of seven trials which compared fluoxetine to a placeboin the treatment of bulimia nervosa; six of which found a statistically significant reduction in symptoms such as vomiting and binge eating.[28] However, no difference was observed between treatment arms when fluoxetine and psychotherapy were compared to psychotherapy alone.
Premenstrual dysphoric disorder
Fluoxetine is used to treat premenstrual dysphoric disorder.[29][30]
Special populations
In children and adolescents, fluoxetine is the antidepressant of choice due to tentative evidence favoring its efficacy and tolerability.[31][32] In pregnancy, fluoxetine is considered a category C drug by the USA FDA. Evidence supporting an increased risk of major fetal malformations resulting from fluoxetine exposure is limited, although the Medicines and Healthcare Products Regulatory Agency(MHRA) of the UK has warned prescribers and patients of the potential for fluoxetine exposure in the first trimester (during organogenesis, formation of the fetal organs) to cause a slight increase in the risk of congenital cardiac malformations in the newborn.[33][34][35] Furthermore, an association between fluoxetine use during the first trimester and an increased risk of minor fetal malformations was observed in one study.[34]
However, a systematic review and meta-analysis of 21 studies – published in the Journal of Obstetrics and Gynaecology Canada – concluded, "the apparent increased risk of fetal cardiac malformations associated with maternal use of fluoxetine has recently been shown also in depressed women who deferred SSRI therapy in pregnancy, and therefore most probably reflects an ascertainment bias. Overall, women who are treated with fluoxetine during the first trimester of pregnancy do not appear to have an increased risk of major fetal malformations."[36]
Per the FDA, infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn. Limited data support this risk, but the FDA recommends physicians consider tapering SSRIs such as fluoxetine during the third trimester.[3] A 2009 review recommended against fluoxetine as a first-line SSRI during lactation, stating, "Fluoxetine should be viewed as a less-preferred SSRI for breastfeeding mothers, particularly with newborn infants, and in those mothers who consumed fluoxetine during gestation."[37]Sertraline is often the preferred SSRI during pregnancy due to the relatively minimal fetal exposure observed and its safety profile while breastfeeding.[38]
Adverse effects
Side effects observed in fluoxetine-treated persons in clinical trials with an incidence >5% and at least twice as common in fluoxetine-treated persons compared to those who received a placebo pill include abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, decreased libido, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawning.[39] Fluoxetine is considered the most stimulating of the SSRIs (that is, it is most prone to causing insomnia and agitation).[40] It also appears to be the most prone of the SSRIs for producing dermatologic reactions (e.g. urticaria (hives), rash, itchiness, etc.).[34]
Sexual dysfunction
Sexual dysfunction, including loss of libido, anorgasmia, lack of vaginal lubrication, and erectile dysfunction, are some of the most commonly encountered adverse effects of treatment with fluoxetine and other SSRIs. While early clinical trials suggested a relatively low rate of sexual dysfunction, more recent studies in which the investigator actively inquires about sexual problems suggest that the incidence is >70%.[41] Symptoms of sexual dysfunction have been reported to persist after discontinuing SSRIs, although this is thought to be occasional.[3][42][43]
Discontinuation syndrome
Antidepressant discontinuation syndrome is an adverse effect of second generation anti-depressants, including fluoxetine. The symptoms appear with rapid discontinuation of one of these drugs, and can include dizziness, disturbance of balance, headache, nausea, insomnia, and vivid dreams. Others can include sensations of tingling or numbness, ‘electric-shock’-like sensations, and irritability, with some case reports of hallucinations. They can generally be prevented by tapering off the drug over a period of four weeks, although evidence is weak for optimal tapering and there is disagreement between experts over the schedule. If a person is informed of the risk of discontinuation syndrome prior to starting the drug and again prior to beginning any tapering, discontinuation symptoms appear to be fewer and less severe, but again evidence is weak. Slower-acting drugs, like fluoxetine, may be less likely to cause discontinuation symptoms, but the evidence for this is weak as well. The mechanism by which discontinuation syndrome occurs in some people is not well understood.[44]
Suicide
In 2007 the FDA required all antidepressants to carry a black box warning stating that antidepressants may increase the risk of suicide in people younger than 25.[45] This warning is based on statistical analyses conducted by two independent groups of FDA experts that found a 2-fold increase of the suicidal ideation and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group. The suicidality was slightly decreased for those older than 24, and statistically significantly lower in the 65 and older group.[46][47][48] This analysis was criticized by Donald Klein, who noted that suicidality, that is suicidal ideation and behavior, is not necessarily a good surrogate marker for completed suicide, and it is still possible that antidepressants may prevent actual suicide while increasing suicidality.[49]
There is less data on fluoxetine than on antidepressants as a whole. For the above analysis on the antidepressant level, the FDA had to combine the results of 295 trials of 11 antidepressants for psychiatric indications to obtain statistically significant results. Considered separately, fluoxetine use in children increased the odds of suicidality by 50%,[50] and in adults decreased the odds of suicidality by approximately 30%.[47][48] Similarly, the analysis conducted by the UK MHRA found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the children and adolescents on fluoxetine as compared to the ones on placebo. According to the MHRA data, for adults fluoxetine did not change the rate of self-harm and statistically significantly decreased suicidal ideation by 50%.[51][52]
