Fluoxetine in the Treatment of Post-traumatic Stress Disorder

1. Fluoxetine in the Treatment of Post-traumatic Stress Disorder James Roseborough

2. History of Fluoxetine • Fluoxetine or Prozac was invented by Dr. Ray W. Fuller, with Drs. Bryan B. Molloy and David Wong who were working for the drug company Eli Lilly. • Fluoxetine hydrochloride was created in response to evidence of the role of serotonin in depression. • On the basis of this hypothesis, efforts to develop agents that inhibit the uptake of 5-HT from the synaptic cleft were initiated, and as a result fluoxetine was created. • Prozac was approved by the FDA in 1987 and on the market in 1988 • In 2001 Eli Lilly lost it’s patent rights, and fluoxetine is now manufactured under a number of brand names around the world. • Fluoxetine commonly known as Prozac, is now also known as Sarafem, FLUX, Fontex, Foxetin, Prozen and numerous more

3. How Fluoxetine Works • Treatment goals in the pharmacotherapy of PTSD include reduction of intrusive thoughts, reduction of avoidance behaviour, improvement of hyperarousal symptoms, and improvement of depressive symptoms. • Fluoxetine is an Selective Serotonin Reuptake Inhibitor (SSRI) • Simply put, it binds the reuptake channels on the presynaptic nerve and blocks serotonin from being reabsorbed. • This action increases the amount of serotonin in the synapse. • Fluoxetine has been approved for treating - major depressive disorder (MDD), obsessive compulsive disorder, bulimia, premenstrual dysphonic disorder and panic disorder. • Fluoxetine is sold - in capsules containing 10, 15, 20, 40, 60 or 90 mg of active ingredient • - in tablets containing 10 mg, or 20 mg • - in liquid form with a concentration of 20 mg/5 ml • Prozac Weekly - 90 mg capsule, taken once every 7 days • A 40 mg dose generally will reach peak plasma concentrations from 15 to 55 ng/mL in 6 to 8 hours

4. General Side Effects and Drug Interactions of Fluoxetine

5. A Review of Side Effects and Adverse Events in PTSD Studies

7. Treatment EfficacyNagy, Morgan, Southwick and Charney (1993) • Open prospective trial of fluoxetine • 27 patients entered the trial, 8 dropped out before week 3 and were excluded from the analysis • All patients were male combat veterans • Dosage: - patients started at 20 mg/day for 4 weeks - dosages were increased by 20 mg every 2 weeks - maximum dosage was 80 mg/day • 11 patients (58%) had comorbid panic disorder • 16 patients (84%) had a current major depressive episode • The reexperiencing subscale of the CAPS-2 decreased significantly - Although “distressing memories of the traumatic event” was the only symptom to decrease significantly (1/4) • Improvement in the avoidance/numbing subscale of the CAPS-2 was statistically significant - “avoiding thoughts or feelings associated with the trauma”, “loss of interest”, “detachment”, “restricted affect”, “sense of foreshortened future” (5/7) • Improvement in the hyperarousal subscale of the CAPS-2 was also statistically significant - “insomnia”, “anger/irritability”, “difficulty concentrating”, “hypervigilance” (4/6) • This data shows that fluoxetine treatment is effective in reducing many key symptoms of PTSD

8. Treatment Efficacy … cont’d Connor, Sutherland, Tupler, Malik and Davidson (1999) • Double-blind placebo randomized study • Subject population was almost all female, 50 of 54 • Dosage: - Dosages ranged from 10 mg/day to 60 mg/day with a median dose of 30 mg/day • Subjects were excluded if they had a history of psychosis, bipolar disorder, antisocial personality disorder, current or recurrent or recent risk of suicide, homicide, and drug or alcohol abuse disorder within the previous six months. • Fluoxetine produced clinically and statistically significant effects on all measures of PTSD severity in this sample of civilian trauma survivors • The onset of drug effect observed as early as week 2.

9. Treatment Efficacy … cont’dMartenyi, Brown, Zhang, Prakash and Koke (2002) • Double blind, Fluoxetine vs. Placebo study • 301 patients met entry criteria after the baseline evaluation period and were randomly assigned to either fluoxetine (N=226) or placebo (N=75) - 81% of the population was male - 48% had been exposed to multiple combat related traumas - 47% had been a witness/victim of war Dosage: Avg. 57 mg/day • From baseline to week 12 in the TOP-8 total score, fluoxetine-treated patients experienced a significantly greater improvement in TOP-8 total score compared with placebo-treated patients. • Significantly greater improvements were seen in the CAPS total score, and CAPS intrusive subscore, and hyperarousal subscore

10. Lack of EfficacyHertzberg, Feldman, Beckham, Kudler and Davidson (2000) • Examining the efficacy of fluoxetine on male subjects with combat related PTSD • Double-blind, fluoxetine vs. placebo, 12 week study • 12 patients who had served in the Vietnam War - 6 in fluoxetine group - 6 in placebo group Dosage: Avg. 48 mg/day • 1 patient was very much improved based on the Duke Global Rating for PTSD Scale, which measures symptom severity and improvement • 2 patients were much improved These results were not statistically significant Limitations • Comorbid disorders: Major depression (8), Simple phobias (4), Obsessive Compulsive Disorder (2), alcohol and marijuana dependence (1) • Numerous patients also had histories of other comorbid disorders • One of the 6 fluoxetine subjects dropped out after 2 weeks due to adverse effects

11. Relapse PreventionDavidson, Connor, Hertzberg, Weisler, Wilson and Payne (2005) • Single center, 12 month study • All participants were on fluoxetine for 6 months, then - half were randomly assigned to a placebo group - half were randomly assigned to continue fluoxetine Dosage: Avg. 48.6 + 15.4 mg/day Participants: 114 subjects began the study - (13 dropped out due to adverse events) 63 completed the first 24 weeks 57 completed the 24 weeks (27 on fluoxetine / 30 on placebo) • Continued use of fluoxetine for 12 months decreased the chances of relapse significantly.

12. Relapse Prevention #2Martenyi and Soldatenkova (2006) • 144 combat-related trauma patients – victim/witness of war event, concentration camp survivor, torture victim, and others 110 in the treatment group Dosage: Avg. 65+17.6 mg/day during first twelve weeks Avg. 64.2 mg/day during last twelve weeks • Patients treated with fluoxetine had significantly greater improvements on the TOP-8 which measured PTSD symptoms After 12 weeks 62 patients qualified to continue the final 12 weeks, 31 were kept on fluoxetine, and 31 were put on a placebo • Patients who remained on fluoxetine had significantly greater improvement than those who didn’t • Placebo patients were 3.56 times more likely to relapse than patients who remained on fluoxetine

13. Antidepressant Efficacy ComparisonÖnder, Tural and Aker (2006) • Compared the efficacy of 3 antidepressants: Fluoxetine - blocks the reuptake of serotonin Moclobemide - serotonin reuptake enhancer Tianeptine - inhibits the enzyme which breaks down serotonin • Efficacy was determined by the drugs ability to reduce the symptom clusters: - re-experiencing - emotional numbness - avoidance - hyperarousal • Number and severity of symptoms was measured using the clinician administered PTSD scale (CAPS) • Subjects: - all of whom were present during the Marmara earthquake in Turkey which killed 15,226 people - excluded if they had bipolar disorder, schizophrenia, alcohol or other substance dependence, or major depression - 38 were assigned to the fluoxetine group Dosage: Avg. 27.4 + 9.8 mg/day

14. Onder, Tural and Aker (2006) … cont’d • All three treatments had a significant effect on CAPS scores • After 12 weeks 70.6% of the fluoxetine patient’s symptoms had been reduced by 50% or more • All symptom cluster scores were significantly reduced by fluoxetine • The most marked improvement was for the hyperarousal cluster of symptoms Limitations: - the study was not double-blind, which makes interviewer bias possible - there was no placebo group - patients were seeking treatment, which may have an effect on recovery and response rates

15. Specific Symptoms Affected by FluoxetineMeltzer-Brody, Connor, Churchill and Davidson (2000) • Fluoxetine vs. placebo study • Examined the symptom cluster and symptom specific effects fluoxetine had on PTSD patients from a prior study (Connor, Sutherland, Tupler, Malik and Davidson, 1999) • The 4 clusters were - intrusion, avoidance, numbing, and hyperarousal • The clusters of symptoms and specific symptoms were measured using: - Davidson Trauma Scale (DTS) - self report - Structured Interview for PTSD (SIP) - an interview • Subjects: - patients who DSM-IV criteria for PTSD diagnosis - all participants were female - patients were excluded if they had - psychosis, bipolar disorder, antisocial personality disorder, were at risk of suicide or homicide or, alcohol or other substance abuse disorder within the past 6 months - 53 participants - 26 in the placebo group - 27 in the fluoxetine group

16. Meltzer-Brody, Connor, Churchill and Davidson (2000) … cont’d Results • Both the DTS and SIP showed that fluoxetine had a significantly greater effect on all 4 symptom clusters than the placebo • Specific symptoms significantly reduced when measured by both DTS and SIP: - being emotionally upset when presented with reminders of the trauma - avoiding thoughts related to the trauma - difficulty enjoying things - feeling distant/estranged - senses of a foreshortened future - concentration difficulties Fluoxetine had little effect on the symptoms of - startle - actual avoidance - nightmares

17. Combating Explosive BehaviorShay (1992) • In a sample of Vietnam veterans 14% reported engaging violent acts 13 or more times in the previous year, 5 times the number reported by a civilian sample. • There is physiological evidence which suggests serotonins role on aggressive and impulsive behavior. • A sample of 28 depressed male Vietnam veterans • Treated with fluoxetine, dosages ranged from 20 mg/day to 80 mg/day • Most of the patients had already been taking fluoxetine • 22 out of 26 patients who were treated for longer than 1 month reported happier moods, less apathy, and more energy • 13 out of 18 patients who had a history of outbursts of rage before treatment showed a decrease in explosiveness after 3 to 6 weeks • They described an increased ability to think before lashing out verbally or physically • Patients also felt they were able to “let go” of feelings of anger faster and with more ease

18. Quality of LifeMalik, Connor, Sutherland, Smith, Davison and Davidson (1999) • Studies have shown that PTSD tend to have a decreased quality of life (QOL). • Medical Outcomes Study (MOS) 36-item Short-Form Health Survey (SF36) to test patients on 8 items associated with QOL 1. physical conditioning 5. vitality 2. role limitations due to physical health 6. social functioning 3. role limitations due to emotional problems 7. bodily pain 4. general health 8. mental health • 15 of the 16 subjects were female • 11 of 16 subjects received fluoxetine • There were significant changes in the treatment group in vitality, social functioning and mental health all of which improved. • Due to the low number of subjects it made it difficult for findings to reach statistical significance, a larger sample may have shown significant improvement in other areas.

19. Cell Proliferation in MiceMalberg and Duman (2003) • Studies have shown that stress decreases cell proliferation in the hippocampus of non-human primates • Animals are placed in a box that has a retractable door in the middle, one side of the box is shocked, and the time it takes for the animal to get to the other side is timed • Experiment 1: - Amount of time it took IS mice to escape from the box was significantly greater than NS mice - Exposure to acute shock decreased cell proliferation regardless of pretest treatment

20. Malberg and Duman (2003) … cont’d • Experiment 2: - The time it took mice to escape was significantly less in the fluoxetine group when compared to the mice who had been shocked previously but received no treatment. - Mice that were shocked had decreased cell proliferation - This effect was significantly reduced in mice that had been treated with fluoxetine Conclusion: Treatment with fluoxetine reverses the effect inescapable shock has on cell proliferation and the behavioral effects it causes in mice.

21. Neurological Case StudyFernandez, Pissiota, Frans, Knorring, Fischer and Fredrikson (2001) • Neuroimaging studies have shown an increased amount of regional cerebral blood flow (rCBF) in the limbic and paralimbic regions of patients with PTSD - areas involved in emotion and memory • Neuroimaging studies have shown a decreased amount of rCBF in the temporal and prefrontal cortices in patients with PTSD after symptom provocation • A cases study using a torture and war related PTSD, torture included, forced standing, beating, attempted drowning, sleep deprivation, etc. • Dosage: Started at 20 mg/day and increased until clinically effective. Maximum dose was 50 mg/day • PTSD checklist scores showed that provoked subjective and physiological anxiety measures to war and trauma related sounds decreased between 50% to 60% with treatment. • The patients urge to flee, was also reduced. • PET imaging showed a significant decrease in blood flow in the…insula, prefrontal, orbitofrontal, and inferior temporal corticies…during provocation - treatment normalized the blood flow in these areas, and may have caused the decrease in anxiety • PET imaging showed a significant increase in blood flow in the…cerebellum, supplementary motor cortex, precuneus, and parietal cortex…during provocation - treatment decreased the blood flow in these areas, and may have cause the decrease in the patient’s urge to flee Overall, areas for emotion, memory, attention and motor control were all altered by fluoxetine treatment.

22. Conclusion • Treatment Advantages - relatively cheap - relatively available - easy to administer, once a day, or once a week - fairly effective for various types of trauma related PTSD • Treatment Disadvantages - it is a drug, and has several side effects, and there can be dangerous drug interactions - maybe not affordable to all people - does not work for everyone - must be taken daily, and most likely for life • Research Limitations - only several types of trauma related PTSD have been studied - there are very few neurological imaging studies which observe the effects fluoxetine has on the brain - studies vary in the assessment and symptom measurement tools - some studies have different exclusion criteria which may have an influence on results I believe that treatment using fluoxetine is fairly effective for most PTSD patients, and should be used. It may be more beneficial if used with CBT, or other drugs. If it is not effective or the side effects are too much for the patient there are other alternative drugs or treatment methods. I think future research should look at the efficacy of fluoxetine when in combination with other drugs or treatment methods. Studies should also look at a wider range of trauma types and possibly limit studies to specific traumas. Overall, I would recommend fluoxetine to anyone suffering from PTSD.

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