Assessment Therapy

1. Assessment Therapy The treatment I will be assessing is that of Selective Serotonin Re-uptake Inhibitors (SSRI’s) in the treatment of Bulimia

2. Background • Bulimia affects anywhere between • 1.7%-2.5% of women • 6% of adolescent girls • 5% of college women (Alexander)

3. History Of SSRI’s • SSRI’s were introduced in 1987. • The first was Fluoxetine (Prozac:Eli Lilly & Company) FDA approved 1987 • Sertraline (Zoloft; Pfizer, Inc) FDA approved 1991 • Paroxetine (Paxil; GlaxoSmithKline) FDA approved 1992 • Citalopram (Celexa; Forest Pharmaceuticals) FDA approved 2000 • Escitalopram (Lexapro; Forest Pharmaceuticals) FDA approved 2002 • alaproclate • Etoperidone • Fluvoxamine • Zimelidine

4. History of SSRI’s • SSRI’s are serotonin boosters. • They act to restore chemical balance in the brain. • SSRI’s act on the neurotransmitter serotonin. It blocks the re-uptake of serotonin at the synaptic cleft, thus making more serotonin available at the post synaptic nerve. • Scientists and doctors are not quite sure how serotonin works but they are aware of its effects in the control : • Mood • Sleep • Body temperature • Appetite

5. Serotonin • Serotonin: • “A compound, also known as 5-hydroxytryptamine (5-HT), derived from tryptophan, an amino acid. It is widely distributed in the animal and vegetable kingdoms. In mammals it is found in gastrointestinal enterochromaffin cells, in blood platelets, and in brain and nerve tissue. Serotonin is a local vasoconstrictor, plays a role in brain and nerve function and in regulation of gastric secretion and intestinal peristalsis, and has pharmacologic properties. Serotonin is concentrated in certain areas of the brain; the hypothalamus and midbrain contain large amounts, while the cortex and cerebellum contain low concentrations. When a serotonin-containing nerve fires, serotonin is released and can bind to any one of a series of at least 14 distinct downstream serotonin receptors (5-HT receptors). SSRIs, act by increasing the amount of active serotonin in nerve synapses in particular brain regions. Conversely, various conditions that lower serotonin levels are associated with depression, suggesting that normal to slightly elevated serotonin levels tend to elevate mood and prevent depression”.(McGraw-Hill Encyclopedia of Science and Technology, 2005)

6. Serotonin and Bulimia • This relates to the neurobiology of Bulimia because bulimics have reduced serotonin • The most common SSRI’s used in the treatment of bulimia are; • Fluoxetine • Fluvoxamine • Paroxetine • Most of the bulimia research focuses on Fluoxetine

7. History Of Fluoxetine (Prozac) It was invented at EliLilly by a team of scientists headed by • Dr. Ray W. Fuller • Drs. Bryan B. Molloy • David T. Wong • They were awarded the Pharmaceutical Discoverers Award from the NARSAD (National Alliance for Research on Schizophrenia and Depression) • Prozac originated from Diphenhydramine, which inhibits the re-uptake of serotonin, discoved in 1960. However, Diphenhydramine had many side effects. Hence Dr. Fuller and his team wanted to invent a drug that produced the same effects as Diphenhydramine but with fewer side effects. • Prozac was then invented, the first of the SSRI’s. The drug became very popular due to the extensive marketing by Lilly.

8. History of Fluoxetine • In 2001 Barr Laboratories disputed Lilly’s patent to Prozac, and they were successful. Today many companies produce Fluoxetine. Fluoxetine is approved for use in; • Obsessive Compulsive Disorder (OCD) • Depression • Bulimia • Premenstrual Dysphonic Disorder • Panic Disorder

9. Side Effects • Akathisia - Motor restlessness, an inability to sit still or lie quietly. • Rage • Restlessness & Insomnia • Weight Loss & Weight Gain • Trembling • Weakness • Skin Rash • Anorgasmia - Failure to achieve orgasm (climax) during sexual intercourse. • Itching • Decrease In Sexual Drive • Hyponathraemia - A deficiency of sodium in the blood. • Suicidal Thoughts

10. Formulations • Sold in capsules of 10, 15, 20, 40, 60 or 90mg. • Prozac weekly-90mg pill with a 7 day slow release • The typical dosage of a bulimic is 60mg/day as compared to that of 20mg for people with depression and OCD • Levels should not exceed 80mg/day • Overdose: 16 confirmed, the amounts varied from 80mg-200mg in persons ranging from 13-51 years of age. No deaths occurred. They were all treated with charcoal. Most people who overdose on any drug get treated with charcoal. • 2 deaths occurred because the drug was mixed with alcohol and other drugs.

11. Pharmokinetics • Fluoxetine is absorbed between 1.5-12hrs depending on the oral dose • It takes 4 to 5 weeks of continuous uses to achieve steady blood plasma states • Bulimics achieve the best results after 16 weeks of use • After discontinuing the drug it may take between 1 and 2 months for the active drug substances to disappear from the body

12. Research • Psychopharmacotherapy of anorexia nervosa, bulimia nervosa and binge-eating disorder. (Kruger, Sidney, Kennedy) Journal of Psychiatry & Neuroscience, 2000. • This research suggests that fluoxetine has been shown to interrupt the binge-eating/purging cycle, even in the absence of depressive symptoms. Fluoxetine is the most rigorously studied SSRI for the treatment of bulimia nervosa. • Fluoxetine treatment must be followed for a least 6 months to reduce the chances of relapse. • This articles suggests that patients with bulimia may suffer from a serotonin (5-HT) deficit. 5-HT receptors are responsible for our response to stimuli i.e. food. 5-HT also allows us to regulate our affective states and moods, and may play a major role in our impulses.

13. Research • This 5-HT deficiency is said to be the driving force behind the dieting, binge-eating and purging associated with the disorder. And it is the SSRI’s that block the re-uptake of serotonin making more available at the 5-HT receptor sites, hence “normalizing” the serotonin levels in the brain accounting for the anti-bulimic effects of fluoxetine.

14. Research • Ghrelin concentrations and cardiac vagal tone are decreased after pharmacologic and cognitive-behavioral treatment in patients with bulimia nervosa. (Tanaka, Nakahara, Muranaga, Kojima, Yasuhara, Ueno, Nakazato, Inui) Hormones and Behavior, 2006. • The purpose of this study was to show if the SSRI paroxetine combined with cognitive behavioral treatment alleviated the bulimic symptoms of increased Ghrelin, decreased leptin, decreased vagal tone. • Ghrelin simulates growth hormone secretion. It increases food intake, enhances appetite and antagonizes leptin action. These all have an effect on eating behavior and energy metabolism via the CNS and the vagal system.

15. Research This study has shown that bulimics have • Increased Ghrelin • Decreased leptin • Decreased vagal tone Participants: • 24 female bulimic patients 19-32 years of age who met the DSM criteria for the disorder, were free of any drugs for 3 months. They had to have binge-eating and vomiting at least 2 times/week for 3 months • 25 matched female volunteers who had no history of eating disorders or mental disorders, with normal blood tests. • For 16 weeks the bulimics took 20mg of paroxetine daily before bed, and 50 min of CBT. Blood work was done before the 16 weeks and after the 16weeks of treatment. A POMS depression scale was conducted prior to treatment and after treatment.

16. Research • The finding of this study suggest the SSRI paroxtine & CBT; • Decrease fasting Gherlin levels • Decreased resting cardiac tone • Decreased binge-eating • Decreased there scores on the depression scale (POMS) • The finding of this study suggest that habitual abnormal eating behavior might be related to the abnormal function of gastrointestinal hormones via the vagal system.

17. Research Strengths of the study: • These finding are important to the future treatments of bulimia because it has provided doctors with a measure of bulimia via blood work (measuring Ghrelin, lipin and vagal tone). This provides doctors with a base line to asses if a pharmacologic treatment is effective. Weakness of the study. • The control group should have been bulimics who did not receive treatment. They should have looked at both treatment options independently. Here we are not exactly sure which treatment is actually causing the person to improve. The improvements can be attested to the CBT or the paroxtine or a combination of the two, it isn’t very clear. A lot of the research in this field uses a combination of treatments so it is hard to distinguish which treatment is improving the overall condition of the patient.

18. Brain Areas affected/Neurobiology: • Fluvoxamine, a selective serotonin reuptake inhibitor appetite-suppressing effects in mice 5-HT1B receptors. (Nonogaki, Nozue, Takahashi, Yamashita, Hiraoka, Kumano, Kuboki, Oka) International Journal of Neuropsychopharmacology, 2006. • This study demonstrated that SSRI’s selective at the 5-HT2c receptor antagonist enhances the increase of extra cellular 5-HT levels induced by SSRI citapran in the hippocampus. • That fluoxetine increases the extra cellular 5-HT levels in the prefrontal cortex and the hippocampus. • That fluvoxamine increased extra cellular 5-HT concentrations, by inactivating the 5-HT2c receptor, this increases the 5-HT1b receptor gene expression and more serotonin is available at the synaptic cleft because it blocks the re-uptake of serotonin.

19. Evaluation: • Advantages: • SSRI’s have relatively few side effects when compared to other antidepressants • SSRI’s are cost effective • SSRI’s are readily available • SSRI’s have been prove to be anti-bulimic • Disadvantages: • SSRI’s have drug interactions with other medications and alcohol. • SSRI’s have been studied in conjunction with other therapies, hence we are not truly certain which treatment is benefiting the patient • There are many 5-HT receptor types, hence we aren’t certain which sites are affected by bulimia and which drugs will target a specified 5-HT receptor. • We don’t know much about the mechanisms of action of these drugs, in many cases we know that they just work, but we don’t know how they specifically work

20. Conclusions: • The use of SSRI seems to provide promise in the treatment of bulimia. More studies need to be done assessing the specific effects of drug treatment on this condition, rather then using a combination of treatments. It seems as though there is limited research on SSRI’s, most of the research available focuses on a few of the SSRI’s, perhaps because they are fairly new in there evolution. It is also important that scientist understand the underlying causes of bulimia. We are not really sure if the behaviors of the disorder account for the brain abnormalities present in these patients or if these patients were born with these brain abnormalities which caused them to develop bulimia. How can we effectively treat a disorder if we aren’t exactly sure of its causes? It is also very complicated to asses the possible causes of the disorder because we do not know who will become bulimic; hence we cannot assess them prior to the onset of illness, a major draw back. Evidence for the anti-bulimic affects of SSRI’s have shown promise in the treatment of bulimia however more research needs to be conducted because we are still in the infancy of using pharmacological treatments for this disorder.