1. BIPOLARDISORDERLeana Atieh, Saira Nawaz, & JessicaPisano

2. BIPOLAR IIDISORDER: Previously known as manic-depressive disorder. Experience mood swings, poor impulse control, impairments of verbal memory, and attention deficiency. Alternates between two poles - depression and mania. Depression is a feeling a worthlessness, lack of motivation, energy, sleep and pleasure in activities. Mania is the opposite of depression, where one expresses over activity, excitement, rambling speech and excessive laughter.*Kapczinski, Machado-Vieira, Soares."Perspectives for the Development of Animal Models of Bipolar Disorder." Progress inNeuro-Psychopharmacology and Biological Psychiatry 28 (2004): 209-24. Print. 3. *Date, Dave, Gandhi, Parekh, Mistry. "Bipolar Disorder." Web. . 4. DSM IV CRITERIA: Bipolar II Disorder: includes milder manic phases known as hypomania. Mania is an intense high where the person feels euphoric, almost indestructiblein areas such as personal finances, business dealings, or relationships. Theymay have an elevated self-esteem, be more talkative than usual, have flight ofideas, a reduced need for sleep, and be easily distracted. The high, although itmay sound appealing, will often lead to severe difficulties in these areas, such asspending much more money than intended, making extremely rash business andpersonal decisions, involvement in dangerous sexual behavior, and/or the use ofdrugs or alcohol. Depression is often experienced as the high quickly fades andas the consequences of their activities becomes apparent, the depressiveepisode can be exacerbated. Bipolar II Disorder is hypo manic, rather than manic. In other words, they havesimilar symptoms to Bipolar l Disorder but they are not severe enough to causemarked impairment in social or occupational functioning and typically do notrequire hospitalization in order to assure the safety of the person.*"Bipolar Disorder in Mood Disorders at ALLPSYCH Online." Psychology Classroom at AllPsych Online. Web. 02 May 2012. . 5. CLINICAL CRITERIA FOR BIPOLAR II DISORDER: Mania Depression MoodElevated, open, irritable Sad, miserable, dysphoric SpeechFast, flight of thoughtsSlow, monotonous EnergyExcessive, increasedLacking, apathetic psychomotor activity, distractible IdeationGrandiose, self confident Guilt, unworthiness, suicidal PhysicalInsomnia, noticeable weight Fatigue, loss of libido loss BehaviorDisinhibition, hypersexuality,Retardation or agitation, poverty excessive spendingof movements or expression*Kapczinski, Machado-Vieira, Soares."Perspectives for the Development of Animal Models of Bipolar Disorder." Progress inNeuro-Psychopharmacology and Biological Psychiatry 28 (2004): 209-24. Print. 6. *"Health Information Web." Bipolar Disorder. 09 Feb. 2009. Web. 02 May 2012. . 7. ETIOLOGY: Research has shown a strong biological component (genetics) forthis disorder, with environmental factors- which can includestress, lifestyle issues, life changing events, alcohol or drugabuse- playing a role in intensifying the symptoms. EPIDEMIOLOGY : Lifetime prevalence of approximately 1.2%. The U.S. has the highest prevalence rate at 4.4%, while India hasthe lowest at 0.1%.*Kapczinski, Machado-Vieira, Soares."Perspectives for the Development of Animal Models of Bipolar Disorder." Progress in Neuro-Psychopharmacology and Biological Psychiatry 28 (2004): 209-24. Print.*"Bipolar Disorder in Mood Disorders at ALLPSYCH Online." Psychology Classroom at AllPsych Online. Web. 02 May 2012. . 8. What is the significance of ourtreatment? Target population: adults 18 to 40 that have been clinically diagnosed with majordepression or Bipolar Disorder. Patient cannot have any otherpsychological disorder or be on any other medication. Our drug is Aripiam which is a combination of Abilify with abenzodiazepine called Clonazapam. Current treatment methods dont seem to alleviate symptoms ofBipolar Disorder such as agitation, anxiety, and irritability inpatients. Abilify is considered a partial agonist, this implies that the drugtargets certain symptoms of the disorder; but it may not completelydiminish or target all of them to the maximum response. 9. What is our rationale for creating anew drug?Our drug will be administered by depot injection so it will have a time released component which will reduce the chance of abuse potential and it will have a longer lasting effect.There is also a higher compliance rate since it will be administered and monitored by a doctor. 10. Why Abilify?Abilify is seen on many television commercials to alleviate the symptoms of depression and when we researched the drug, we learned that it is also used to treat Bipolar Disorder. Although individuals taking Abilify can experience similar side effects as other drugs, we were curious to research how the drug would act in conjunction with a benzodiazepine. 11. WHATS IN A DRUGS NAME? Chemical:7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}- 3,4- dihydroquinolin-2(1H)- 5-(2-chlorophenyl)-7-nitro-2,3-dihydro-1,4-benzodiazepin-2-one Generic: Trade: 12. CURRENT TREATMENT METHODS: Treatment for Bipolar Disorder can be divided into three groups: Acute treatment focuses on suppressing current symptoms andcontinues until remission, which occurs when the symptoms arediminished for a period of time. Continuation treatment prevents a return of symptoms from thesame manic or depressive episode. Maintenance treatment prevents a recurrence of symptoms. Therisks of long-term medication use must be weighed against therisk of getting sick again (relapse).*Prien, Robert F., and James H. Kocsis. "Long-Term Treatment of Mood Disorders." Home. 2000. Web. 02 May 2012. 13. CURRENT MEDICATIONS FOR BIPOLAR DISORDER:Lithium (most commonly used)Depakote SprinkleRisperdal ConstaAbilify*Segal, Robert. "Treatment for Bipolar Disorder." Helpguide.com. 2012. Web..*Abraham, Raya. "Medications for Bipolar Disorder." Www.webmd.com. 2010. Web. < http://www.wedmd.com/bipolar-disorder/bipolar-disorder-medications>. 14. EFFECTIVE TREATMENT METHODS: Medication is not enough! Cognitive Behavioral Therapy (CBT) Support System Educating yourself and your family about the disorder*Haggerty, Jim. "Combination Therapy for Bipolar." Psychcentral.com. 2006. Web. http://psychcentral.com/lib/2006/combination-therapy-for-bipolar-disorder/.*Tracy, Natasha. "Cognitive Behavioral Therapy Effective for Bipolar Disorder." Pdresources.wordpress.com. Web. 2012. . 15. PHARMACOKINETICS 16. PHARMACOKINETICS: Aripiam activity is primarily due to the parent drug, aripiprazole, andto a lesser extent, to its major metabolite, dehydro-aripiprazole, whichhas been shown to have affinities for D2 receptors similar to theparent drug and represents 40% of the parent drug exposure inplasma. The mean elimination half-lives are about 75 hours and 94 hours foraripiprazole and dehydro-aripiprazole, respectively. Steady-stateconcentrations are attained within 14 days of dosing for both activemoieties. Aripiprazole accumulation is predictable from single-dosepharmacokinetics. At steady state, the pharmacokinetics ofaripiprazole are dose-proportional. Elimination of aripiprazole ismainly through hepatic metabolism involving two P450isozymes, CYP2D6 and CYP3A4.*Bristol Myers Squibb Company. "Abilify." (2005): 1-39. Web. http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021713s004,021436s007lbl.pdf. 17. ROUTE OF ADMINISTRATION AND ABSORPTION: The process of a substance entering the bloodcirculation. Aripiam will be admininstered through an intramuscular injection with peak plasma concentrations at one and three hours. A 5 mg intramuscular injection of Aripiam had an absolute bioavailability of 100%.*Bristol Myers Squibb Company. "Abilify." (2005): 1-39. Web. http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021713s004,021436s007lbl.pdf. 18. DISTRIBUTION: The spreading of substances throughout the fluids andtissues of the body. The steady-state volume of distribution of Aripiam following intravenous administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. At therapeutic concentrations, Aripiam and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin.*Bristol Myers Squibb Company. "Abilify." (2005): 1-39. Web. http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021713s004,021436s007lbl.pdf. 19. METABOLISM: The irreversible transformation of parent compounds into daughter metabolites. Aripiam is metabolized primarily by three biotransformation pathways:dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitrostudies, CYP3A4 and CYP2D6 enzymes are responsible fordehydrogenation and hydroxylation of aripiprazole, and N-dealkylationis catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety inthe systemic circulation. At steady state, dehydro-aripiprazole, theactive metabolite, represents about 40% of aripiprazole AUC in plasma. Clonazepam is metabolized through cytochrome P450, includingCYP3A. Biotransformation occurs mainly by reduction of the 7-nitrogroup to the 4-amino derivative. This derivative can beacetylated, hydroxylated, and glucuronidated.*Bristol Myers Squibb Company. "Abilify." (2005): 1-39. Web. http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021713s004,021436s007lbl.pdf.*GENONE ALBERTA AND GENOME CANADA. "DrugBank: Clonazepam (DB01068)." DrugBank. 2005. Web. 02 May 2012. http://www.drugbank.ca/drugs/DB01068. 20. EXCRETION: The elimination of the substances from the body. The elimination of Aripiam is approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Clonazepam is highly metabolized, with less than 2% unchanged Clonazepam being excreted in the urine. Metabolites of Clonazepam are excreted by the kidneys.*Bristol Myers Squibb Company. "Abilify." (2005): 1-39. Web. http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021713s004,021436s007lbl.pdf.*GENONE ALBERTA AND GENOME CANADA. "DrugBank: Clonazepam (DB01068)." DrugBank. 2005. Web. 02 May 2012. http://www.drugbank.ca/drugs/DB01068. 21. PHARMACODYNAMICS 22. ARIPIAM Abilify, as already stated, is a partial agonist. It is able to regulatedopamine levels by behaving as an agonist when there is too littledopamine, and behaving as an antagonist when there is too muchdopamine present. Animal studies suggest that when levels ofdopamine in the brain are low, Abilify may enhance the dopamineeffect by stimulating the D2 receptor. Clorazepam is a benzodiazepine and works on the GABA receptorto reduce the chemical activity of the brain. Irritability, agitation and anxiety result from high levels of dopaminewhich result from the administration of Abilify. Aripiam is a combination of Abilify (which is used to treat BipolarDisorder) and Clorazepam (a benzodiazepine).*"Coming Off Psychiatric Medication - Atypical." Coming Off Psychiatric Medication. Web. 02 May 2012. . 23. RECEPTOR ACTIVITY AbilifClonazepam y*Paulev-Zubieta. "Chapter 2." New Human Physiology. 2nd ed. Copenhagen, Denmark. New Human Physiology Ch 2.Web. 01 May 2012. . 24. MECHANISM*Key: D2 Receptor Glutamate Receptor Abilify Metabolite (Stimulator) Dopamine Clonazepam Metabolite (Inhibitor) Chloride Ion (Polarize)*This will take place in the substantianigra, 25. PHARMACODYNAMIC TOLERANCE Pharmacodynamics tolerance to anti-anxiety effects ofbenzodiazepines develops with chronic use. Thisoccurs because of a decrease of benzodiazepine bindingsites. Dosage of Aripiam administered will be titrated.*Longo & Johnson. "Tolerance." Mark Nawrot, NDSU Department of Psychology. Web. 15 Apr. 2012. http://nawrot.psych.ndsu.nodak.edu/courses/465Projects06/Benzo/Tolerance.htm. 26. ANIMAL MODELS 27. ANIMAL MODELS: Behavioral changes in animal models of mania can presenttwo basic and distinct dimensions, the subjective andobjective aspects. Subjective changes include modulation of emotions, such as fear, aggressiveness, irritability, social behavior, and dysphoria (i.e. an emotional state marked by anxiety, depression, and restlessness). Objective changes include aspects related to locomotor activity and circadian rhythm.*Kapczinski, Machado-Vieira, Soares."Perspectives for the Development of Animal Models of Bipolar Disorder." Progress inNeuro-Psychopharmacology and Biological Psychiatry 28 (2004): 209-24. Print. 28. Continuation Each group consisted of 20 rats for a total of 60 rats. Our experiment was based on the Genetics model in whichthe rats genes were altered prior to shipment enabling themto display symptoms of Bipolar Disorder (we were not requiredto alter the rats in any way to induce Bipolar Disorder). Each group was given the same dosage of eithersaline, Abilify, or Aripiam at the same time daily for threeweeks. We monitored the rats behavior for the first two weeks. At thestart of the third week, we videotaped our rats and specialencoders watched the video to encode behavioral changes inour subjects. 29. ANIMAL MODELControl Give saline shows no change in behavior over timeAbilfy Relieves behavior while maintaining anxiety, irritability &agitationAripiam Relieves the expected side effects except foranxiety, which is reduced 30. DOSE RESPONSE CURVE Dose-Response Curves Aripiam 100ED50 =150mgTD50=500mg75LD50=1500mg Response5025Margin of safety/ TI=1500/150 = 100 0 20 4060 80 100 150 200 250 300 500 1500 2000 Dose mg EffectiveToxic/Side Effects Lethal*Kapczinski, Machado-Vieira, Soares."Perspectives for the Development of Animal Models of Bipolar Disorder." Progress inNeuro-Psychopharmacology and Biological Psychiatry 28 (2004): 209-24. Print. 31. IN HUMANS MARGIN OF SAFETY:500/150= 3.33 This is a very low TI, but thats OKAY becausehumans will be administered a depot injection ratherthan pill form. This injection can only be given by thedoctor and is unavailable at the pharmacy or byprescription. The dosage may be titrated. 32. ASSESSMENT OF ABUSE POTENTIAL/LIABILITYConditioned PlacePreference 33. Animals will spend 33.3% Abilify of their time in this chamber Test day- animals Animals will get noSalinespend 33.3% treatment, they will be placed in this injectionof their time in chamber andthis chamber decide where to go. Animals will spend 33.3%Nothing of their time in this chamber**This shows that Abilify has no abuse potential because the animalsspend equal amount of their time in each chamber. 34. Animals will Clonazopa spend 99% of m their time in this chamber Test day- animals Animals will get no treatment, they will Saline spend less than be placed in thisinjection 1% of their time chamber andin this chamber decide where to go. Animals will spend less than Nothing 1% of their time in this chamber**Based on this model, clonazopam has a very high abuse potential. 35. Animals will spend 40% of Aripiam their time in this chamberTest day- animals Animals willget notreatment, they will Saline spend 30% ofbe placed in this injection their time in thischamber and chamberdecide where to go. Animals will spend 30% of Nothing their time in this chamber**Based on this model, Aripiam has very little abusepotential because although the animals spend more time in the Aripiamchamber, the percentage isnt much greater. 36. In the futureBased on our findings, future studies should test for thelethal dose (LD50) and the toxic dose (TD50) becausethey are currently undefined for Bipolar Disorder.Future studies should also eliminate the separationbetween depression and mania in animalmodels/studies. 37. AcknowledgmentsWe would like to thank Professor Kristine Stigi Bonacchi for all her wonderful support and advice throughout the semester.We would also like to thank all the psychology studies done in an effort to further advance and treat Bipolar Disorder.Of course we would not have been able to test our drug without thehelp of the National Rat Lab (NRL) and all their rodents.And where would we be without the marvelous wonders of google. 38. References*Kapczinski, Machado-Vieira, Soares."Perspectives for the Development of Animal Models of Bipolar Disorder." Progress in Neuro-Psychopharmacology and Biological Psychiatry 28 (2004): 209-24. Print.*Date, Dave, Gandhi, Parekh, Mistry. "Bipolar Disorder." Web. .*"Bipolar Disorder in Mood Disorders at ALLPSYCH Online." Psychology Classroom at AllPsych Online. Web. 02 May 2012. .*"Health Information Web." Bipolar Disorder. 09 Feb. 2009. Web. 02 May 2012. .*Prien, Robert F., and James H. Kocsis. "Long-Term Treatment of Mood Disorders." Home. 2000. Web. 02 May 2012. *Segal, Robert. "Treatment for Bipolar Disorder." Helpguide.com. 2012. Web. .*Abraham, Raya. "Medications for Bipolar Disorder." Www.webmd.com. 2010. Web. < http://www.wedmd.com/bipolar- disorder/bipolar-disorder-medications>.*Haggerty, Jim. "Combination Therapy for Bipolar." Psychcentral.com. 2006. Web. http://psychcentral.com/lib/2006/combination-therapy-for-bipolar-disorder/.*Tracy, Natasha. "Cognitive Behavioral Therapy Effective for Bipolar Disorder." Pdresources.wordpress.com. Web. 2012. .*Bristol Myers Squibb Company. "Abilify." (2005): 1-39. Web. http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021713s004,021436s007lbl.pdf.*"Coming Off Psychiatric Medication - Atypical." Coming Off Psychiatric Medication. Web. 02 May 2012. .*Paulev-Zubieta. "Chapter 2." New Human Physiology. 2nd ed. Copenhagen, Denmark. New Human Physiology Ch 2. Web. 01 May 2012. .*Longo & Johnson. "Tolerance." Mark Nawrot, NDSU Department of Psychology. Web. 15 Apr. 2012. http://nawrot.psych.ndsu.nodak.edu/courses/465Projects06/Benzo/Tolerance.htm.*GENONE ALBERTA AND GENOME CANADA. "DrugBank: Clonazepam (DB01068)." DrugBank. 2005. Web. 02 May 2012. http://www.drugbank.ca/drugs/DB01068.