Depression Management

Depression Management By: Hani Hamed Dessoki, M.D. Psychiatry Lecturer of Psychiatry Beni-Suef University 2008

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Depression Genetic factors Biochemicalcal Depression factors Environmental factors

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Neurotransmitter Neurotransmitters are chemicals made by the nerve cel s in the brain that send messages back and forth across the space between the cel s (synapse).

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The Biochemical Theory of Depression • The brain has a number of neurotransmitters, which are chemical substances that are responsible for the transmission of nerve impulses. The most studied of these neurotransmitters are: • serotonin • norepinephrine • dopamine

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The Biochemical Theory of Depression A recent hypothesis of depression is that it is the result of a neurochemical imbalance or a functional deficiency of serotonin and/or norepinephrine. This hypothesis is based on the discovery that depressive symptoms can be al eviated by drugs that promote the augmentation of these neurotransmitters in the brain. Depression occurs because of impaired transmission resulting from a lower-than-normal concentration of the neurotransmitters serotonin and norepinephrine at the receptor. Mania, the opposite of depression, is seen as a possible overabundance of norepinephrine at the receptor.

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Serotonin5HT and NorepinephrineNE in the brain Limbic System Prefrontal Cortex Locus Ceruleus Raphe Nuclei (NE Source) (5-HT source) Cooper JR, Bloom FE. The Biochemical Basis of Neuropharmacology. 1996.

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Serotonin5HT and NorepinephrineNE in the brain Functional domains of Serotonin and Norepinephrine1-4 Serotonin (5-HT) Norepinephrine (NE) Depressed Mood Sex Concentration Anxiety Vague Aches Appetite Interest and pain Aggression Irritability Motivation Thought process • Both serotonin and norepinephrine mediate a broad spectrum of depressive symptoms 2. Blier P, et al. J Psychiatry Neurosci. 2001;26(1):37-43. References: 3. Doraiswamy PM. J Clin Psychiatry. 2001;62(suppl 12):30-35. 1. Adapted from: Stahl SM. In: Essential Psychopharmacology: 4. Verma S, et al. Int Rev Psychiatry. 2000;12:103-114. Neuroscientific Basis and Practical Applications: 2nd ed. Cambridge University Press 2000.

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The neurotransmitter pathway story It’s not all in your head • Dysregulation of Serotonin (5HT) and Norepinephrine (NE) in the brain are strongly associated with depression • Dysregulation of 5HT and NE in the Descending Pathway spinal cord may explain an Descending increased pain perception among Pathway Ascending depressed patients1-3 Pathway • Imbalances of 5HT and NE may explain the presence of both emotional and physical symptoms of Ascending Pathway depression. Adapted from References:1. Stahl SM. J. Clin Psych. 2002;63:203-220. 2. Verma S, et al. Int Rev Psychiatry. 2000;12:103-114.3. Blier P, et al. J Psychiatry Neurosci. 2001;26(1):37-43.

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Other receptor sites Other receptor sites: In addition to receptors for serotonin, dopamine and norepinephrine, you should be familiar with: Muscarinic or cholinergic receptors; Adrenergic receptors; Histamine receptors Individual drugs might also have an affinity for other receptors. Based on the strength of this affinity for other receptor sites, patients may experience side effects mediated by interaction with these receptors.

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Mode Of Action Of Antidepressants • Most antidepressants are believed to work by slowing the removal of certain neurotransmitters from the brain (such as serotonin and norepinephrine). Which are needed for normal brain function and are involved in the control of mood and in other responses and functions, such as eating, sleep, pain, and thinking.

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Antidepressants 1. Tricyclic Antidepressant. “TCAs”. 2. Atypical antidepressants. 3. Mon Amine Oxidase Inhibitors “MAO-I” 4. Selective Serotonin Reuptake Inhibitors. “SSRI” 5. Serotonin Norepinephrine Reuptake Inhibitors. “SNRI” 6. Others.

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Tricyclic Antidepressant. “TCAs” First agents marketed in 1950’s Examples: Imipramine ( Tofranil ) Clomipramine ( Supranil ) Amitriptyline ( Tryptizol ) Nortriptyline Desipramine

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Tricyclic Antidepressant. “TCAs” Mechanism of Action Immediate Effect: Block reuptake of Serotonin (5HT) and Norepinephrine (NE) Onset of antidepressant effect: 3-4 weeks

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Tricyclic Antidepressant. “TCAs” Other Receptor EffectsAlpha-1 Blockade: orthostasis, sexual dysfunction, potential for cardiac conduction delays (QT prolongation) Histamine Blockade: potential for weight gain, sedation Acetylcholine Blockade: Cognitive Dulling. Blurring of Vision. Tachycardia. Exacerbation of Asthma. Sexual Dysfunction .

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Tricyclic Antidepressant. “TCAs” Side Effects Dry mouth. Blurred vision. Constipation. Difficulty urinating. Worsening of glaucoma. Impaired thinking and tiredness. These antidepressants can also affect a person’s blood pressure and heart rate.

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Tricyclic Antidepressant. “TCAs” Contraindications Hypertensive patients Cardiac conduction abnormalities (esp. prolonged QT) Acute narrow angle glaucoma GI dismotility syndromes Benign Prostatic Hypertrophy

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Tricyclic Antidepressant. “TCAs” Competitative analysis Strengths Weaknesses Effective, especial y in severe Anticholinergic SEs. depression. Cardiovascular toxicity in Low cost. overdose. Sedation perceived as a weight Gain. benefit. Multiple daily dosing. Titration. Overall SE Profile.

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Mono Amine Oxidase Inhibitors (MAO inhibitors) Mode Of Action Act by preventing the degradation of the neurotransmitters by enzymes, al owing more neurotransmitters to be available in the nerve cel . MAOI: Non-selectively and irreversibly block Monoamine Oxidase (MAO)

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Mono Amine Oxidase Inhibitors (MAO inhibitors) Mode Of Action

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Mono Amine Oxidase Inhibitors (MAO inhibitors) Side Effects• Difficulty getting to sleep. • Dizziness, lightheadedness, and fainting. • Dry mouth, blurred vision, and appetite changes. • High blood pressure “hypertensive crisis" "cheese reaction" • Changes in heart rate and rhythm. • Feelings of restlessness. • Loss of sexual desire or ability. • Weight gain. • Negative interactions with other medications and some foods

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Mono Amine Oxidase Inhibitors (MAO inhibitors) Contraindications• Serious heart problems. • Epilepsy. • Bronchitis. • Asthma. • High blood pressure

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Mono Amine Oxidase Inhibitors (MAO inhibitors) Examples Active constituent Drug Price Tranylcypromine Parnetil 2.40 Moclobemide Aurorix 53.50

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Mono Amine Oxidase Inhibitors (MAO inhibitors) Drug – Drug Interactions • Allergy medicines (including nasal • Insulin drops or sprays) • Ludiomil • Appetite suppressants • MAO-I (other) • Antihistamines (Actifed ) • Norflex • Antipsychotics • Phenergan • Asthma drugs • Sinus medicine • Blood-pressure medicine • Tegretol • BuSpar , Prozac • Wel butrin • Tricyclic antidepressants • Cold medicines • Cocaine

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Selective serotonin reuptake inhibitors (SSRIs), – Fluoxetine (Prozac, Fluoxetine, Flutin & Octozac) , – Fuvoxamine (Favarin) – Sertraline (Moodapex, Lustral, Sirto, Serlift & Seserine) – Citalopram (Cipram, Sedopram, Citalo & cipramax) – Escitalopram (Cipralex & Cipra pro).

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Selective serotonin reuptake inhibitors (SSRIs), Mode Of Action Selectively Block Reuptake of Serotonin• They have no or only weak effects at other monoamine transporter, thus having little direct influence on the level of other neurotransmitters. That distinguishes them from the older TCAs, thus they are named selective. • i.e. SSRIs act only on the neurotransmitter serotonin, while TCAs and MAO-I act on both serotonin and another neurotransmitter, norepinephrine, and may also interact with other chemicals throughout the body.

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Selective serotonin reuptake inhibitors (SSRIs), SSRIs are considered to be safer than TCAs, since the toxic dose is much higher and they have fewer and less strong side effects and drug interactions. • Widely used, first-line treatments for depression and anxiety • Multiple FDA indications • Safety in overdose • Tolerability- better side effect profiles than older drugs like TCAs and MAOIs

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Selective serotonin reuptake inhibitors (SSRIs), Side Effects Anxiety/ akathisia Insomnia vs. sedation GI upset: diarrhea, nausea vs. constipation Anorexia Sexual Dysfunction

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Fluoxetine • Eli Lil y’s Prozac was approved by the FDA on December 29 , 1987 and introduced in the US at the beginning of 1988. • The drug became very popular, with mil ions around the world having taken the medication

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Fluoxetine Pharmacokinetics Absorption Fluoxetine is wel absorbed after oral administration Peak plasma concentrations of fluoxetine observed after 6 to 8 hours Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption inconsequential y. Fluoxetine may be administered with or without food.

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Fluoxetine Pharmacokinetics Fluoxetine is extensively metabolized in the liver to norfluoxetine, and other, unidentified metabolites. The pharmacological activity of norfluoxetine, which is formed by demethylation of fluoxetine appears to be similar to that of the parent drug. Norfluoxetine contributes to the long duration of action of Prozac.

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Fluoxetine Pharmacokinetics • Approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α -glycoprotein. 1 • Due to high plasma protein binding of fluoxetine, it has a relatively long elimination half life (t ) 1/2 • Elimination half-life Fluoxetine : 4-6 days Norfluoxetine :4-16• Steady state: 4-5 weeks.

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Fluoxetine Desmethylation Fluoxetine Norfluoxetine (SSRI) (SSRI) Single dose half life : 2 days 8.6 days Multiple dose half life: 4 days 9.3 days

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Fluoxetine • These long half-lives may be helpful in those patients with compliance issues, but Fluoxetine is most effective when taken daily. Other SSRIs have, by comparison, a very short half-life. • Nevertheless, its long half life is also relevant because suddenly discontinuing SSRIs is known to produce both somatic and psychological withdrawal symptoms, a phenomenon known as "SSRI discontinuation syndrome".

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Fluoxetine Excretion The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. 11 Urine 2 5 feces As norfluoxetine 10 As glucourinatedfluoxetine andnorfluoxetine 60 Unchanged 12 As unidentifiablemetabolites

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Fluoxetine Common adverse effects include : Anxiety .Restlessness and insomnia. GIT (vomiting, nausea)weight loss .Weakness.skin rash.Itching.A decrease in sexual drive, have also been reported. Final y it has been reported to cause subsequent weight gain .

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Fluoxetine Special Populations: • The safety and efficacy has not been evaluated in pediatric patients. • Due to the metabolic pathway of fluoxetine, a dosage adjustment is necessary in patients with liver disease. • However, no adjustment is necessary in renal y compromised patients. • Pregnancy.

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Fluoxetine INDICATIONS Fluoxetine hydrochloride is approved in the United States to treat • depression, • OCD, • premenstrual dysphoric disorder • panic disorder .

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Fluoxetine INDICATIONS In the United Kingdom, it is approved to treat • depression with or without anxiety, • bulimia nervosa • OCD.

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Fluoxetine Dose Depression • Adults: The recommended initial dosage is 20 mg administered once daily in the morning. • A gradual dose increase should be considered only after a trial period of several weeks if the expected clinical improvement does not occur. • Dosage should not exceed a maximum of 80 mg/day since clinical experience with doses above 80 mg/day is very limited., OCD A dose range of 40 mg/day to 60 mg/day

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Fluoxetine CONTRAINDICATIONS • contraindicated in patients with a known hypersensitivity to fluoxetine or any of its ingredients. • MAOIs within fourteen days.

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Fluoxetine Drug – Drug interactions • Interactions could occur if Fluoxetine is given with other medications that also increase the levels of serotonin. • Like other SSRIs, an overdose of Fluoxetine or combining it with other antidepressants can lead to Serotonin Syndrome.

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Fluoxetine Drug – Drug interactions Fluoxetine is metabolized by the enzyme CYP2D6. • When a poor metabolizer takes several doses of Fluoxetine it accumulates to higher than usual levels in the blood resulting in a larger exposure to Fluoxetine than occurs in patients who have this enzyme. • This could lead to adverse drug reactions including anorexia, nervousness, tremor, tachycardia, and seizures.

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Fluoxetine Drug – Drug interactions • The enzyme CYP2D6 can also be inhibited by amiodarone (a medication for cardiac arrhythmias), haloperidol (an antipsychotic medication), and guanidine (a medicine for heart arrhythmias. • If a patient taking Fluoxetine is also taking a medication that inhibits CYP2D6, Fluoxetine can accumulate in the blood, in the same way that it does in a poor metabolizer, and lead to adverse drug reactions.

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Fluoxetine Drug – Drug interactions • Fluoxetine is also a potent inhibitor of CYP2D6 ,i.e. that Fluoxetine can inhibit the elimination, and cause accumulation, of other medications metabolized by CYP2D6. • E.g. .codeine. In the case of the pain medication codeine, Fluoxetine can prevent the body from converting the drug to its active form: morphine and as a result patients prescribed codeine for pain may not experience any benefit if they are taking Fluoxetine at the same time.

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Fluoxetine Drug – Drug interactions• Other drugs metabolized by CYP2D6 include amitriptyline, imipramine, and desipramine and thioridazine (antipsychotic). • Fluoxetine also inhibits enzymes known as CYP2C9 and CYP2C19, and could interfere with the elimination of many medications including warfarin (an anticoagulant) and phenytoin (anti-epileptic). • An accumulation of any of these medications could result in serious and potential y life-threatening adverse drug reactions.

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Low potential for drug-drug interactions Cytochrome P450 Isozyme Inhibition In Vitro/In Vivo 3A4 2D6 1A2 2C19 2C9 Escitalopram 0 + 0 0 0 Citalopram 0 + + 0 0 Fluoxetine ++ +++ + ++ ++ Paroxetine + +++ + + + Venlafaxine + + 0 0 0 Fluvoxamine ++ + +++ +++ ++ Sertraline + + + ++ + 0 = • N A eg nt liigi – ble ++ = Moderate interaction • C a + a nta g o nis ts • C a ffe ine • Dia ze pa m + = A V r er rh y y w t e h ak m iint c eraction +++ = Strong •inter Mi a c cotion na zo le • E rythro m y c in • C ipro flo x a•cPin ro pra no lo l • P he nyto in • K e to c o•na B -zbolloec ke rs • T he o phy lli•ne Mo c lo b e m ide • S -w a rfa rin • L ido c a i•ne Ha lo pe rido l • V e ra pa m il• Im ipra m ine 1. Von Moltke et al. Drug Metab Dispos 2001;29:1102-9 • N S AIDs • • N e uro le ptic s 2. Greenb C la a ttn ect a e l.r J tClhine Prsayc p hiia e trsy 1998;59:19-27 3. Albers et al. Psychiatry Res 2000;96:235-243

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Response and Remission defined Hamilton Depression Rating Scale (HAM-D): 17 Items, Total Score 0 – 52 HAM-D 17 Scores Depression (Major Depressive Disorder) 15 Response ♦ ≥ 50% reduction from baseline HAM-D score 7 Remission: HAM-D Score ≤ 7 References:1. Frank E. Conceptualization and rationale for consensus definition terms in MDD, Arch Gen Psych. 1991; 48:851-855.

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Definitions • Response/responder: improvement over 50 %• Remission/remitter: scores are normal (HAM-D < 7) for first few months • Recovery: scores are normal for over 6 – 12 months• Relapse: when depression returns before there is a full remission of symptoms or within the first several months following remission • Recurrence: when depression returns after patient has recovered

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Response and Remission Remission Relapse Recurrence Euthymia Relapse + P t r Response Symptoms o o g d creased r i severity s e In o s r s + d io e n Syndrome r Acute Continuation Maintenance Treatment phases (6 to 12 wk) (4 to 9 mo) (≥1 yr) Time Adapted from: Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34.

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Recurrence Recurrence Becomes More Likely With Each Episode of Depression First ≈50% episode Second ≈70% episode Third + episode >90% 0 20 40 60 80 100 % of patients expected to experience recurrence within 5 years from recovery of previous episode Keller MB, Boland RJ. Biol Psychiatry. 1998.;44:348-360.

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Duration of Treatment Guidelines •Single episode: treatment duration 4-9 months after complete remission •first recurrence: treatment duration 12 months after complete remission •two or more recurrences: consider life- long treatment

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Depression: Current treatment outcomes1 • Up to 70% of depressed patients respond (≥ 50% decrease in HAM-D score) to treatment but fail to achieve remission from their emotional and physical symptoms1* • Approximately 30% of depressed patients achieve remission (≤ 7 score on the HAM-D) with treatment1* * Antidepressant clinical drug trials. References:1. O’Reardon JR, et al. Psychiatr Ann. 1998;28:633-640.

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Antidepressant Noncompliance • Early Discontinuation of antidepressant : 7 2 .4 8 0 6 0 4 2 .4 4 0 2 0 0 L e s s t h a n 3 0 d a y s L e s s t h a n 9 0 d a y s % o f p a t ie n t s t o p p e d t h e t r e a t m e n t American Journal of psychiatry.2006;163:101-108

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Reasons for Drop-Out % patients Feeling better 55% Adverse events 23% Fear of drug dependence 10% Uncomfortable feeling 10% Lack of efficacy 10% ‘I’ have to do it myself 9% Personal communication, K. Demyttenaere, 2000.

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DURAZAC

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DURAZAC 90 mg of regular enteric-coated Fluoxetine taken every 7 days

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DURAZAC Rationale for Once-Weekly Dosing• Durazac Weekly: A simple, once-weekly dosing regimen which could be a convenient alternative for many patients during long-term treatment of depression • Simple Once weekly formulation allows for new flexibility for Both the clinician and the patient in continuation treatment of depression Burke WJ, et al. Psychopharm Bul . 1996;32(1):27-32. Schmidt ME, et al. J Clin Psychiatry. 2000;61(11):851-857. Claxton AJ, et al. J Clin Psychiatry. 2000;61(12):928-932.

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DURAZAC Pharmacokinetics of Fluoxetine• 90 mg fluoxetine (enteric coated) pel ets.• Onset of absorption is delayed 1 to 2 hours.• Steady state: 4-5 weeks. • Elimination half-life Fluoxetine : 4-6 days Norfluoxetine :4-16

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DURAZAC • After absorption 94.5% of fluoxetine is bound to plasma proteins. • Due to their Plasma protein binding affinity both fluoxetine and norfluoxetine have relatively long half-lives. • The long half-lives of fluoxetine and norfluoxetine al owed the development of delayed-release formulation containing 90mg of fluoxetine per capsule for once-weekly oral administration. • Levels of fluoxetine and norfluoxetine in the serum after once weekly dose are within therapeutic levels needed for clinical improvement.

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DURAZAC Drug-Drug Interactions • No theoretical difference in the drug-drug interaction profile for Durazac Weekly and daily Fluoxetine • Adverse events profile in clinical trials with Durazac Weekly has been virtual y identical to that of the daily preparation

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DURAZAC Dose• Switching from daily Fluoxetine After 1 week• Switching from Other SSRI Switch immediately Durazac once weekly (90mg) = 20 mg/dayDurazac Twice weekly (180mg)= 40 mg/day

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Durazac Weekly Patient Types Who May Benefit : 3 Patients wishing to avoid perceived stigma 3 Patients with unstructured schedules (i.e., travelers) 3 Patients successful y treated and more susceptible to missing a dose as they see less need to continue the use of an antidepressant 3 Patients who do not like the idea of taking medications or swal owing pil s 3 Patients who have compliance issues 3 Young/adolescent patients, 3 Polypharmacy patients, elderly patients, etc.

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Durazac Weekly Clinician Advantage : Existence of a formulation targeted to long-term treatment may help the physician reinforce the importance of continuing treatment Easy increase patient commitment to continuation treatment thereby reducing risk of relapse May increase flexibility in dosing during continuation treatment

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Durazac Weekly •Is as effective in continuation treatment after switching from Fluoxetine daily or other SSRIs. •Produce higher rate of remission & lower rate of relapse in chronic depression •Ensure ful Recovery of symptom of depression •Is safe and wel tolerated with a safety profile similar to fluoxetine 20 mg daily •Results in a level of compliance higher than once-daily regimen during the long-term treatment of depression

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CONCLUSION Durazac is the only 90 mg Fluoxetine once weekly fulfil the unmet need with other SSRI that ensure full recovery of depression • ensure maximum compliance ( 4 capsules monthly ) • That reflects excel ent efficacy (no missed dose ) • Patients continue treatment to the desired period • Low incidence of side effect ( 90 mg instead of 140 mg )

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