2Outline of Antidepressants IntroductionTreatment of depressionDrug treatmentTricyclic Antidepressants (TCA)Serotonin - Specific Reuptake Inhibitors (SSRI)Monamine Oxidase Inhibitors (MAOI)Heterocyclic Antidepressants
3Definition of Depression “An affective disorder characterized by loss of interest or pleasure in almost all a person’s usual activities or pastimes.”وابسته به عاطفه و احساس، عاطفی، انفعالی، خود بهره ورaffective
4Symptoms Associated With Depression Sadness, Despair, Guilt, PessimismDecrease in energyDecrease in sex driveInsomnia and fatigueThoughts of death and suicideMental slowing, lack of conc
5Depression types Reactive or Secondary (~60%) Melancholic (~25%) Non pharmacologic treatmentReactive or Secondary (~60%)Related to some “loss”, physical illness (MI, Cancer),Drugs, (alcohol, beta blockers, prednisone, reserpine, cocaine)Other psychiatric disorders (senility)Melancholic (~25%)Major or EndogenousNo clear/adequate precipitating eventBipolar affective(Manic-depressive)Episodes of mania associated with depressionDepression alone - occasional; Mania alone – rarePharmacologic treatmentmel·an·cho·li·a (mln-kl-)n.A mental disorder characterized by severe depression, guilt, hopelessness, and withdrawal.Mood stabilizer (lithium)
6Other Types of Depression Chronic or Dysthymia (~3-6%)Less severe, but long lasting (>2 yrs)AtypicalPatients overeat, oversleep, react strongly to rejectionSeasonal affective disorderAnnual episodes of depression during fall or winter
10Molecular bases of depression Amine hypothesis: Depression is associated with decreased amine-dependent synaptic transmission.Almost all antidepressants affect metabolism or reuptake of serotonin, NE, or both.Several brain circuits have also become dysfunctional.Some are also selective antagonists of serotonin or norepinephrine.The full clinical effects of drugs requires 4-8 weeks.
13TREATMENT FOR DEPRESSION PsychotherapyElectroconvulsive therapyNatural alternativesMedicationPsycotherapy/talk therapy – especially useful when combined with meds. Goal is to teach good coping skills for every day stressorsECT – electric shock is applied to scalp through electrodes, results in seizure in the brain. Fast and effecitve in patients with depression or suicidal thoughts (good for suicide bc doesn’t have the same delayed onset as meds). Usually given up to three times a week for two to four weeksNatural alternatives – St. John’s wort (sold in teas and tablets, and in diet pills) not good for severe depression but can help mild depression
14Drug therapy of depression Drugs first introduced 50 years ago that were were used for treatment of other disorders including:Anxiety disorders, dysthymia, chronic pain and behavioral problemsAntidepressants discovered accidentally while investigating antipsychotic phenothiazinesImipramine - first antidepressant discovered
15ضد افسردگی های سه حلقه ای Drugs & structureMechanism of ActionSide effectsOverdose
16ضد افسردگی های سه حلقه ای ایمی پرامین (Imipramine)دسی پرامین (Desipramine)آمی تریپتیلین (Amitriptyline)پروتریپتیلین (Protryptyline)کلومیپرامین (Clomipramine)ترمیپرامین (Trimipramine)نورتریپتیلین(Nortriptyline)دوکسپین (Doxepin)
20TCA side effects Phenothiazine like “side effects”: Antimuscarinic (M1): dry mouth, constipation, urinary retention, aggravation of glaucomaAntihistamine (H1): sedation (tolerance can develop)Na channel block: QRS, arrhythmias*alpha blockade (α1) : orthostatic hypotension, tachycardia** erectile dysfunction
21Overdose of TCAs Are extremely dangerous in overdose More than 1 g of a tricyclic is potentially lethalTCAs increase suicidal risks.Manifestations are: mydriasis, respiratory depression, seizure, cardiac arrhythmia and coma
22Serotonin - Specific Reuptake Inhibitors (SSRI) Drugs & structuresMOA & UsesSide effectsProperties of individual drugs
23SSRI Fluoxetine Paroxetine Sertraline Fluvoxamine Citalopram Its active metabolite has a half-life of 7-9 days.
25SSRI Available for the past 15 years MOA: Allows for more serotonin to be available to stimulate postsynaptic receptorsAvailable to treat depression, anxiety disorders, ADHD, obesity, alcohol abuse, childhood anxiety, etc.
28Schematic diagram showing some of the potential sites of action of antidepressant drugs. The primary neuron is shown as releasing a transmitter amine (NT). A modulating neuron may release a second transmitter (NTx), regulating the activity of the primary neuron. The most consistent observed effect of the antidepressants (other than MAO inhibitors) is inhibition of the reuptake transporters (T) for norepinephrine or serotonin. The MAO inhibitors increase the vesicular stores of both NE and 5-HT. Other direct or indirect effects include initial increase in activation of pre- and postsynaptic receptors and subsequent desensitization or down-regulation of transmitter synthesis from an amino acid (AA), receptor numbers, or postreceptor mechanisms. Desensitization resulting from antidepressant use has been reported for a2, b, and 5-HT1A systems (color). VAT denotes a vesicle-associated transporter.
29SSRI’ side effects Serotonin syndrome: When a SSRI is used with a MAOI causes marked increases of serotonin in the synapses.Characterized by: muscle rigidity, myoclonus, hyperthermia & rapid changes in mental status and vital signs. It may be fatal.Serotonin withdrawal syndrome: within a few days and can persist 3-4 weeks. Symptoms: disequilibrium, gastrointestinal problems, flu-like symptoms, sensory disturbances, sleep disturbances
30SSRI’sFluoxetine (Prozac) – first SSRI available, long half life, slow onset of action, can cause sexual dysfunction, anxiety, insomnia and agitation, Nausea, Headache, Insomnia, Weight gainSertraline (Zoloft) – second SSRI approved, low risk of toxicity, few interactions, more selective and potent than ProzacParoxetine (Paxil) – third SSRI available, more selective than Prozac, highly effective in reducing anxiety and posttraumatic stress disorder (PTSD) as well as OCD, panic disorder, social phobia, and chronic headache.
31SSRI’sFluvoxamine (Luvox) – structural derivative of Prozac, became available for OCD, also treats PTSD, dysphoria, panic disorder, and social phobiaCitalopram (Celexa) – well absorbed orally, few drug interactions, treats major depression, social phobia, panic disorder and OCD
32SERT vs NETSSRIs are more selective for 5-HT transporter than NE transporter (300 to 7000).Trazodone, nefazodone, & mirtazapine antagonize serotonin receptors.
33MAOIs History, Isoniazid,Iproniazid MAO and depression Current Drugs Mechanism of ActionSide EffectsIsoniazidBoth early drugs developed in sixties for anti tuberculosis but found to have antidepressant effects, got off market due to toxicityMAOIs were the first class of antidepressants to be developed. They fell out of favor because of concerns about interactions with certain foods and numerous drug interactions. MAOIs elevate the levels of norepinephrine, serotonin, and dopamine by inhibiting an enzyme called monoamine oxidase. Monoamine oxidase breaks down norepinephrine, serotonin, and dopamine. When monoamine oxidase is inhibited, norepinephrine, serotonin, and dopamine are not broken down, increasing the concentration of all three neurotransmitters in the brain. They are also used for treating Parkinson's.Iproniazid
34MAO & DEPRESSIONMAO catalyze deamination of intracellular monoamines (NEP, EP, Serotonin, DA …).MAO-A oxidizes NEP, EP, Serotonin and DAMAO-B oxidizes phenylethylamineBoth oxidize dopamine nonpreferentiallyMAO transporters reuptake extracellular monoamine
37Reuptake of NE Monoamine oxidase, located on outer membrane of mitochondria; deaminates catecholamines free innerve terminal that are not protected by vesiclesStimulantCocaine blocks the NETReuptake of NE
38MAOI side effectsMAO-A metabolizes norepinephrine, serotonin & tyramine.MAO-B is more selective for dopamine.Nonselective MAO inhibitors can lead to hypertensive reactions due to tyramine in ingested food.Tyramine is found in banana, fermented food (cheese) & fermented beverages.
39Interaction Between Dietary Tyramine and MAOIs Food with tri-amine (pepporoni, sausage, some cheese)- interaction causes promotion of release of accumulated NE stores, thereby causing massive vasoconstriction and excessive stimulation of heart (hypertension)
45ضد افسردگی اتیپیک مکانیسم: مکانیسم مشترکی ندارند آثارشان دیر ظاهر می شودعوارض متفاوت و کمتر از TCA
46VenlafaxineSNRIs act upon two neurotransmitters in the brain that are known to play an important part in mood.SNRIs were developed more recently than SSRIs, and there are relatively few of them.Their efficacy as well as their tolerability appears to be somewhat better than the SSRIs, owing to their compound effect.Because of their specificity for the serotonin and norepinephrine reuptake proteins, lack most of the adverse side effects of TCA and MAOI.
47Venlafaxine (Effexor) Venlafaxine hydrochloride first introduced by Wyeth in 1993.It is used primarily for the treatment of depression, generalized anxiety disorder, and social anxiety disorder in adults.Venlafaxine is the first and most commonly used SNRI.Venlafaxine has a single chiral centre and exists as a racemic mixture of R-(–)- and S-(+)-enantiomers. The R-enantiomer exhibits dual presynaptic inhibition of serotonin and noradrenaline reuptake, while the S-enantiomer is predominantly a serotonin reuptake inhibitor.In vitro, venlafaxine is approximately 3- to 5-fold more potent at inhibiting serotonin than noradrenaline reuptake. It has low affinity for muscarinic cholinergic, histamine H1 and adrenergic receptors.
48Venlafaxine Dosage and Side Effects Because of its relatively short half-life of 4 hours, Effexor should be administered in divided dosages throughout the day.Side effects may include nausea, dizziness, sleepiness, abnormal ejaculation, sweating, dry mouth, gas or stomach pain, abnormal vision, nervousness, insomnia, loss of appetite, constipation, confusion/agitation, tremors, and drowsiness.
49Bupropion Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)
50Norepinephrine and Dopamine Reuptake Inhibitor (NDRI) These are a class of antidepressants that are not really categorized as a special group of antidepressants.The only antidepressant in this group is Bupropion, which is an antidepressant chemically unrelated to tricyclics or SSRIs. It is similar in structure to the stimulant cathinone, and to phenethylamines in general.
51Bupropion Bupropion was first synthesized in 1966 It was approved by the FDA in 1985 and marketed under the name Wellbutrin as an antidepressant.
52Bupropion MOABupropion is a selective catecholamine (norepinephrine and dopamine) reuptake inhibitor.
53Bupropion and its Metabolites Bupropion is metabolised in the liver. It has at least three active metabolites; hydroxybupropion, threohydrobupropion and erythrohydrobupropion.These active metabolites are further metabolised to inactive metabolites and eliminated through excretion into the urine. The half-life of bupropion is 20 hours as is hydroxybupropion's.Threohydrobupropion's half-life is 37 hours and erythrohydrobupropion's 33 hours.
54Bupropion Side Effects Common side effects include dry mouth, tremors, anxiety, loss of appetite, agitation, dizziness, headache, excessive sweating, increased risk of seizure, and insomnia. Bupropion causes less insomnia if it is taken just before going to bed.Sexual side effects normally accompanying SSRI's do not accompany bupropion. Interestingly, patients commonly report increased libido, perhaps evidence of its dopaminergic properties.
55Drug ChoiceComparisons of the antidepressants showed that they are roughly equivalent in efficacy.Individual patients may respond better to one drug than to another.Patients depressed enough to be hospitalized respond better to classic TCAs than to SSRIs.Outpatient studies also show a greater efficacy of TCAs over SSRIs.
56Drug Choice Cont,dSSRIs are not sedative, safe in overdose and have mild adverse effects so they are widely prescribed.Finding the right drug and the right dose must be accomplished empirically.If it is the first depressive episode and if the treatment was satisfactory, withdraw treatment after 6-9 months.A patient who has had previous episodes of depression is a candidate for maintenance therapy.The duration of maintenance treatment varies and may continue indefinitely.
57Atomoxetin (NET inhibitor) Clinical ApplicationDepressionPanic disorderObsessive-compulsive disordersEnuresisChronic painAttention deficit hyperkinetic disorder (ADHD)Definitely requires pharmacologic treatment given the high rate of suicide in patientsAre acute episodes of anxietyBenzodiazepines are preferred drugsFluoxetine and clomipramineEffect of drug lasts as long as treatment is continuedUsed for elderly institutionalized patientsDrug therapy is NOT the choice treatmentTCAs are useful, SSRIs have no effectAtomoxetin (NET inhibitor)
107Lithium Effective in treating bipolar (manic - depressive) disorder. A “mood stabilizer”Has multiple effects including inhibiting enzymes involved in PI recycling
108HypothesisIn mania, there is increased activity of NTs utilizing DAG/IP3 2nd messengersLi “reduces” the response produced by these overactive NTsSelective depression of “overactive circuits”
109Lithium side effectsSide Effects: polydypsia, polyuria*, edema, weight gain, thyroid enlargement, hypothyroidism (5%)Toxicity:Low dose: nausea & vomitingHigh dose: seizures, circulatory collapse, comaAvoid dehydration, diarrhea, vomiting, diureticsAlternative drugs for bipolar disorderValproic acid & carbamezepineSSRIs can unmask mania in patients with a bipolar disorder*Li causes the renal collecting duct to become resistant to ADHPolydypsia=عطش بیش از حد
111Antidepressants Available in the Market (Worldwide)1 1) Tricyclics and Tetracyclics (TCA)Imipramine Doxepin Desipramine Amoxepine TrimipramineMaprotiline Clomipramine Amitriptyline Nortriptyline Protriptyline2) Monoamine Oxidase Inhibitors (MAOIs)Tranylcypramine Phenelzine Moclobemide3) Serotonin Selective Reuptake Inhibitors (SSRIs)Fluoxetine FluvoxamineSertraline Paroxetine Citalopram4) Dual Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)Venlafaxine Duloxetine5) Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs)Nefazodone Trazodone6) Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)Bupropion7) Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs)Mirtazapine8) Noradrenalin Specific Reuptake Inhibitor (NRI)Reboxetine9) Serotonin Reuptake EnhancerTianeptine
112انتخاب داروهای ضد افسردگی TCA’sLess well tolerated in elderlyLess expensiveHigher overdose potentialSSRIs & HeterocyclicsEmpirical selectionBupropion has less sexual side effects* & may help smokers “quit” the habit(contraindicated in pts. w/ seizure history)Escitalopram (Lexapro ®) - no weight gainAtypical DepressionMAOI (phenelzine)Manic-DepressiveLi, carbamazepine, valproic acid