£, . DEPARTMENT OF NEUROSCIENCES AND BEHAVIORAL MEDICINE es TY OF MEDICINE & SURGE! CUNVERSITY OF SANTO 1 ou q.Mental Disorder DSM-5 DEFINITION v Syndrome characterized by clinically significant disturbance in an individual’s cognition, emotion regulation, or behavior that _feflects a dysfunction in the psychological, biological, or developmental processes underlying mental functioning. ¥ Usually associated with significant distress or disability in social, occupational, personal care/hygiene or other important activities. v An expectable or culturally approved response to a common stressor or loss, such as the death of a loved one, is not a mental disorder. Y¥ Socially deviant behavior (e. g., political, religious, or sexual) and conflicts that are primarily between the individual and society are not mental disorders unless the deviance or conflict results from the dysfunction in the individual, as described above.EE a Psychotropic Drugs = Antipsychotics = Anti-depressants = Mood stabilizers = AnxiolyticsGeneral Pharmacology STRATEGIES Indication - establish a diagnosis and identify the target symptoms, based on established functional & anatomical substrates, that will be used to monitor therapy response. Choice of agent and dosage - select an l agent/molecule with efficacy and an acceptable side effect profile and use the lowest effective dose.General Pharmacology STRATEGIES = Develop skills to establish informed consent - patient should understand the benefits and risks of the medication. Make sure to document this discussion including patient understanding and agreement. In fertile women make sure to document teratogenicity discussion. = Implement a monitoring program - track and document compliance, side effects, target symptom response, blood levels and blood tests as appropriate.General Pharmacology STRATEGIES m Management - Adjust dosage for optimum benefit, safety and compliance. Use adjunctive and combination therapies if needed however always strive for the simplest regimen. Keep your therapeutic endpoint in mind. wePsychiatric Illnesses BURDEN « DISEASE2 — Antipsychotics: CLINICAL INDICATIONS = Psychoses Schizophrenia Schizoaffective Schizophreniform ~ Brief reactive psychosis Bipolar Mood Disorder — Manic phase Delusional disorders ~ Psychoses associated with organic brain diseasesAntipsychotics: CLINICAL INDICATIONS = Psychoses = Non-psychotic disorders ~ Alzheimer’s disease — behavioral manifestations Gilles dela Tourette ~ Tetanus - Antiemetic ~ intractable cingultus Pre-operative medication ~ antihistaminicEEE Antipsychotics CONTRAINDICATIONS = Depressed sensorium = Parkinsonism = Pregnancy = Respiratory depression ( ™ Medically ill geriatric patients2 — Clinical Case Martin is a 21 year-old business major at a large university. Over the past few weeks his family and friends have noticed increasingly bizarre behaviors. On many occasions they've overheard him whispering in an agitated voice, even though there is no one nearby. Lately, he has refused to answer or make calls on his cell phone, claiming that if he does it will activate a deadly chip that was implanted in his brain by evil aliens. His parents have tried to get him to go with them to a psychiatrist for an evaluation, but he refuses. He has accused them on several occasions of conspiring with the aliens to have him killed so they can remove his l brain and put it inside one of their own. He has stopped attended classes altogether. He is now so far behind in his coursework that he will fail if something doesn’t change very soon. He has an estranged aunt who has been in and out of psychiatric hospitals over the years due to erratic and bizarre behavior.Which of the following neural pathways will explain the symptoms in this case? A. tuberoinfundibular B. mesolimbic C. nigrostriatal D. mesocorticalThe dopaminergic pathways Basal gangliaThe dopaminergic pathways MESOLIMBIC SYSTEM § vel Cer M nL} POSITIVE symptoms of Genre suesnel Mesolimbic dopamine pathway Mesocortical dopamine pathway Tuberoinfundibular dopamine pathway1 The CNS dopaminergic pathways Mesocortical Mesolimbic _Nigrostriatal a Tuberoinfundibular Goodman and Gilman's Therapeutic Basis of Pharmacology2 The CNS dopaminergic pathways Mesocortical Mesolimbic Nigrostriatal \ > x SS Tuberoinfundibular Goodman and Gilman's Therapeutic Basis of PharmacologyClinical Case 23-year-old male accounting major graduate who has been described as a loner, was brought in the emergency room because of deterioration in personal hygiene that has been going on for over half a year already. The patient preferred to be in his room alone, eats there and noticed to have restricted range of expressed emotions with affective flattening. He is relatively immobile seated on the floor in the same spot for hours with unresponsive facial expressions, often accompanied by poor eye contact and little body language or movement approaching catatonia. He has extremely reduced total speech output and reduced verbal fluency. He lost the will or desire to participate in activities or to do things and had none of the social and interpersonal interactions. He denies any perceptual distortions.Which of the following neural pathways will explain the symptoms in this case? A. tuberoinfundibular B. mesolimbic C. nigrostriatal D. mesocorticalWhich of the following neural pathways will explain the symptoms in this case? A. tuberoinfundibular B. mesolimbic C. nigrostriatal , D.mesocorticalEEE The dopaminergic pathways Basal ganglia Nigrostriatal dopamine pathway Mesolimbic dopamine pathway Mesocortical dopamine pathway Tuberoinfundibular dopamine pathwayMESOCORTICAL SYSTE ecole. NEGATIVE symptoms of Rene aieae Nigrostriatal dopamine pathway Mesolimbic dopamine pathway Tuberoinfundibular dopamine pathwayae The CNS dopaminergic pathways Excess DA Mesocortical Mesolimbic Nigrostriatal ¢ fa Ba ypy Tuberoinfundibular Goodman and Gilman's Therapeutic Basis of Pharmacology1 The CNS dopaminergic pathways Deficient DA Mesocortical Mesolimbic Nigrostriatal Tuberoinfundibular Goodman and Gilman's Therapeutic Basis of Pharmacology1 The CNS dopaminergic pathways Meascoical Mesolimbic — Nigrostriatal Tuberoinfundibular Goodman and Gilman's Therapeutic Basis of PharmacologyDopamine Hypothesis of Schizophrenia a Mesolimbic pathway: Hyperactivity - related to Positive Syndrome (Delusion, Hallucination, thought disorder) = Mesocortical pathway: Hypoactivity - related to Negative/Cognitive Syndrome (cognitive blunting, social isolation) = Nigrostriatal pathway - related to EPS/Movement disorder (Akathisia, Dystonia, Dyskinesia) m Tuberoinfundibular pathway - related to Hyperprolactinemia eeCORE SYMPTOM DOMAINS Positive Delusions Hallucinations Unusual behavior Social and Occupation: Dysfunctio: Negative Flat affect Social withdrawal Emotional withdrawal Black DW et al. Introductory Textbook of Psychiatry. 2001,204-228, Sitis SG. Scnizophrema, 1995,128-146, Harvey PD et al Am J Psych 2001.158:176-184 Stahl SM. Essenta! wmCORE SYMPTOM DOMAINS Positive Affective Delusions Dysphoria Hallucinations Depression Unusual behavior ~ Negative Cognitive Flat affect Attention Social withdrawal Memory Emotional withdrawal Executive function Decision making Black DW et al. Inroductory Textbook of Peychiatry. 2001,204-228 Sins 8G, Schizophrenia 1998.128-145. Harvey PO et al Am. Psych 2001,158 176-184 Stahi SM. Essential Psychopnarmacology. 2000:99-133, 135-197. 365-399, 401-458. »Which of the following antipsychotics will NOT provide therapeutic benefits for the last case? A. haloperidol B. quetiapine C. risperidone D. aripiprazoleWhich of the following antipsychotics will NOT provide therapeutic benefits for the last case? A. haloperidol B. quetiapine C. risperidone { D. aripiprazoleWhich of the following antipsychotics will NOT provide therapeutic benefits for the last case? A. haloperidol B. quetiapine C. risperidone D. aripiprazoleSS Antipsychotics = D, Antagonist (TyPicavicLassicaL)*— Antipsychotics = D, Antagonist (tvPicauicLassicat) Phenothiazines v chlorpromazine v thioridazine v_ trifluoperazine Butyrophenones v haloperidol Thioxanthenes v thiothixeneAntipsychotics = Dz Antagonist (rvpicavctassicaL) - Phenothiazines v chlorpromazine v thioridazine v trifluoperazine { ~ Butyrophenones v haloperidol ~ Thioxanthenes v_ thiothixenea Antipsychotics = D, Antagonist (rypicavictassicaL) = D,/5-HT2, Antagonist (atyPicauisGa/sDA) ~ Tight Dz binding ¥ dihydroindolones — ziprazidone ‘ dibenzoxazepines — loxapine v dibenzodiazepines — clozapine v benzisoxazole — risperidone, paliperidone v arylpiperidylindole — sertindole ¥ thienobenzodizepines — olanzapine ¥ benzamide — sulpiride, amisulpirideAntipsychotics = D, Antagonist (rypicavicLassicaL) = D,/5-HT >, Antagonist (atypicaL/sca/spA) ~ Tight D, binding ~ Readily D, dissociating y dibenzothiazepine — quetiapineAntipsychotics a D, Antagonist (tvPicAuicLassicaL) a D,/5-HT>, Antagonist (atyPIcALSGA/SDA) ~ Tight D2 binding ~ Readily D2 dissociating = Partial Dz Agonist (atypicauisca) Dihydocarbostyril - aripiprazole. — - Developments in Medical Treatments for Psychotic Disorders cin) ‘0 70s | Haloperidol ECT Fluphenazine Thioridazine Loxapine Perphenazine Chlorpromazine~ Developments in Medical Treatments for Psychotic Disorders These ‘typical’ antipsychotics were a great advance, but associated with * EPS (dystonia, akathisia, pseudo-parkinsonism) Prolactin elevation Negative symptoms Cognitive impairment Tardive dyskinesia Burris et al. J Pharmacol Exp Ther. 2 Kapur andES Clinical implications of blockade of D2 receptors by antipsychotics Receptors Lele utile Dis erneaes as PTS Temata’ ieee enero Efficacy on agitationDe we ag Deen ced eeu eisd Laie coal be PS ee (oo Pe ume eee ae)* — Clinical implications of blockade of D2 receptors by antipsychotics Receptors aii eS Dye cle rea icons ate Ss Mu urs Efficacy on positive sx eee ea) Chey ieee meen) Pein ane cnc tardive dyskinesia) arsine ul) (eel ee ene lear} Pca ty Pare Mua UF Cre CMLL smePe Phenothiazines STRUCTURE ACTIVITY RELATIONSHIP Chemical Class Side Chain Drug Phonothiazines ¢ (low!medium potency agents) Chlorpromazine Levomepromazine Promazine Trilupromazino Piporidine (low/medium potency agents) Mesoridazino Pericyazine l Pipotiazine Thioridazine Piperazine (medium/high-potency agants) Perphenazino Fluphenazine Trifluoperazino_———— Clinical implications orblockade of various receptors by high potency D, antagonistClinical implications ofblockade of various receptors py low potency Dz antagonist eS TE =| Histamine S Anti ant blockade cholinergic | blockade +++ +++ | ++++ | | +++ t+4++ t+tt+ +++ +444 + +++ +++ ++gE D. Antagonist ADVERSE EFFECTS Prior safety concerns Deir aie) EPS + TDSchizophrenia DOPAMINE-BASED (DA) HYPOTHESIS = Limitations: ~ often effective for treating positive symptoms, they have little impact on negative symptoms and cognitive deficits - poor functional outcome — in a substantial number of patients, positive symptoms are resistant to currently available medications S Miyamoto et, al, Molecular Psychiatey (2012) 17, 1206-1227 »“ Developments in Medical Treatments for Psychotic Disorders Clozapine CeCe Euler’ MacDonald GJ, Bartolomé JM. Prog Med Chem. 2010:49:37-80, Burrs et al.J Pharmacol Exp Kapur and Remington, tnmu Re Roth etal. Preskorn SH. J Psychiatr Garver DL. Curr Drag Ta:7 Developments in Medical Treatments for Psychotic Disorders : Clozapine (1993) Quetiapine (1 XB co l oo MacDonald GJ, Bartolomé JM. Prog Med Chem, 2010;49:37-80,“ Developments in Medical Treatments for Psychotic Disorders Hy oN Nn? Nah OO, H SCH, Clozapine ; a » (a dibenzodiazepine) Olanzapine (1993) Quetiapine (1997) n-O N-S OH 9° Ny’ fs 4 ron Oo a > ote oa, > at oy Haloperidol ee (a butyrophenone) Risperidone (1993) Ziprasidone (2001) Kapur and Remington. nnu Resoe ee “ Developments in Medical Treatments for Psychotic Disorders MacDonald GJ, Bartolomé JM. Prog Med Chem. 2010:49:37-80, Burris et al. J Pharmacol Exp Ther. 201 Kapur and Remington, nnu Rev Med. 2001zz Developments in Medical Treatments for Psychotic Disorders oN So q Partial PW etn 3 MacDonald GJ, Bartolomé JM. Prog Med Chem. 2010;49:37-80. Burris tal. J Pharmacol Exp Ther.Schizophrenia SEROTONIN-BASED HYPOTHESIS = Concept of “atypicality” v high affinity to 5-HT2, receptors v Lower affinity to D2 receptors + high ratio of 5-HT2, receptor to D, receptor blockade confers this AP ‘atypicality’ Increase dopaminergic transmission in the nigrostriatal pathway, thus reducing the risk for EPS ~ improve negative symptoms and cognitive impairment in schizophrenia by increasing release of dopamine, acetylcholine (Ach) or both in the prefrontal cortex (PFC)Schizophrenia SEROTONIN-BASED HYPOTHESIS = Concept of “atypicality” high affinity to 5-HT2, receptors Lower affinity to D2 receptors = high ratio of 5-HT2, receptor to D2 receptor blockade confers this AP ‘atypicality’ Increase dopaminergic transmission in the nigrostriatal pathway, thus reducing the risk for EPS ~ improve negative symptoms and cognitive impairment in schizophrenia by increasing release of dopamine, acetylcholine (Ach) or both in the prefrontal cortex (PFC)What significant adverse effect is expected to be observed for the “2"¢ Generation” antipsychotics (SGA)? A.dryness of the mouth B.weight gain C.orthostatic hypotension D.extrapyramidal side effectsWhat significant adverse effect is expected to be observed for the “2"4 Generation” antipsychotics (SGA)? A.dryness of the mouth B.weight gain C.orthostatic hypotension D.extrapyramidal side effectsClinical implications of blockade of various receptors by atypical antipsychotics Dose Cee eal =) ror a Generic name (class) erin terse Creare sey DIBENZODIAZEPINES Clozapine THEINOBENZODIAZEPINE 5 ++ 0 + > Olanzapine DIBENZOTHIAZEPINE 150 + 0 + + Quetiapine DIHYDROCARBOSTYRIL 10 0 0 0 + AripiprazoleAlthough Much Improved From Typicals, Atypical Agents Come With a Range of Side Effects at aa Rett prs Shin Atipiprazole +h + + 4 + Clozapine see +e +h +h + Olanzapine | +444 te + +h + Paliperidone| ++ + ae +H = Quetiapine 44+ + | oe +h + Risperidone ys +4 +H +H + Ziprasidone +h +h + + + Deshmukh $ ot al. Internet J Pharmacol. 2009;7:27EEE D./5-HT,, Antagonist ADVERSE EFFECTS Prior safety concerns Current safety concerns1. ———L D,/5-HT», Antagonist ADVERSE EFFECTS Less effects on: vEPS, negative symptoms and cognition Adifferent set of concerns: v Weight gain (get baseline weight) Y Akathisia ¥ Sedation ¥ Hyperglycemia/Hyperlipidemia(baseline fasting lipids and glucose) ¥ Dizziness (orthostatic hypotension; check BP) ( ¥ In dementia increase mortality and risk of cardiovascular events ¥ Risk of agranulocytosis and seizure (dose dependent) with ClozapineWhich of the following laboratory examinations will provide the most information in decisions regarding the choice of antipsychotics? A. 12 Lead ECG B. fasting blood sugar C. total cholesterol D. all are correct eo.Which of the following laboratory examinations will provide the most information in decisions regarding the choice of antipsychotics? A. 12 Lead ECG B. fasting blood sugar C. total cholesterol D. all are correctWhich of the following antipsychotics will offer the best treatment strategy with the least of significant adverse effects? A. olanzapine B. quetiapine C. asenapine D. aripiprazoleWhich of the following antipsychotics will offer the best treatment strategy with the least of significant adverse effects? A. olanzapine B. quetiapine C. asenapine D. aripiprazoleEvolution from Typical to Atypical Antipsychotics Evolution From Typical to Atypical Antipsychotics + Goal in creating atypical antipsychotics was to produce molecules ~ =” With higher binding affinity for the 5-HT,, than for the D, receptor Cee Cone ing ‘Shahid Mt al. J Paychopharmacol. 2009; Preskorn SHI Pasehlate Pract. 2010; 1 MacDonald G2, Bartolomé IM. Prog Med Chem - 2010:Newer Agents Becoming Available: Asenapine Mirtazapine (~ Asenapine® K, (nM) onvushay SHTyc SHTy, SHT, SH, me D2 tu tae Hy U st jit Strong Moderate Weak ‘+ Improvement in cognitive parameters (eg, verbal learning and speed of processing) and negative and affective symptoms * Potentially reduced effect on sedation and weight gain * Approved in Canada as of October 7, 2011 Shahid M et al. J Psychopharmacol, 2009;23:65-73, MacDonald GJ, Bartolomé JM. Prog Med Chom, 2010:49:37-80. ‘Stahl SM, Mignon L. Stahl tllustrated. 2010. Citrome L. Nouropsychiatr Dis Treat. 2011:7:325-339.Newer Agents Becoming Available: lloperidone Risperidone lloperidone® M CO,H 500 400 300 200 100 K, (nM) ST Dr Ds Da ST. SHT) uy SHT DH Strong Moderate Weak + Good efficacy vs positive symptoms, with a low EPS liability + Potentially minimal risk of sedation, weight gain, metabolic syndrome or cognitive impairment = Moderate interaction with «a, receptors seems to lead to prolongation of QTc, increases in heart rate, and orthostatic hypotension * Introduced in 2010 in the US; as of October 2011, not yet approved in Canada MacDonald GJ, Bartolomé JM. Prog Med Chem. 2010;49:37-80. Citrome L. Expert Opin Drug Motab Toxicol. 2010;6:1551-1564.Newer Agents Becoming Available: Lurasidone Ziprasidone Lurasidone™® HN. S N OF aos » 40 5 30 = 20 10 ce, = aaa SH, | SH, S-HT yg et % Strong Stronger than other atypical Weak Also low affinity for D, and 5-HT,c and no binding to H, or M, receptors '* Not associated with a propensity to cause QTc prolongation * Favourable metabolic, sedation, and cognitive profile * Introduced in 2010 in the US; as of October 2011, not yet approved in Canada, » Similar to ziprasidone, but represents a novel chemotype, a chiral benzisothiazol derivative. MacDonald GJ, Bartolomé JM. Prog Med Chem. 2010;49:37-80. Ishibashi T et al. J Pharmacol Exp Ther. 2010;334:171-181.Schizophrenia GLUTAMATE-BASED HYPOTHESIS » NMDA Receptor Hypofunctioning v The Glutamate Theory vs the Dopamine Theory v Cerebellar Glutamate Hypofunctioning Theory v The anti NMDA-R Antibodies Encephalitis » Neurodevelopmental Theory ( » Neurodegenarative TheoryGlutamate-linked Treatments 1. NMDA partial antagonists (earty...even late stages SCZ) 2. NMDA partial agonists (middle stages SCZ): Glycine site allosteric modulator/co-agonists Glycine transporters inhibitors 3. NMDA modulators i - mGlu autoreceptors co-agonists minocycline 52/ The dopaminergic pathwe Nace Men Me hMenneLy valved (Hh the Nl: GATIVE PV REL POE lt | vi MESGLIMBIE PORITIVE aymptame of Behieophrenta Mtoinestinntsle - Hhegoinratin psattinvayeSchizophrenia Spectrum and Other Psychotic Disorders Schizotypal Personality Disorder Delusional Disorder Brief Psychotic Disorder Schizophrenifarm Disorder Schizophrenia Schizoaffective Disorder Substance/Medication-Induced Psychotic Disorder Psychotic Disorder Due to Another Medical Condition Catatonia Associated with Another Mental Disorder (Catatonia Specifier) 10. Catatonic Disorder Due to Another Medical Condition 11. Unspecified Catatonia 12. Other Specified Schizophrenia Spectrum and Other Psychotic Disorder 13. Unspecified Schizophrenia Spectrum and Other Psychotic Disorder PON ag PonSS Clinical implications orblockade of various receptors by low potency D, antagonist Anti ont cholinergic | blockade Generic name cass) Histamine sere Ty) | blockade eel eieeir rainy a ttt teete Cedar staleg Ur rat Eiri) Biter rr iet 100 ttt piperidine) ore + (Optemiartees restr) ++ Triflupromazine lel2S Antipsychotics ADVERSE EFFECTS - (neurological) a Epileptogenic = Dystonias = Parkinsonism = Akathisia = Tardive dyskinesia = Neuroleptic malignant syndrome (NMS)Mood Disorders in DSM-IV and DSM-5 Emphasis on Polarity MooD DISORDERS UNIPOLAR MAJOR DEPRESSION | BIPOLAR I | BIPOLAR IL | | oom DYSTHYMIA pemistont depression| Mood Disorders CLINICAL PRESENTATIONS ve “Pups ; . ore = halanced, chronicall, low low low vps ve i: vp! upedownar “episedes normaly OW Yow the SOME Time Within 12 ow fon ANOnthSSEVERE DEPRESSION MILD/MODERATE - DEPRESSION Sao weeks of hopelessness. | svsPTOMS: Similar to eer) severe depression but not parca) parts Not all bipolar states are alike. The three major forms of the Pe ee re eee on een re ea een eee eed Sometimes confused with bipolar but stay fixed in one emotional state. feted errr ety ee eevee cece ne Sine esl neice een enee Rirenennpee ine ats ‘Kluger, J. & Song, S. (Aug. 19, 2002). Young and bipolar. Time, 160(8). 98-4‘SEVERE DEPRESSION Blaonnke pore rears Not all bipolar states are alike. The three major forms of the disorder—bipolar 1, bipolar Il and cyclothymia—cover different parts of the Sn te ee ee rey ‘sometimes confused with bipolar but stay fixed in one emotional state. ‘MILO/MODERATE DEPRESSION Peace ond Sac A teproenernetiog 1, | srmptoms: Atleast a ‘severe depression but not. | tmaljnterteres with le et eiat papers rearerte penis pemqaeareg tery vin corkedMa at Pe pola ors sometimes confused with bipolar but stay ffxed in one emotional state. A B ‘MILD/MODERATE DEPRESSION Ks of hopelessness, | SYMPTOMS: Similar to ee ett pees neneaet 2 long lasting oF debitatingte Clinical Case 45 year old female, bank manager, presented with feelings of sadness and loss of pleasure to activities she previously derived happiness since the time she got divorced three years ago. She's tearful most especially at night when she feels pity for herself. Sleep has been disturbed, appetite decreased with weight loss and she feels fatigued when she wakes up in the morning. She feels helplessness and sometimes hopelessness. She complains of forgetfulness and being out focus. But even then, she is still able to go to work everyday and attend to her duties in the bank and even visits her mother during weekends.What is the appropriate clinical impression of this case? _A.major depressive disorder B. dysthymic disorder — persistent depressive disorder C.double depression D.cyclothymic disorderThe biological substrate that will be consistent with this clinical situation is a deficiency of which of the following neurotransmitters? A. serotonin B. serotonin and norepinephrine C. serotonin, norepinephrine and dopamine D. dopamineThe biological substrate that will be consistent with this Clinical situation is a deficiency of which of the following neurotransmitters? A. serotonin B. serotonin and norepinephrine C. serotonin, norepinephrine and dopamine D. dopamineHierarchical Model DISORDER-SPECIFIC ANTIDEPRESSANTS NON-MELANCHOLIC fae sase)| (-90%) ‘Selective action ‘Serotonin only l aSSRIsEEE te Hierarchical Model DISORDER-SPECIFIC ANTIDEPRESSANTS NON-PSYCHOTIC MELANCHOLIA (eat) Dual action ‘Norepinephrine ‘Serotonin Venlafaxine sMirazapine Duloxetine Selective action Serotonin only aSSRIsHierarchical Model DISORDER-SPECIFIC ANTIDEPRESSANTS aden oni es NON-PSYCHOTIC NON-MELANCHOLIC MELANCHOLIA MELANCHOLIA eae a0)\) (1-5%) (2-10%) (-96%) Broad action Dual action Selective action Norepinephrine ~~ | mNorepinephrine ‘Serotonin only Serotonin Serotonin Dopamine [| =TCAs Venlafaxine sMirtazapine DuloxetineDepression MANAGEMENT = Pharmacotherapy - antidepressants - Tricyclic antidepressants (TCA) - Selective Serotonin Re-uptake Inhibitors (SSRI) - Monoamine oxidase inhibitors (MAO!) - Other and atypical antidepressant = Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) = Serotonin and Noradrenaline Reuptake Inhibitors (SNRI) # Noradrenaline and Dopamine Reuptake Inhibitors (NDRI) = Noradrenaline Reuptake Inhibitors (NaRI) = Noradrenergic/Specific Serotonergic Antidepressants (NaSSA) = Non-pharmacological treatment - Psychotherapy - Light therapy - Electroconvulsive therapy (ECT)6 EEE Classes or Antidepressant Drugs |. Reuptake Inhibitors ll. Enzyme Inhibitors Ill. Receptor Blockers|. Reuptake Inhibitors = Tricyclic antidepressants (TCA) - amitriptyline, maprotiline, dothiepen, clomipramine, imipramine l l HaCHNICH)2 HCH .NH(CHs) amitriptyline nortriptyline oe. ie.! Tricyclic antidepressant: MECHANISM OF ACTIONTricyclic antidepressant: CLINICAL INDICATIONS ® Clinical depression — MDD, dysthymic m Neuropathic pain - diabetic painful neuropathy = ADHD = Nocturnal enuresis (Imipramine) = Panic disorder (Imipramine) = OCD (Clomipramine) = Others: eating disorders, narcolepsy weTricyclic antidepressant: CONTRAINDICATIONS = Agranulocytosis m_ Severe liver damage Glaucoma a Prostatic hyperplasia = Epilepsy = lactationTricyclic antidepressant: SIDE EFFECT PROFILE a Antihistamine — weight gain & sedation = Anticholinergic — dryness of the mouth, urinary retention = al-adrenergic blockade - dizziness, orthostatic hypotension = Blockade of fast sodium channels — prolongation of QTc (risk of Torsades) weEE Tricyclic antidepressant: RARE but DANGEROUS SIDE EFFECTS = Torsades de Pointes v EKG - rule out bradycardia and prolonged QTc ¥ lytes — rule out electrolyte imbalance ¥ make sure not on type 1 or 3 anti-arrythmic drugs = SIADH = “Serotonin Syndrome”|. Reuptake Inhibitors = Tricyclic antidepressants (TCA) — amitriptyline, maprotiline, dothiepen, clomipramine, imipramine = Selective serotonin reuptake inhibitor (SSRI) citalopram, escitalopram, paroxetine, fluoxetine, sertraline IL oe eal aay F Y ~Selective serotonin reuptake inhibitor (SSRI): CLINICAL INDICATIONS MDD Augmentation in BPD Premenstrual Dysphoric Disorder Anxiety Disorders ¥ GAD v Panic Disorder ¥ Social phobia v PTSD y OCD v Bulimia nervosa y Pathologic gambling| I Selective serotonin reuptake inhibitor MECHANISM of ACTION ay oy ii i Serotonin transporter protein SERT "an ® SSRIs/SNRIs bind to the primary binding site, responsible for serotonin re- uptake © The net result is ah intermittent blockade of the serotonin transporter protein Seroionn transporter Prmary ste Atostene ste ‘Sanchez et al. , Psychopharmacology 2004:174:163-176!: Serotonin transporter protein SERT Serotonin transporter l Prmary site Escitalopram binds to both the primary binding site and the allosteric site Escitalopram has a high affinity for the allosteric site which results in a more lasting binding of escitalopram at the primary site The net result is a more efficient blockade of the serotonin transporter protein ‘Sanchez et al. , Psychopharmacology 2004:174:163-176)Selective serotonin reuptake inhibitor SIDE EFFECT PROFILE m_ Headache = Anxiety (limbic projections) and Agitation (basal ganglia projections) Nausea (chemoreceptor trigger zone) Diarrhea (peripheral GI 5HT3 & SHT4 receptors) Sexual dysfunction (spinal projections) and Sleep l disruption or Somnolence (Brainstem sleep centre)Selective serotonin reuptake inhibitor RARE but DANGEROUS SIDE EFFECT UGHbleeding (platelet dysfunction) SIADH SSRI discontinuation syndrome (slow taper) “Serotonin Syndrome”7 Serotonin Syndrome MAJOR CRITERIA MINOR CRITERIA MENTAL impaired consciousness, elevated mood, coma/semicoma restlessness, insomnia AUTONOMIC fever, sweating Tachycardia, dyspnea, diarrhea NEUROLOGICAL myoclonus, tremor, shivering, rigidity, hyperreflexia uncoordination, dilated pupils, akathisia Co-incidence with the addition or increase of a serotenergic agent Development of at least 4 major or 3 major plus 2 minor criteria »1 |. Reuptake Inhibitors = Tricyclic antidepressants (TCA) — amitripsytine, maprotiline, dothiepen, clomipramine, imipramine = Selective serotonin reuptake inhibitor (SSRI) citalopram, escitalopram, paroxetine, fluoxetine, sertraline = Noradrenaline reuptake inhibitor (Nar) - reboxetine|. Reuptake Inhibitors = Tricyclic antidepressants (TCA) - amitriptyline, maprotiline, dothiepen, clomipramine, imipramine = Selective serotonin reuptake inhibitor (SSRI) citalopram, escitalopram, paroxetine, fluoxetine, sertraline = Noradrenaline reuptake inhibitor (war - reboxetine = Selective serotonin a noradrenaline l reuptake inhibitor (SNRI) - venlafaxine, duloxetine HE oy| Serotonin & NA reuptake inhibitor MECHANISM of ACTION } a 2) Le ) mitochodis Co: Serotonin & NA reuptake inhibitor MECHANISM of ACTIONSerotonin & NA reuptake Inhibitors: MECHANISM OF ACTION (Venlafaxine/Effexor) = Blockade of serotonin reuptake up to about 150 mg = Blockade of serotonin and norepinephrine reuptake from about 150-225mg = Blockade of serotonin, norepinephrine and dopamine reuptake above 225 mgSerotonin & NA reuptake Inhibitors: SIDE EFFECT PROFILE = Same as SSRI up to 150 mg m >150 mg, may also see sustained increase in diastolic BP & other noradrenergic-type side effects (see NDRI)Serotonin & NA reuptake Inhibitors: RARE but DANGEROUS SIDE EFFECT = As with SSRI's ~Et |. Reuptake Inhibitors = Tricyclic antidepressants (TCA) — amitriptyline, maprotiline, dothiepen, clomipramine, imipramine = Selective serotonin reuptake inhibitor (SSRI) citalopram, escitalopram, paroxetine, fluoxetine, sertraline @ Noradrenaline reuptake inhibitor (Narn - reboxetine @ Selective serotonin a noradrenaline reuptake inhibitor (SNRI) - venlafaxine, duloxetine @ Noradrenaline « dopamine reuptake inhibitor (NDRI) - bupropion i en, al SI. NA & Dopamine Reuptake Inhibitor: MECHANISM OF ACTION (Bupropion/Wellbutrin) = Blockade of norepinephrine and dopamine reuptake pumps, leads to similar cascade as with SSRI’s: ie NA & Dopamine Reuptake Inhibitor: SIDE EFFECT PROFILE = Seizures (not with SR formulation & following correct dosing; contraindicated with Bulimia or electrolyte disturbances) Headache Agitation (limbic cortex) Rash Emesis Sleep disruption (limbic cortex) and Shaking (cerebellum): Il. Enzyme Inhibitors = Monoamine oxidase inhibitor (mao - “isocarboxazid, phenelzine, tranylcypromine of l @ Reversible inhibitor of MAO-A rma moclobemide OLr| MOA: MONOAMINE OXIDASE INHIBITOR (MAOI)a Monoamine oxidase inhibitors: MECHANISM OF ACTION = Irreversibly bind MAO (2 wks) & destroy its function, therefore decrease monoamine breakdown, increasing 5HT, NE & DA ‘en. SS Monoamine oxidase inhibitors: SIDE EFFECT PROFILE m Side effects related to increase in serotonin norepinepherine & dopamine (see SSRI’s & NDRI's) = Orthostatic hypotensionMonoamine oxidase inhibitors: RARE but DANGEROUS SIDE EFFECTS Blood dyscrasias Hepatotoxicity Teratogenicity Serotonin Syndrome - (even more susceptable than with other serotonergic antidepressants) + When you see an MAO), get a pharmacy consult, the patient should consult their pharmacist about any over - the — counter medications Hypertensive crisis + Consult the dietician re: MAO! diet * Patients need to avoid all foods with tyramine (aged foods such as cheese and wine)Hypertensive Crisis = Norepinephrine is the amine most closely linked with control of blood pressure = MAO normally inactivates norepinepherine m= Tyramine, an amine present in aged foods, causes release of norepinepherine = Inthe presence of MAOI, this increased NE cannot be broken down, resulting in a hypertensive crisis weNA Specific Serotonin AD MECHANISM OF ACTION = Blocks a, autoreceptors on norepinephrine neurons & heteroreceptors on serotonin neurons, causing more NE & SHT to be released (puts the brakes on the brakes) = NE neurons from the locus coeruleus innervate midbrain raphe 5SHT neurons. Therefore, increased NE causes a further increase in SHT release = Blocks SHT, receptors, having an anxiolytic effect & blocking sleep & sexual side effects = Blocks 5HT3, blocking Gl side effects from peripheral receptors & l from brainstem chemoreceptor trigger zone = Blocks H, histamine receptors, causing sedation & weight gainNA Specific Serotonin AD SIDE EFFECT PROFILE = Weight gain (H, blockade) # Anticholinergic: constipation, urinary retention, dry mouth, blurred vision, drowsiness, sinus tachycardia, confusion/delirium, fever (red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare; bowel & [ bladder lose their tone & the heart goes off alone) . Drowsiness (H, blockade) = Equilibrium wea NA Specific Serotonin AD RARE but DANGEROUS SIDE EFFECTS Neutropenia Serotonin syndrome Hepatotoxicity Possibly SIADH we1 ———= Ill. Mix Receptor Blockers = Noradrenergic & specific serotonin antidepressant (Nassa) — mitazapine, mianserin @ Serotonin antagonist & reuptake inhibitor (sarn - trazodone, ngteypdone aA 3 { Ce (— EEE ~ Serotonin Antagonist & Reuptake Inhibitor: MECHANISM OF ACTION a Primarily blocks 5HT2,, reducing sexual dysfunction & sleep disruption & increasing effect of SHT,, stimulation (5HT 2, & SHT;, Oppose one another) m Weak 5HT reuptake inhibitor, increasing 5HT stimulation of 5HT,, (therapeutic effects) = H, blockade causes sedation (2% blockade leads to orthostatic hypotension ~- Serotonin Antagonist & Reuptake Inhibitor: sine EFFECT PROFILE = Orthostatic hypotension = Sedation. a Serotonin Antagonist & Reuptake Inhibitor: RARE su DANGEROUS SIDE EFFECT a Serotonin syndromeEh Starting Antidepressants: General Guidelines = Start with a reuptake inhibitor or mirtazepine (not a TCA or MAOI) = Start at lowest possible dose (half of this with anxiety and in the elderly and medically frail) = Increase by this increment about every five half lives (or about once a week) until one of the following endpoints: v intolerable side effects ji Y full response v¥ maximum dose = Continue to monitor for therapeutic effects, side effects and safetyae ~ Standard & New Generation Antidepressants MECHANISMS OF ACTION Tennis bees _] | macarama bare madonna ee | | nas omamtcese]| | mao re non] fewa (on| Paataees] Gee [ee] [ Meciate prysiciogia!| eiasnicn ‘effects other than we wpteka innion antidepressant efficacy of antidepressant mechanisms of “Aavanced Geatration: iikgnosis | Bipolar, Disorder mood! yy yessive ren otal epre -Bipolar ania pisodes ami any ~ peoples” ar gs fie c > 28 DisorderEEE Psychotropic Drugs agg Repraduct weer Cart a a = Mood stabilizersone eens SEVERE DEPRESSION. Bian ene coer pee nee) MILD/MODERATE ee een ead eae paper eer eid severe depression but not | that interferes with fe peers Peso au rd. & Song, S. (Aug. 19, 2092). YouBipolar Disorder: CLINICAL PRESENTATION -— text book Mania | : Hypomania Subsyndromal mania | (hypomania or hyperthymia) ‘Subsyndromal depression t (dysthymia) DepressionBipolar Disorder: CLINICAL PRESENTATION -— text book Mania | ' Hypomania Subsyndromal mania | (hypomania or hyperthymia) ‘Subsyndromal depression t (dysthymia) Depression: Bipolar Disorder: CLINICAL PRESENTATION - real lifeee Manic Depressive BIOLOGICAL SUBSTRATE = Abnormal neurotransmission = Altered intracellular signal transduction = Altered gene expression = Chronic neuronal damageManic Depressive TREATMENT GOAL = MOOD STABILIZATION ~ Amelioration of affective and psychotic symptoms during acute manic episodes ~ Improvement in depression episodes during acute bipolar depressive episodes ~ Prevention of future mood episodes with sustained treatment at therapeutic levels (prophylactic benefit)zz " Proposed definition of a Mood Stabilizer = Lithium inspired = Efficacy in acute mania Efficacy in acute depression Efficacy in preventing manic & depressive episodes = Uniphasic Efficacy in at least one phase of the illness without exacerbating another phase = Comprehensive l - Efficacy in acute affective symptoms ~ Efficacy in psychotic symptoms ~ Efficacy in behavioral symptoms Efficacy in cognitive symptoms ~ Efficacy in preventing manic, mixed, & depressive episodes: Bipolar Mood Disorder: MOOD STABILIZERS = Lithium carbonate - inositol phosphate metabolism modulation a inhibition of IMPase ?? = modulates PKC signaling activity ~ reduces intracellular sodium in BPD ~ changes on neurotransmitter signaling, induced by modifying monoamine NT l concentrations ~ attenuates the fluctuations of cAMP Berridge MJ, Downes CP, Hanley MR. Biochem J 206: 587-595, 1982: Bipolar Mood Disorder: MOOD STABILIZERS = Lithium carbonate ~ neuroprotection = reduces pro-apoptotic functions directly inhibiting GSK-38 activity indirectly inhibiting NMDA-receptor-mediated Ca** influx = increases the levels of neuroprotective proteins such as Bcl-2 e4/frau»A ie Bipolar Mood Disorder: MOOD STABILIZERS = Lithium carbonate = limitations a. mixed states ». rapid cycling c. multiple prior episodes da. comorbid substance use disordersLithium ADVERSE EFFECT = Nausea, vomiting, diarrhea Weight gain & edema Tremors Fatigue A Mild cognitive impairment Polyuria & polydipsiaLithium ADVERSE EFFECT Goiter & hypothyroidism T-wave flattening Alopecia, worsens psoriasis, acneiform rashes Ebstein’s anomaly Lithium toxicityTremor Oliguria, anuria Nausea Vertigo | Ataxia Vomiting |Weakness Hyperreflexia Diarrhea [Confusion Muscle fasciculation Slurred speech |Drowsiness Downbeat nystagmus Blurred vision Seizures Tinnitus Impaired | consciousness* Bipolar Mood Disorder: MOOD STABILIZERS w Antiepileptic drugs welamino | ‘Neuropsychopharmacology PEVIEWS (2012) 37, 77-101- Bipolar Mood Disorder: MOOD STABILIZERS w Antiepileptic drugs ~ divalproex, CBZ, LTG — limitations a. not an effective anti-manic agent b. specific use for bipolar. depression c. FDA only approved for maintenance phase l a. serious adverse eventsEE Bipolar Mood Disorder: MOOD STABILIZERS = Antidepressants ~ generally cause more problems than benefit do not work, or only work for a short period of time induce mania or hypomania (switch) { - increase cycle rate predispose to mixed state with elements of mania and depression simultaneously (high suicide risk) Sachs G et et. 2007. N Engl I Med 386:17 11-1722 weEEE “Bipolar Mood Disorder: MOOD STABILIZERS = Antidepressants ~ Still recommended in many guidelines ~ European psychiatrists more positive about their use than North American psychiatrists ~ Australasian specialist use of antidepressants is declining ~ US guidelines say “use mood stabilisers first” ~ In clinical practice in USA > 60% given AD first Sachs G etal. 2007. N Engl J Med 386:1711-1722Sl EE E Bipolar Mood Disorder: MOOD STABILIZERS a Antipsychotics ~ All antipsychotics he/pful for bipolar mania ~ Typical agents generally ineffective for bipolar depression ~ Some atypical antipsychotics usefu/ for bipolar depression symptoms - asenapine, olanzapine, quetiapine ~ Treat to remission and for maintenance, and not only acute psychosis »2 EEE Bipolar Mood Disorder: MOOD STABILIZERS = Antipsychotics - Atypicals now first line ~ Not all atypicals help mixed states...most not l approved SSl Acute Manic Episodes MANAGEMENT Step! Review general principles & asseas medication status et Step 2 Initiate/optimize, cheek compliance mencae | switeh therapy Noresponse Step4 Add-on or switch therapy No response + Step 5 Add-on novel or ‘experimental agents On first AAP, of 2-deug combination pvp Lithium or = (Lior DVP + AAP) 1 ‘Add or saviteh to AAP Addl or se Lior DVP nto Replace one or both agents with other agents q — first Replace one or both mis with other |}-——* ‘Consider ackhing oF swuitehing to second or ator BCTAcute Manic Episodes MANAGEMENT First Tine~ ‘Second line ‘Third line Mone (nat yet comm: l Combination therapy: Ithium or divalproex + i Not recommended Monctherapy: gabapentin, topiramate. Combination therapy. jone + carbamazesACUTE MANIC EPISODES FIRST LINE SECON LINE THIRD LINE 2009 Lithium, divalproex, olanzapine, risperidone, quetiapine, quetiapine XR, aripiprazole, ziprasidone, lithium or divalproex + risperidone, lithium or divalproex + quetiapine, lithium or divalproex + olanzapine, lithium or divalproex + aripiprazole Carbamazepine, ECT, lithium + divalproex, asenapine, lithium or divalproex + asenapine, paliperidone monotherapy Haloperidol, chlorpromazine, lithium or divalproex + haloperidol, lithium + carbamazepine, clozapine, oxcarbazepine, tamoxifen 2013 Monotherapy: lithium, divalproex, divalproex ER, olanzapineb , risperidone, quetiapine, quetiapine XR, aripiprazole, ziprasidone, asenapine, paliperidone ER Adjunctive therapy with lithium or divalproex: risperidone, quetiapine, olanzapine, aripiprazole, asenapine Monotherapy: carbamazepine, carbamazepine ER, ECT, haloperidol Combination therapy: lithium + divalproex Monotherapy: chlorpromazine, clozapine, oxcarbazepine, tamoxifen, cariprazine a (not yet commercially available) Combination therapy. lithium or divalproex + haloperidol, lithium + carbamazepine, adjunctive tamoxifen yeee Bipolar | Depression MANAGEMENTFIRST LINE SECON LINE THIRD LINE 2009 Lithium, lamotrigino, quetiapine, quotiapine XR, lithium or divalproox + SSRI, olanzapine + SSRI, lithium + divalproox, lithium or divalproox + bupropion Quetlapine + SSRI, divalproex, lithium or divalproox + lamotrigino, adjunctive modatinil Carbamazepine, olanzapine, lithium + carbamazepino, lithium + pramipexole, lithium or divalproox + venlafaxino, lithium + MAOI, ECT, lithium or divalproex or AAP + TCA, lithium or divalproox or carbamazopino + SSRI + lamotrigine, adjunctive EPA, adjunctive riluzole, adjunctive topiramate WCW cel! 201 Monothorapy: lithium, lamotrigine, quollapine, quotiapine XR Combination thorapy: \ithiurn or divalproax + SSRI, olanzapine + SSRI, lithium + divalproox, lithium or divalproex + bupropion Monothorapy: divalproox, luranidone Combination thorapy. quotiapine + SSRI adjunctive modafinil, lithium or divalproox + lamotrigine , lithium or divalproox + lurasidone Monothorapy: carbamazopino, olanzapino, ECT Combination thorapy. lithium + carbamazapine, lithium * pramipexolo, lithium or divalproox + vonlafaxino, lithium + MAOI, lithium or divalproox or AAP + TCA, lithium or divalproox or carbamazepine + SSRI + lamotrigine, quetiapine + lamotrigineAcute Bipolar Il Depression MANAGEMENT First line Second line Third line { Not recommended cine. quetiapine XR* ithium, lamotrigine, divalproe, it antipsych is + ante Antidepressant monotheraoy (orariy for those wih intequent hypor: ‘ anlidgpressant, quetiapine + lamotrigine’ adjunctive ECT* adjunctive NAC* adjunctive T3* See text on antidepressants for recommendations regarding antidep ex + antidepres2009 FIRST Queene Lithium, lamotrigine, divalproex, SECON lithium or & DO divalproex + antidepressants, LINE lithium + divalproex, atypical antipsychotics + antidepressants Antidepressant monotherapy THIRD (particularly for those with LINE inffequent hypomanias), switch to alternate antidepressant, ziprasidone BIPOLAR II DEPRESSION 2013 Quetiapine, quetiapine XR Lithium, lamotrigine, divalproex, lithium or divalproex + antidepressants, lithium + divalproex, atypical antipsychotic agents + antidepressants Antidepressant monotherapy (primarily for those with infrequent hypomanias), switch to alternate antidepressant, quetiapine + lamotrigine, adjunctive ECT, adjunctive NAC, adjunctive T3 ZBipolar II Disorder MAINTENANCE MEDICATION First line Second line + Third line Not recommendedPsychotropic Drugs = Anxiolytics: Anxiety SYMPTOMS = Awareness of physiological sensations - Diarrhea Dizziness - Hyperhydrosis ~ Palpitations ~ Tachycardia ~ Tremors mu Awareness of being nervous or frightenedAnxiety SYMPTOMS = Affection of thinking, perception, and learning = Confusion = Poor concentration = Poor memory = Selective attention YeDSM-IV Anxiety Disorders in DSM-5 = Anxiety Disorders - Panic, Specific Phobia, Social Phobia, GAD etc. = OC, Stereotypic, and Related Disorders - OCD, Body Dysmorphic, Hoarding, Hair Pulling, Skin Picking, ete. = Trauma and Stressor-Related Disorders - PTSD, ASD, ADs, RAD, DSES = Dissociative Disorders - DID, Depersonalization/Derealization, Dissociative, Amnesia, etc.Anxiety Disorders OMPNBALRWNS 10. 11. 12. Separation Anxiety Disorder Selective Mutism Specific Phobia Social Anxiety Disorder (Social Phobia) Panic Disorder Panic Attack Agoraphobia Generalized Anxiety Disorder Substance/Medication-Induced Anxiety Disorder Anxiety Disorder Due to Another Medical Condition Other Specified Anxiety Disorder Unspecified Anxiety Disorder i=] a = a a a GS es a ° = Fy $ cs aeEE Generalized Anxiety Disorder NEUROBIOLOGICAL SUBSTRATEzz Generalized Anxiety Disorder NEUROBIOLOGICAL SUBSTRATEGeneralized Anxiety Disorder NEUROBIOLOGICAL SUBSTRATE otto2 Anxiolytics = Drugs acting via amino acid transmission Benzodiazepines AEDs : =_ Drugs acting via monoaminergic neurotransmission Antidepressants — TCAs, MAOI, SSRI, SNRI, NaSSA = Antipsychotics >Benzodiazepines CLASSIFICATION — DURATION of ACTION Alprazolam Triazolam Oxazepam Estazolam Lorazepam Temazepam Clorazepate Chlordiazepoxide Diazepam Flurazepam l Quzepam- Benzodiazepines CLINICAL INDICATIONS = Anxiety associated with depression alprazolam lorazepam = Panic disorder clonazepam alprazolam muscle tension Insomnia status epilepticus myoclonic epilepsy preoperative anesthesia alcohol withdrawal| eC SSRI Benzodiazepines l RIMA Anticonvulsants 2 well tolerated 12 teats co-morbid depression 18 low tisk of mortality in overdose when used as 2 single agent = quick onset of effect well tolerated 12 teats co-morbid cepression '= treats co-morbid depression 8 reduced cietary resinctons compared with MAO! ‘© quick onset of effect Dead 8 slow onset of effect (4-12 weeis) @ may worsen symptoms intialy" eS SSRI Benzodiazepines TCA MAO! l RIMA Anticonvulsants Ceeres 8 well tolerated 18 treats co-morbid depression 18 low risk of mortality in ‘overdose when used as 2 single agent 1 quick onset of effect {8 welltoterated 8 treats co-morbid depression 18 treats co-morbid depression 8 reduced dietary restrictions ‘compared with MAO! = quick onset of effect oo nocd 8 slow onset of effect (4-12 weeks) @ may worsen symptoms initially = sedation © rebound anxiety on withdrawal @ risk of dependence © cardiotoxicity '® anticholinergic effects 2 risk in overdose = low tyramine dietary requirement '® risk of hypertensive crisis © less effective than MAO! 9 low levels of evidence ‘= sedation ‘© there may be the potential for tolerance/dependence, but this has yet to be established ‘= Pharmaceutical Benefits ‘Scheme status issuesl ——_— “ Generalized anxiety disorder: treatment approaches supported by placebo-controlled studies ‘Acute efficacy Long-term efficacy Relapse prevention Enhances the efficacy of psychological treatment After non-response Tes lopram Imipramine Alprazolam Paroxetine Diazepam Sertraline Escitalopram Paroxetine Paroxetine Escitalopram DiazepamAcute Panic Disorder NEUROBIOLOGICAL SUBSTRATEa Panic disorder: treatment approaches ‘SSRIS TCAs Benzodiazepines Acute panic attack Alprazolam Acute efficacy Citalopram Clomipramine Alprazolam Escitalopram Imipramine Clonazepam Fluoxetine Diazepam Fuvoramine Lorazepam Sertraline Long-term efficacy Citalopram Clomipramine Alprazolam l Fluoxetine Imipramine Paroxetine Sertraline Relapse prevention Fluoxetine Imipramine Sertraline Enhances the efficacy of psychological treatment Paroxetine Antidepressants (meta-analysis) (meta-analysis) Buspirone After non-response Paroxetine (prior CBT)Social Phobia: treatment approaches supported by placebo-controlled studies After non-response SSRIs TCAs Benzodiazepines Acute efficacy Escitalopram Bromazepam a Fluoxetine Clonazepam Fluvoxamine Moclobemide Paroxetine Venlafaxine Sertraline Gabapentin Long-term efficacy Escitalopram Fluvoxamine Paroxetine Sertraline Relapse prevention Escitalopram Clonazepam cer Paroxetine Sertraline Enhances the efficacy of psychological treatment SertralinePTSD: treatment approaches supported by placebo-controlled studies SSRIs Prevention of post-traumatic symptoms? Acute efficacy Fluoxetine Amitriptyline Paroxetine Imipramine Sertraline Long-term efficacy Sertraline Relapse prevention Fluoxetine Sertraline Enhances the efficacy of psychological treatment After non-response Benzodiazepines Alprazolam———— OCD: treatment approaches supported by placebo-controlled studies SSRIS Tes Benzodiazepines Acute efficacy Citalopram Clomipramine Clonazepam? Fluoxetine Imipramine Fluvoxamine Paroxetine Sertraline Long-term efficacy Fluoxetine Clomipramine Sertraline Relapse prevention Fluoxetine Paroxetine l Sertraline Enhances the efficacy of psychological treatment Fluvoxamine Clomipramine After non-response ClonazepamEEE a Panic disorder (vitvwitot agnraphcbiaP SSRI(I) ‘ctalopram (Il) esctalopram(tt) ‘fucxetine (11) fuvoxamine (i) pparoxetin sertratine (il) Social anxiety disorder’ ‘SSRI (I citalopram (tl) escitalopram (il) ‘fuucxetine (I!) fuvoxamine (ll) paroxetine (I!) serrate (il) SSRI(I) escitalopram (I!) fuoxetine (11) fuvoxamine (I) paroxetine (11) sertraline (I) ean SSRI)? paroxetine (I! escitalopram (i) sertraline (Il) l ‘SNRI venlafaxine (11) tn SSRI ‘fuoxetine (I!)a"® paroxetine (1) sertraline (Ia citalopram (Iv) escitalopram (IV)