PHARM 445 Pain and Mental Health PDF

PHARM 445 Pain and Mental Health OBJECTIVES ANTIPSYCHOTICS 1. Identify the main classes of antidepressants and drugs within them 2. Identify common and rare AE associated with different classes of antidepressants 3. Identify significant drug-drug and drug-food interactions and their potential clinical implications 4. Describe the process and considerations for switching a patient from one antidepressant to another 5. Utilize clinical tools and resources to facilitate safe and effective antidepressant switching 6. Identify the symptoms of discontinuation syndrome 7. Explain the management strategies to prevent and treat discontinuation syndrome ANTIPSYCHOTICS 2 1. Understand the dopamine hypothesis and how dopamine 2 (D2) receptor trgets work within this hypothesis 2. Differentiate between first, second, and third generation antipsychotics 3. Understand key differences between antipsychotics within each class 4. Identify antipsychotic side effects and their general management ANTIPSYCHOTICS 3 1. Identify the major classes of medications used in BPD and understand their mechanism of action 2. Describe the common side effects of antipsychotics, lithium, and antiepileptic medications 3. Recognize when therapeutic drug monitoring may be used and understand how to interpret results 4. Develop an awareness of prominent drug interactions that may impact medication therapy in BPD ANXIETY DISORDERS 1. Describe the epidemiology and burden of anxiety disorders and GAD 2. Demonstrate how DSM 5 TR diagnostic criteria can be used to diagnose GAD 3. Describe risk factors, medical conditions, and medications associated with anxiety disorders 4. Recognize and use rating scales to screen, assess, and monitor patients with anxiety disorders 5. Describe the pharmacological and non-pharmacological treatment options for GAD 6. Demonstrate how a clinician can appropriately monitor the outcomes of therapy for GAD SCHIZOPHRENIA 1. Differentiate between positive and negative symptoms of SCZ 2. Describe hallucinations and the different types of delusions 3. Define key features required for diagnosis of SCZ 4. Understand the epidemiology, age of onset, and trajectory of SCZ 5. Gain an awareness of SCZ spectrum disorder and how they differ from each other 6. Identify medications that can be used in acute agitation 7. Understand the patient specific nature of antipsychotic selection 8. Explain treatment recommendations in different phases of SCZ 9. Recognize available long-acting injectables (LAIs) in Canada 10. Identify the strategies to encourage medication adherence, including use of LAIs 11. Understand the novelty of clozapine, it’s multiple receptor targets, and potential side effects SUBSTANCE USE DISORDER 1. Epidemiology in Canada 2. Impact and costs PHARM 445 Pain and Mental Health 3. Etiology of SUD 4. Diagnostic criteria for SUD 5. Public health approach OPIOID USE DISORDER 1. Understand current data and perspective surrounding Canada’s opioid epidemic 2. Define key features required for diagnosing opioid use disorder 3. Understand key symptoms, assessment, and interventions for withdrawal management 4. Understand role of naloxone has opioid poisoning reversal agent 5. Describer Alberta Opioid Dependence Treatment Intensity Continuum 6. Describe pharmacist role in supporting patients with OUD 7. Understand the spectrum of treatment for OUD 7.1. Buprenorphine/naloxone 7.2. Buprenorphine extended release injection 7.3. Methadone 7.4. Slow release oral morphine (SROM) 7.5. Injectable OAT/NTS (DND) PHARM 445 Pain and Mental Health ANTIPSYCHOTICS PART 1 TERMS: - Unfortunate start: AE high for a few weeks with no sign of benefit. After 1-2 months AE subside and benefits become noticeable. Antidepressant Drug Classes SAFETY MONITORING Anticholinergic AE - Dry mouth, blurred vision/dry eyes, constipation, urinary retention, confusion, tachycardia CNS AE: - Headache (generally resolves in 1-2w), insomnia, sedation - Management: o Sedation = take QHS o Insomnia = take QAM o Lower dose if sx early and significant, or switch therapy if not resolving GI AE: - NVD o Lots of 5HT receptors in GIT → SSRIs activate 5HTR - Constipation o Often due to anticholinergic AE (TCAs, paroxetine, bupropion NDRI, mirtazapine NaSSA) Weight Gain: - Mirtazapine > TCAs > SSRI > SNRI - Mainly due to H1 blockade - Sometimes it’s a benefit: o Decreased appetite on antipsychotics leads to significant weight loss and mirtazapine can be used to increase weight and appetite. Sexual Dysfunction: - Decreased interest, decreased arousal, inability to orgasm, ED - These symptoms DO NOT improve with time o But they are dose relat3ed and reversible - SSRIs ( esp. paroxetine) > SNRIs o Low risk options: bupropion, mirtazapine Cardiovascular: - Tdp: prolonged QTc = surrogate marker o Es/citalopram, TCAs o Risk does not dissipate o Monitor: ECG, lytes (K and Mg) o Educate patient to monitor for signs and symptoms (palpitations, dizziness, syncope) - Hypertension - Orthostatic hypotension - Tachycardia, palpitations - Uncommon but serious: o SSRIs: hyponatremia/SIADH, risk of falls, GI bleeding o TCAs: seizure risk Serotonin Syndrome - Usually symptoms begin within 24 hours of initiation, increasing dose, addition of serotonergic drug - Mild symptoms: HTN, tachycardia, dilate pupils, sweating/shivering, tremor, afebrile PHARM 445 Pain and Mental Health - Moderate symptoms: above + hyperthermia - Severe symptoms: above + delirium, muscle rigidity, death - Sus agents: o MAOi+ (serotonergic or sympathomimetic drugs) o Combo of serotonergic agents (SSRI, SNIR, TCAs, tramadol, dextromethorphan) Suicidality: - Increased risk in adolescents because only severely ill adolescents are prescribed Ads - Reduced risk in in adults and elderly PK/PD CYP interactions: - Potent inhibitors: paroxetine, fluoxetine, bupropion, fluvoxamine o Moderate inhibitors: duloxetine, fluoxetine, sertraline - Inducers: St. John’s Wort PGP interactions: move drug out of BBB - Many Ads are substrates for PGP transporters. o PGP inhibitors will increase CNS AD concentration o PGP inducers (St. John’s wort) will decrease CNS AD concentration. Monitoring - Labs: o Hepatic (LFTs) o Renal (SCr) o CBC (bleed risk) o Lytes (Na imbalance, SIADH, K/Mg) - Overall: o Vitals o SxHx, pregnancy status, adherence o AE, symptom severity, suicide/homicide risk Switching Ads Discontinuation Syndrome - Common with Ads with short half-life (paroxetine and SNRIs) o Fluoxetine can be tapered rapidly because of its long half life - See symptoms 1-7 days post dose reduction - Symptoms = FINISH _ depressed mood and akathisia o Flu like, insomnia, nausea, imbalance (dizzy/vertigo), sensory disturbance, hyperarousal (anxiety) PHARM 445 Pain and Mental Health - Linear vs proportionate (preferred) taper o No more than 25% taper per week - Management: increase dose or reintroduce drug if stopped Anticholinergic: TCA, paroxetine (SSRI) Sedating: mirtazapine (low dose), trazodone (low dose), TCAs Insomnia: bupropion NVD: SSRIs Constipation: TCAs, paroxetine, bupropion, mirtazapine Weight gain: Mirtazapine > TCAs > SSRI > SNRI Tdp: Es/citalopram, TCAs PHARM 445 Pain and Mental Health ANTIPSYCHOTICS PART 2 (Psychotropic drugs in SCZ) Terms - VTA = collection of dopaminergic neuron cell bodies - SN = midbrain dopaminergic nucleus - NAc = involved in reward and motivation - DA pathways: o Mesolimbic: reward and positive symptoms of SCZ ▪ Block = less positive symptoms of SCZ o Mesocorticol: executive functions ▪ Block = more negative symptoms and impaired cognition o Tuberoinfundibular: prolactin production ▪ Block = sexual AE o Nigrostriatal: movement and motor function ▪ Block = EPS DOPAMINE HYPOTHESIS - DA drugs produce psychotic behaviours similar to what is observed in SCZ o Mesolimbic pathway most implicated in SCZ o Positive symptoms of SCZ thought to be due to DA hyperactivity - Solution: block D2 receptors - Problem: D2 blockade works on ALL pathways ANTIPSYCHOTICS PHARMACOLOGY Receptor target Effect D2R antagonist - Antipsychotic effect via mesolimbic path - AE via effect on Mesocorticol, nigrostriatal, and tuberoinfundibular paths H1R antagonist - Sedation - Increased appetite and weight gain M1R antagonist - Anticholinergic AE - Decreased EPS Alpha-1R antagonist - Postural hypotension, dizziness - sedation 5HT1AR antagonist - precognitive, anxiolytic, antidepressant 5HT2AR antagonist - reduced EPS - improved negative cognitive symptoms Typical antipsychotics = first generation Atypical antipsychotics = second and third generation First Generation Antipsychotics MOA = D2 blockade (+ alpha 1, H1, M1 block) Potency: haloperidol > perphenazine, loxapine, zuclopenthixol > chlorpromazine - haloperidol and loxapine used in acute agitation - zuclopenthixol used in cases of EXTREME agitation AE: - EPS PHARM 445 Pain and Mental Health - Tdp with chlorpromazine and haloperidol - Less potent FGAs have alpha 1, H1, M1 effects (postural hypotension, anticholinergic effect, sedation) Place in therapy: - NOT first line due to: o high risk of EPS (mostly tardive dyskinesia) o no effect on negative symptoms - haloperidol, loxapine, zuclopenthixol used in acute agitation Second Generation Antipsychotics MOA: 5HT2A and D2 blockage - 5HT2A antagonism increases DA transmission OUTSIDE mesolimbic system so have reduced risk of EPS and hyperprolactinemia, and helps negative and cognitive symptoms - Faster dissociation form D2R also leads to less EPS AE: - Prominent metabolic AE (weight gain, db, CVD), less with ziprasidone and lurasidone Examples: clozapine, olanzapine, asenapine, paliperidone, risperidone, ziprasidone, lurasidone Third Generation Antipsychotics MOA: - D2/3R partial agonists: in areas of high DA activity partial agonists decrease overall dopaminergic activity. In areas of low DA activity, partial agonists increase overall dopaminergic activity - 5HT2AR antagonist - 5HT1AR agonist Examples: ABC: aripiprazole, brexipiprazole, cariprazine - Aripiprazole: Injection start requires 14 day PO overlap - Cariprazine: D2 and D3 partial agonist. EXTREMELY long half life. Place in therapy: very good first line option for treatment of first episode of psychosis AE: - Less metabolic AE and weight neutral - Less sedating - No anticholinergic AE - High risk of akathisia (restlessness) AE of Antipsychotics Nigrostriatal pathway - EPS = extrapyramidal symptoms = antipsychotic induced movement disorder o Often due to DA and acetylcholine imbalance → treat with anticholinergics (diphenhydramine, benztropine) o Progression: acute dystonia → akathisia → drug induced parkinsonism → tardive syndromes - Acute dystonia: within 1st week of treatment o Highest risk in high potency FGAs o Presentation: contraction of muscles +/- jerking (mostly in jaw, neck, eyes) o Management: ▪ Acute = anticholinergics: IM benztropine or diphenhydramine ▪ Long term = po benztropine or switch offending agent - Akathisia: within first 6 weeks of treatment o Highest risk with TGAs aripiprazole and cariprazine o Presentation: inner restlessness, pacing, fidgeting PHARM 445 Pain and Mental Health o Management: ▪ reduce or switch antipsychotic ▪ benzodiazepine (lorazepam, clonazepam) ▪ low dose mirtazapine - Drug Induced Parkinsonism: within first 6 weeks of treatment o Presentation: tremor, impaired gait, rigidity, bradykinesia, reduced facial expression and speech o Management: ▪ Reduce or switch antipsychotic (quetiapine, clozapine, aripiprazole have lower risk) ▪ Anticholinergics: benztropine ▪ Amantadine (when anticholinergics not tolerated) - Tardive Syndromes (tardive dyskinesia): occurs after prolonged use (>3 months) o Higher risk with FGAs o Presentation: repetitive movement with out purpose or control (mostly with mouth, tongue, lips), piano playing o Management: ▪ Avoid anticholinergics (worsen tardive syndromes) ▪ VMAT2 inhibitor: tetrabenazine ▪ Switch to SGA or partial agonist (clozapine) Tuberoinfundibular Pathway - Hyperprolactinemia: within weeks to months o MOA: normally DA inhibits prolactin release, with D2 blockade we have increased prolactin o Highest risk with paliperidone and risperidone o Presentation: amenorrhea, breast tenderness, gynecomastia, galactorrhea, reduced BMD with chronic use. PHARM 445 Pain and Mental Health ANTIPSYCHOTICS PART 3 Typical antipsychotics = First generation antipsychotics = FGA - D2 receptor antagonists Atypical antipsychotics - D2 receptor antagonists = second generation antipsychotics = SGA - DA (D2 and D3) partial agonists = third generation antipsychotics = TGA FGA SGA TGA - Haloperidol - Quetiapine - Aripiprazole - Olanzapine - Brexipiprazole - Asenapine - cariprazine - Paliperidone - Risperidone - Ziprasidone - Lurasidone - Clozapine Mood Stabilizers Generally refers to anticonvulsants + lithium - TDM for ACA and lithium? o Check adherence o Ensure levels are within safe limits, especially during dose changes o Assess for drug toxicity and associated signs and symptoms present o AS PART of assessment of efficacy - Anticonvulsants: o Valproate/divalproex, carbamazepine, lamotrigine o Decrease excitatory pathways by: ^ GABA activity X Na+ channels X Ca++ channels ^ 5HT activity Drug Valproate Lamotrigine Carbamazepine Therapeutics - Hepatic metabolism Prolonged titration Lots of interactions due - 1:1 conversion with valproic acid to minimize to CYP3A4 induction - TDM: linear PK. Draw level 12h post SJS/TEN risk and autoinduction AM dose AE - NV - Nausea - NV - Drowsiness - dizziness - Weight gain - Rarely = elevated liver enzymes PHARM 445 Pain and Mental Health Notes Symptoms of toxicity: - NVD - Anorexia - Thrombocytopenia (dose related) - hepatotoxicity Lithium AE: - drowsiness, headache - fine tremor - initial polydipsia and polyuria - acne, weight gain, SD PD: - renal clearance o reduced by NSAIDs, ACEi, ARBs, diuretics o increased by salt intake o influenced by dehydration, volume loss - TDM o Lithium has linear PK: draw level 12h post dose ▪ If dosed BID or TID, draw level prior to first dose of day Risks: - Renal o irreversible GFR decline with prolonged use o nephrogenic db insipidus - Thyroid – lithium induced hypothyroidism PHARM 445 Pain and Mental Health PGX Phenoconversion is focus ANALGESICS: - Non opioids vs opioids - Choose based on interindividual variability (CKD), pain scale, functionality, EBM - Opioids: o PK: phase 1 and phase 2 elimination (cyp2d6, cyp3a4, ugt2b7, compt o PD: mu, delta, kappa OR, PGP1 o Metabolisers: poor, intermediate, extensive, ultrarapid ▪ Drug vs prodrug ▪ Codeine and tramadol = prodrugs CODEINE - Prodrug, activated to morphine via cyp2d6 - Ultrarapid metabolizer will have high morphine in short time = ^ toxicity - Poor metabolizer will have very low morphine = analgesia not achieved IBUPROFEN - Metabolized by cyp2c9 into inactive metabolite o Intermediate or poor metabolizers will have increased toxicity o Cyp2c9 interactions: phenytoin and warfarin PSYCHIATRIC PGX - 2 main therapy goals: o Minimize AE of psych meds o Id psych meds that will have best efficacy probability for specific pt - Psych drugs take a long time to see effect (2-4 months) and patients can lose hope or condition may get worse? - Resistance: Physicians/HCPs not trusting the data and not incorporating it into their practice (don’t recommend pts for pgx testing) CITALOPRAM/ESCITALOPRAM - Metabolized by cyp2c19 into inactive metabolite PHENOCONVERSION - Mismatch bw genotype based prediction of drug metabolism and true/phenotypic drug metabolism due to NON GENETIC FACTORS. o Inflammation, pregnancy, liver failure, GFR, smoking, gender o Case: pt is starting codeine for pain. It works well, thy re normal metabolizer. 1 month later pt starts fluoxetine for depression. Fluoxetine works well, but pain no longer well controlled. o Fluoxetine = strong inhibitor of cyp2d6. If pt is on codeine and fluoxetine together, even if pt is normal metabolizer of cyp2d6, the drug interaction will lead to phenoconversion to poor metabolizer for codeine → cyp2d6 → morphine. Therefore, this pt will not have effective analgesia from codeine and it would be a good option to change pt to active form of codeine (morphine) PHARM 445 Pain and Mental Health ANXIETY DISORDERS Terms: - GAD: excessive, difficult to control anxiety and worry accompanied by symptoms of restlessness and muscle tension Epidemiology: - Most common mental disorder o Yet underdiagnosed/treated and associated with increased risk of suicide attempts - Median age of onset: ~30y - More common in AFAB Background: Disease course: - Symptoms chronic, but wax and wane and remission is unlikely Diagnosis: - Anxiety over various things for more than 50% of time over 6 months - Difficulty managing anxiety - Anxiety associated with 3 of the following symptoms: ConFIRMS o Concentrating difficult, fatigue, irritability, restlessness, muscle tension, sleep disturbance - Impaired functioning - Not attributed to another condition or substance Risk factors: - FxHx, personal history, ACE (adverse childhood event) - Female - Chronic medical illness - Behavioural inhibition, over protective parenting Screening questions: - Over the past 4 weeks, have you been anxious or worried for most of the time? - Are you frequently tense, irritable, or have trouble sleeping? - Over the past 2 weeks how much have you been bothered by nervousness, anxiousness, worry, panic? Scales: - HAM-A, CGI = clinician rated o CGI-S looks at severity of illness and CGI-I looks at improvement - PHQ9 and GAD7 = patient rated Treatment Non-Pharmacological - Psychotherapy (first line option) = CBT, MBCT (mindful based cognitive therapy) o Not routinely recommended to combine with pharmacotherapy as first line - Resistance or aerobic exercise, yoga Pharmacotherapy: - First line: SSRI/SNRI/Pregabalin - Second line: benzodiazepines > bupropion, quetiapine, hydroxyzine, imipramine Anxiolytics: benzos - PK/PD: major phase 1 metabolism → compromised by age and cyp inhibitor - Shorter half-life agents: o Withdrawal between doses o Anterograde amnesia o Increased abuse potential PHARM 445 Pain and Mental Health - Longer half-life agents: o Hangover effect - In elderly only use if severe GAD because they have increased sensitivity and decreased metabolism - AE: sedation/fatigue, memory/cognitive impairment, - Associated effects: dependence, withdrawal, rebound anxiety - Discontinuation: 10-20% q307 days. Usually decreased over 6-12 weeks Buspirone: - AE: dizzy, lightheaded, headache - Effect seen in 2-4w - Not effective if used PRN Hydroxyzine: - Antihistamine, and anxiolytic effects due to serotonergic and dopaminergic activity - AE: dizzy, sedation, qtc prolongation Combination therapy options: - SSRI/SNRI + benzo - SSRI/SNRI + anticonvulsant - SSRI/SNRI + atypical antipsychotic - SSRI/SNRI + psychotherapy PHARM 445 Pain and Mental Health SCHIZOPHRENIA Terms: - Psychosis: altered mental state with loss of contact with reality Symptoms of Psychosis Positive Negative - Delusions - Anhedonia - Hallucinations - Asociality - Disorganized thinking - Blunted affect - Abnormal motor behaviours - Avolition (lack of motivation) - Alogia (speaks less) Presentation: - Delusions (+) = fixed beliefs that don’t change even when conflicting evidence present o Bizarre delusions: clearly impossible – aliens replacing blood with mercury o Non bizarre delusions: plausible – RCMP tracking my phone o Persecutory delusions: believe you're being threatened o Referential delusions: think everything in their surroundings is referring to them o Grandiose delusions: o Erotomanic delusions: believe someone is in love with them o Nihilistic delusions: believe a major catastrophic event will happen o Somatic delusions: beliefs around their health or organ function - Hallucinations (+) = perception without external stimuli o Could be any senses effected o Auditory hallucinations most common: dangerous when they are command hallucinations - Disorganized thinking (+) = can only be interpreted through pts speech o Derailment: loose associations o Tangentiality: completely switching topics out of no where o Incoherent: word salad - Abnormal motor behaviours (+) = variation in presentation o Sudden agitation o No goal directed behaviour o Catatonia (abnormal behaviours, may be slow: mimicking -if you wave, they wave back) - Negative symptoms = absence of normal behaviour (generally present before positive symptoms) o Interest and motivation related: ▪ Avolition, anhedonia, Asociality o Expressive function: ▪ Blunted affect, alogia Acute Phase: - Criteria: o 2 or more of the following symptoms present for significant time in 1 month period + at least one symptom is 1, 2, or 3 + decreased function + persists for 6 months i. Delusions ii. Hallucinations iii. Disorganized speech iv. Abnormal/catatonic motor behaviours v. Negative symptoms - Symptoms categories: positive, negative, cognitive PHARM 445 Pain and Mental Health - Risk factors: Substance Use Related Non-Substance Related - Stimulants - Prenatal/perinatal events - Cannabis (high potency THC) - Birth in late winter/early spring o Often see conversion of cannabis- - Migration status induced psychosis to SCZ - Urban environment - Nicotine - Adverse childhood events - Genetics (high heritability) - Morbidity: negative symptoms associated with higher burden of illness and hospitalization (mostly due to medication non-adherence) - Mortality: most commonly from suicide or CVD - Trajectory o Prodromal = early adolescence ▪ Mostly negative symptoms (decline in cognitive and social function) o First episode of psychosis = late adolescence to early adulthood o Progressive = cycles of positive symptoms o Residual Substance or Medication-induced Disorder - Presentation: o Delusions/hallucinations after ingestion or withdrawal of substance (including meds) ▪ Cannabis, stimulants (amphetamines, cocaine) ▪ Prescription medications ▪ OH, hallucinogens, sedatives, inhalants - Must not be better explained by another disorder, no delirium (confusion), and symptoms continue as long as substance use continues *Note: no established clinical efficacy of one antipsychotic over another* Alberta Mental Health Act Form 1 - Admission certificate (can be appealed by patient) Form 8 - Warrant Form 10 - Statement of Peace Officer on Apprehension Form 11 - Patient deemed incompetent to make decisions (have substitute decision maker) - Initiated when patient refuses therapy Form 23 - Community treatment order apprehension order Acute Agitation - Requires fast onset agents for sedation - IM route preferred Haloperidol Lorazepam PO or IM PO or IM, SL IM can be given in same syringe as haloperidol Olanzapine Zuclopenthixol Acetate PO or IM, ODT IM Avoid coadministration with parenteral olanzapine For extreme agitation, aggression due to increase sedation and cardio depression Risk of acute dystonia and excessive sedation PHARM 445 Pain and Mental Health Treatment Trajectories: First Episode - Duration of untreated psychosis (DUP) = time between onset of psychotic symptoms and first effective treatment → need early management to reduce DUP and improve outcomes - Good response to antipsychotics so need lower doses - Use SGAs as they are better tolerated than FGAs o Continue for 2 weeks minimum, if no response at 4 weeks then switch, if partial response at 8 weeks o Monitor response (adjust dose if needed) and check adherence o Treatment duration: 18 months minimum after resolution of positive symptom Acute Exacerbation: - Symptoms wax and wane - Reasons for acute exacerbation: medication non-adherence, substance use - Intervention: o Restart or switch antipsychotic o Dose adjustment o Address contributory factors (non adherence, substance use) Relapse Prevention and Maintenance Therapy - Maintenance therapy: should be continued for 2-5 years, but generally tends to be life lonf o Reduces risk of relapse at 1 years - Non Adherence: o Reasons: ▪ don’t know why they need the medication ▪ Socioeconomic challenges ▪ Substance use ▪ Stigma ▪ Cognitive difficulties o Oral med most culprit: switch to LAI ▪ LAI reduce risk of relapse and hospitalization and can be used in ALL PHASES of treatment o LAIs in Canada: IM in deltoids or glutes ▪ FGAs: haloperidol, flupenthixol, zuclopenthixol ▪ SGAs: risperidone, palperidone Loading doses of palperidone must be given in delts x1 months ▪ TGAs: aripiprazole o Improve: ▪ Psychoeducation, blister packs, help from family and friends, community treatment orders Treatment Resistant SCZ: - Failure on 2+ different antipsychotics at therapeutic dose and adequate trial of 6+ weeks - Clozapine is gold standard for TRS and psychosis with aggression o Adequate trial is >12 weeks at >400mg PHARM 445 Pain and Mental Health Clozapine resistant SCZ - No specific treatment recommendation - Augment other agents or therapies, or add other therapies (consider ECT) Clozapine Mechanism of Action Blocks serotonin and dopamine receptors Dosing/Admin *low and slow titration* to reduce AE risk Counselling - Smoking will reduce serum clozapine levels due to CYP1A2 induction (let HCP know if smoking habits change) - Tolerance is lost quickly, if missing 2+ days, dose reduction required (consequence is severe hypotension and seizures) - High risk of severe infection due to reduced neutrophil count (mandated CBC monitoring) → if confirmed neutropenia, not rechallengeable Monitoring - CBC: brand specific monitoring, brands NOT interchangeable o Interval: first 26 weeks = weekly; next 26 weeks = q2w; afterwards = q4w o Green = continue therapy o Yellow = continue and monitor q2w until back to green zone o Red = draw another sample in 24h and STOP therapy if confirmed Risks Cardiac - Hypotension/ postural hypotension - Tachycardia (due to anticholinergic effect and alpha blockade) o Consider beta blocker if cardiac etiology ruled out - Clozapine induced myocarditis (fever, chest pain, SOB, palpitations, elevated troponin and CRP) Seizure risk - Clozapine reduces seizure threshold, caution in patient with uncontrolled seizures or concurrent seizure threshold lowering meds Sialorrhea - VERY common - Due to reduced swallowing rather than increased salivary flow - Manage: atropine 1% eyedrops administered SL; ipratropium 0.03% nasal spray SL; towel on pillow; sugarless gum Constipation - Due to anticholinergic effect Nocturnal Enuresis = bed wetting - Manage: desmopressin; anticholinergics for OAB; void before bed; no OH or caffeine before bed *akathisia: subjective need to constantly move *antipsychotics can generally cause QTc prolongation so do ECG baseline when monitoring *aripiprazole = 3rd gen and weight neutral, elss metabolic, generally first lien agent BPD: *measure lithium lvls in AM *cross multiplication for linear PK PHARM 445 Pain and Mental Health SUBSTANCE USE DISORDER Risk factors - Genetic (gene-environment, epigenetics, prenatal exposure) - Concurrent disorders o Mental health disorders (SUD can exacerbate, mimic, hide, and affect efficacy or adherence of mental health disorders and their pharmacotherapy) - Environment (early initiation, trauma, childhood abuse, household dysfunction) Substances of Abuse - OH, caffeine, tobacco, cannabis - Opioids, sedatives/hypnotics/anxiolytics - Stimulants, hallucinogens, inhalants - Other Substance Induced Disorders: - Intoxication, withdrawal - Substance induced mental disorders (psychosis, BPD, depression, anxiety) Substance Use Disorders: Multiple symptoms indicating person continues using substance despite significant substance related problems - Impaired control o Using more substance than intended o Difficult controlling use o Spending lots on finding or recovering from substance o craving - Social impairment o Continued use impairs personal and professional duties o Continued use despite social problems o Giving up other activities because of use - Risky use o Using in hazardous situations o Continued use despite worsening physical or mental health - Pharmacological criteria o Tolerance, withdrawal Mild Moderate Severe 2-3 symptoms 4-5 symptoms 6+ symptoms Neurobiological Framework - Predisposes individuals to substance use o Intoxication/binge ▪ Creates rewarding experience o Withdrawal/negative effect ▪ Experience negative emotional state in absence of substance o Preoccupation/anticipation ▪ Substance seeking after period of abstinence - Pathophysiology: Basal ganglia Pleasure and habit forming (binge/intoxication) Extended amygdala Stress and negative feelings of withdrawal PHARM 445 Pain and Mental Health Prefrontal cortex Executive function – exerting control over substance use (preoccupation/ anticipation) DA circuits Reduced D2 receptors, reduced sensitivity of reward system Biopsychosocial (plus) Model - Interaction between biological, psychological, social, cultural, and spiritual aspects on SUD Goals: Increase Decrease - Employment for substance users - Stigma - Public knowledge of SUB - Overdosing and early deaths - Referral to treatment programs - HIV infection - Access to health care - Needles in public spaces - Sharing of equipment - Crime - Health care costs - Recovery aims to: o Address bio/psycho/socio/cultural/spiritual factors o Improve QOL via: ▪ Consistent abstinence ▪ Improved behavioural control ▪ Relieve symptoms and cravings PHARM 445 Pain and Mental Health OPIOID USE DISORDER I Stats: - 47k opioid deaths in 10y - Prevalence greater in BC, AB, ON - More deaths in males, ages 30-39, involving fentanyl - Increasing since 2020 Opioid use disorder Problematic opioid use leading to clinically significant impairment or distress, involving at least 2 of the following designated criteria within a 12 month period - Impaired control o Using more substance than intended o Difficult controlling use o Spending lots on finding or recovering from substance o craving - Social impairment o Continued use impairs personal and professional duties o Continued use despite social problems o Giving up other activities because of use - Risky use o Using in hazardous situations o Continued use despite worsening physical or mental health - Pharmacological criteria o (tolerance and withdrawal count as 1 criteria) Opioid Characteristics: Reinforcing Adverse Effects Tolerance; withdrawal - Analgesia - Constipation - Euphoria - Dry mouth - Warmth, numbness - Hypogonadism - Anxiolytics - Weight gain - CNS/ respiratory depression Identifying Acute Withdrawal - Subjective withdrawal 12-30 hours after last opioid use Emergence Peak Lasts Short acting 12h from last use 24-48h 3-5d Intermediate acting 12h from last use 48h 7d Long acting 30h from last use 3-7d 10d - Symptoms of withdrawal o Tachycardia, diaphoresis, restless, mydriasis (dilated pupils) o Muscle aches, anxiety, irritability, restless, tremor o Runny eyes/nose, NVD, GI cramps, piloerection (goosebumps) Managing Acute Withdrawal - Prioritize patient safety (minimize patient self-management and patient initiated d/c) - Provide comfort (symptom relief ASAP) - Initiate OAT Non-opioid medications for managing acute withdrawal PHARM 445 Pain and Mental Health - APAP, ibuprofen, loperamide, clonidine (for sweating, tremors, chills, anxiety), dimenhydrinate, ondansetron Naloxone - Opioid antagonist - Rapidly reverses CNS and respiratory depression due to opioid overuse (onset 2-3 minutes) - Typically use IM in community, but nasal kits covered by NIHB Good Samaritan Drug OD Act - Protects individuals that experience or witness an OD from charges of possession of controlled substances Supervised Consumption Sites - Manage OD and reduce mortality - Enhance safe injection and disposal practices - Decrease public drug use - Increase uptake of treatment and other healthcare services - Prevent transmission of blood borne diseases PHARM 445 Pain and Mental Health OPIOID USE DISORDER II Buprenorphine/Naloxone (Suboxone) - Partial mu opioid R agonist (high binding affinity, thus can precipitate withdrawal) - Kappa opioid R antagonist - Slow dissociation and long half life - Better safety profile o Decreased risk of OD (respiratory depression has ceiling effect) o Standard dose well below lethal threshold for opioid naïve patients - Limited AE and euphoria - Risk: precipitated withdrawal o Acute and severe withdrawal that occurs if initial dose of buprenorphine is given while person still has other opioids active on receptors. This is because buprenorphine has high affinity for opioid receptors but only partial agonist activity so patient will not be getting the full opioid effect. Buprenorphine Extended Release Injection (Sublocade) - Initiated in patients stabilized on equivalent 8-24mg/day SL for a minimum of 7 days - Typical dose: o 300mg SC q1m x2m then 100 mg SC q1m ▪ Doses can be provided 26-42 days apart - Unknown safety in pregnancy, discuss contraception in patients of child bearing potential - RPh must complete Indivior’s Sublocade Certification to administer - Viscous product with large gauge (speed of injection as per patient preference) Methadone - Full mu opioid R agonist o Slow onset, long elimination half life (titrate slowly to avoid accumulation) - More interaction (CYP3A4) o Reduce MMT levels: CBZ, PHT, chronic OH o Increase MMT levels: ciprofloxacin, acute OH, SSRI, macrolides - More AE (constipation, sweating, weight gain, dental concerns, hypogonadism) - High risk of respiratory depression - Loss of tolerance occurs quickly (important to ask last dose because if its been a while, you will need to reduce the methadone dose) - Contraindication: allergy, MAOi use within last 14 days, respiratory compromise - Safe in pregnancy Slow Release Oral Morphone (SROM; Kadian) - Preferred in patients not stabilized on have contraindications to above treatment options - Better than MMT for reducing cravings, symptoms, and persistent mild depression - Dosing: o Starting: 50-300 mg (depending on tolerance) o Increase 100mg q24-48h o Full range: 60-1200mg/d - Once daily dosing (only 24h product studied) - Contraindication: allergy, MAOi use within last 14 days, respiratory compromise, CKD, paralytic ileus Injectable opioid agonist treatment - High intensity treatment option *led by specialist* - Goal: harm reduction o Infections from IVDU, transmission of blood borne diseases (HIV, HCV) PHARM 445 Pain and Mental Health o Engage patient in care - Patients self inject pre-filled hydromorphone IV/IM up to TID ins upervised setting OAT - Suboxone o First line treatment in AB o Sublingual tablet or film with 4:1 ratio of buprenorphine: naloxone o Safe in pregnancy and lactation o Max dose 24mg/day o Traditional vs low dose initiation regimens o Missed dose protocol: 6 days without return to full agonist Re-titration required (reach previous stable dose within few days) 5 days with return to full agonist Re-induction required - Sublocade o Only for patients already stabilized on buprenorphine/naloxone SL o SC only (no IV or IM) o Missed dose protocol: Up to 2 week delay (42 days since last Receive next dose ASAP and continue monthly injections thereafter dose) More than 2 week delay (>42 days Re-induction needed. Patient needs to restart since last dose) buprenorphine/naloxone - Methadone o OAT uses liquid > tablets o Starting dose dependent on tolerance level (5-40mg, increase by ~10mg q3d) o No max dose, but balance withdrawal and cravings with AE o Missed dose protocol: 1-3 consecutive missed doses Same dose (no change) 4 consecutive missed doses Cancel Rx. Assess, resume at 50% of previous dose or 30mg (whichever is higher) 5+ consecutive missed doses Cancel Rx. Assess, resume at 30-40mg (depending on tolerance) - Kadian o Need to be diligent to avoid diversion and mitigate OD risk o Capsules opened and pellet ingestion witnessed (can be mixed with apple sauce but must be swallowed, cannot crush or chew) o Missed dose protocol 1-3 consecutive missed doses Same dose (no change) 4 consecutive missed doses Cancel Rx. Assess, resume at 50% of previous dose or initiation dose (whichever is higher) 5+ consecutive missed doses Cancel Rx. Assess, restart at initiation dose Monitoring: - ECG: specific for methadone maintenance monitoring o Timing: ▪ prior to initiation of methadone PHARM 445 Pain and Mental Health ▪ within 30 days of initiation ▪ if dose meets or exceeds 100 mg, and thereafter at every dose than exceeds multiple of 20mg ▪ patient presents with unexplained syncope, seizures, cardiac involvement ▪ patient initiated on medication that prolongs qtc - Urine Drug screening: integrated into treatment plan for OAT o Purpose: ▪ Confirm substance use, id concerning substance, monitor efficacy and adherence o Frequency dependent on patient factors Acute Pain Management in OUD - Untreated acute pain can be a risk factor for opioid use disorder - Include non-opioid pharmacotherapy - Opioid can be used for pain management in patients with OUD, but monitor carefully - Complaints of pain should be taken seriously Therapeutic Choices in Bipolar Disorder Vanessa Hill, BSc(Hons), PharmD Pharmacist, Inpatient Mental Health Peter Lougheed Centre Southern Alberta Forensic Psychiatry Centre (SAFPC) [email protected] Lecture Objectives Apply the Diagnostic and Statistical Manual V (DSM-V) criteria of mania, bipolar I depression, hypomania, and bipolar II depression when assessing a patient and their treatment needs Select therapy within each applicable phase of treatment based on guideline recommendations and individual patient factors Non-pharmacological Interventions First Line: Psychoeducation Second Line: Cognitive behavioural therapy (CBT) Family-focused therapy (FFT) Electroconvulsive therapy (ECT) - second line in acute bipolar mania and depression CANMAT 2018 Guidelines Bipolar I Disorder DSM-V Definition of Bipolar I Disorder Criteria have been met for at least one manic episode DSM-V Acute Bipolar Mania Mania Euthymia Depression DSM-V Criteria of Mania Abnormally and persistently elevated, expansive, or irritable mood AND Persistently increased activity or energy present FOR most of the day, nearly every day, for at least 1 week (less if hospitalized) DSM-V Manic Episode DSM-V Criteria continued At least 3 of (or 4 if mood is only irritable): Distractibility Indiscretion Grandiosity Flight of ideas Activity (goal-directed) or psychomotor agitation Sleep (Decreased need) Talkative (more than usual) or pressured speech These lead to impaired functioning or hospitalization, or are accompanied by psychotic features. The episode is also not substance-induced. DSM-V Manic Episodes with Psychotic Features Seen in 50% of manic episodes Should resolve with manic symptoms CANMAT 2018 Guidelines Mental Status Exam (MSE) Example Level of consciousness Normal Appearance and behaviour Looks stated age. Unkempt with mismatched clothing. Wearing sunglasses Psychomotor behaviour Agitated and animated. Furiously writing content on a piece of paper Speech Speeded and pressured. Difficult to interrupt Affect and mood Affect: Labile and irritable. Mood: Rates mood as 10/10 - “I feel amazing!” Perception Denies hallucinations, but appears to be responding to internal stimuli Thought Content Grandiose delusions of being a bestselling author and CEO of Tesla Thought Process Disorganized and tangential Insight/judgment Poor Cognition Not formally assessed, but oriented to person, place, and time Bipolar I Disorder Agitation DSM-V definition: “Excessive motor activity associated with a feeling of inner tension” How do we manage this? Treat the mania Short-acting antipsychotics (IM or PO) Benzodiazepines (IM/PO/SL) Example: Haloperidol 5 mg PO/IM Q6H PRN + Lorazepam 1 mg PO/IM Q4H PRN CANMAT 2018 Guidelines Before starting medications, consider: Substance use Stimulants, hallucinogens, opioids Cannabis Caffeine Contributing medications Antidepressants! Prescription stimulants Corticosteroids Dopamine agonists First line monotherapy options in acute mania Mood Stabilizers Lithium Divalproex Atypical antipsychotics Quetiapine Aripiprazole Asenapine (SL route) Risperidone Paliperidone (over 6 mg) Cariprazine CANMAT 2018 Guidelines First line combination therapy options in acute mania Atypical antipsychotic + “mood stabilizer” Quetiapine + Lithium/Divalproex Aripiprazole + Lithium/Divalproex Risperidone + Lithium/Divalproex Asenapine + Lithium/Divalproex CANMAT 2018 Guidelines Second line options in acute mania Monotherapy Olanzapine* Carbamazepine* Olanzapine + lithium/divalproex Lithium + divalproex Ziprasidone* Haloperidol* *Good efficacy, but second line due to safety and tolerability CANMAT 2018 Guidelines Clinical Pearls Clonazepam Used off-label as an adjunct in acute mania Possible antimanic effects via inhibiting dopamine release Olanzapine Will often see low-doses (e.g., 5 to 10 mg) alongside acute phase treatment Anti-manic and helps with sleep Lappas et al., J Clin Med 2023 Monotherapy vs. Combination Therapy Monotherapy Combination More tolerated Response is more rapid Able to attribute side effects Preferred in severe mania to a specific drug Used if monotherapy was More patient-friendly previously ineffective Recommended if psychotic features are present or in rapid cycling (four or more mood episodes per year) CANMAT 2018 Guidelines Recommendations for therapy Choose a first-line option ↓ Optimize the dose(s) ↓ If inadequate response: switch to or add an alternate first-line agent(s) ↓ Optimize the dose(s) ↓ If inadequate response: trial other first-line agent(s) ↓ If multiple first line agent(s) tried and inadequate: move on to second line then third line agents CANMAT 2018 Guidelines Acute Bipolar I Depression Mania Euthymia Depression Bipolar I Depression The most pervasive mood state Can cause significant functional impairment DSM-V Criteria for a Major Depressive Episode At least five of the following symptoms, with at least 1) or 2) being present daily in a 2-week period: 1) Depressed mood 2) Loss of interest or pleasure (anhedonia) 3) Significant, unintentional weight loss or weight gain 4) Insomnia or hypersomnia 5) Psychomotor agitation or retardation (observed and subjective) 6) Fatigue or low energy 7) Feelings of worthlessness or guilt 8) Poor concentration 9) Suicidal ideation +/- a specific plan, or a suicide attempt Symptoms must reflect a change from previous functioning and are not attributable to a substance or medical condition DSM-V First line options in bipolar I depression Quetiapine Lurasidone + Lithium/Divalproex Lithium Lamotrigine Lurasidone CANMAT 2018 Guidelines Second line options in bipolar I depression Divalproex Selective serotonin reuptake inhibitors (SSRIs) or bupropion as an adjunct* Lithium Cariprazine Olanzapine-fluoxetine (combination medication not in Canada) CANMAT 2018 Guidelines Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Depression Study type: Multi-centre, double-blind, placebo-controlled, parallel-study group Study duration: Up to 26 weeks P Age ≥ 18, with a major depressive episode associated with Bipolar I or Bipolar II disorder I Addition of paroxetine (10-40 mg) or bupropion SR (150-375mg) to their existing mood stabilizer therapy C Placebo + existing mood stabilizer therapy O Primary: Durable recovery (Euthymia for at least 8 weeks) Outcomes: No statistical differences between antidepressant vs. placebo for any outcome Primary outcome: Antidepressant + mood stabilizer: 42/179 (23.5%) Placebo + mood stabilizer: 51/187 (27.3%) p = 0.4 No differences seen between Bipolar I and Bipolar II disorder Adverse effects Non-significant difference in treatment emergent manic switch (10.1% vs 10.7%) Bottom line: Adjunctive antidepressant therapy is not more efficacious in treating a depressive episode compared to mood stabilizer/antimanic therapy on its own More on antidepressants in Bipolar I Not as monotherapy! Should be “opposed” by an antipsychotic or mood stabilizer Bupropion may have lower risk of manic switch. Venlafaxine had the highest risk (Leverich et al., 2006) Avoid in those with history of treatment-emergent manic switch However, also consider psychiatric comorbidity Recommendations for therapy in Bipolar I Depression If on no treatment: Consider quetiapine If having a breakthrough depressive episode on current therapy, choose adjuncts ↓ Optimize the dose Monitor for early improvement (within 1-2 weeks) ↓ If inadequate response: switch to or add an alternate first-line agent(s) ↓ Optimize the dose(s) CANMAT 2018 Guidelines Other considerations Quetiapine and lurasidone therapy may result in faster response Lamotrigine is limited by its titration Why is titration done slowly? Maintenance Therapy in Bipolar I Disorder Maintenance therapy in bipolar I disorder ALL patients require maintenance therapy Should be started early Reverses cognitive impairment Risk of recurrence is 25% if on treatment, compared to 40% if not on treatment CANMAT 2018 Guidelines Medications for Maintenance Therapy Evidence is focused on prevention of mood episodes There is some overlap with acute treatment choices In general, we continue medications from the acute phase Important notes: Lamotrigine has limited evidence in mania Antidepressants may not be beneficial long-term CANMAT 2018 Guidelines Gold standard for maintenance treatment: Lithium Prevents both manic and depressive episodes Antisuicidal effects Neuroprotective First line agents for maintenance therapy in Bipolar I Disorder Lithium Quetiapine Divalproex Lamotrigine Asenapine Combinations Quetiapine + Lithium/Divalproex Aripiprazole + Lithium Divalproex Aripiprazole (PO or LAI) CANMAT 2018 Guidelines Second line agents Use after multiple first-line agents have been tried via switch or add-on strategies Olanzapine Risperidone LAI (monotherapy or adjunct) Carbamazepine Paliperidone (>6 mg) Lurasidone + Lithium/DVP Ziprasidone + Lithium/DVP CANMAT 2018 Guidelines Combination therapy (antipsychotic + lithium/divalproex) If used in acute phase, continue for 6 months in the maintenance phase to reduce recurrence Reevaluate need for the antipsychotic at the 6 month mark CANMAT 2018 Guidelines Commonalities between treatment phases in Bipolar I First-line agent Acute Mania Acute Bipolar I Maintenance Depression Lithium ✓ ✓ ✓ Quetiapine ✓ ✓ ✓ CANMAT 2018 Guidelines Treatment-refractory Bipolar I Disorder May necessitate exploring second and third line options Clozapine may also be used May help to decrease overall medication burden CANMAT 2018 Guidelines Treatment-refractory Bipolar I Disorder Example Paliperidone palmitate 150 mg IM Q28days Quetiapine 400 mg PO QHS Clonazepam 0.5 mg PO BID Divalproex DR 1500 mg PO QHS ↓started clozapine Clozapine 375 mg PO QHS Divalproex DR 1500 mg PO QHS Clonazepam 0.25 mg PO BID (tapering to discontinue) Tapered quetiapine Stopped paliperidone palmitate (self tapers) Mania Hypomania Euthymia Depression Bipolar II Disorder DSM-V Criteria for Bipolar II Disorder Criteria are met for at least one hypomanic episode and at least one major depressive episode There has never been a manic episode Hypomanic and major depressive episodes are not better explained by other diagnoses (such as schizoaffective disorder, schizophrenia, or other psychotic disorders) DSM-V Bipolar II Can transition to Bipolar I disorder early in illness May be a prodrome of Bipolar I disorder Grande et al., Lancet 2016 Bipolar II continued Pharmacotherapy has been less studied than in Bipolar I Little to no published evidence for lithium and atypical antipsychotics Therefore, understand the overarching recommendations for each phase ○ Only first-line options will be examined CANMAT 2018 Guidelines Acute hypomania Mania Hypomania Euthymia Depression Hypomania Abnormally and persistently elevated, expansive, or irritable mood AND Persistently increased activity or energy present FOR most of the day, nearly every day, for at least 4 days DSM-V Hypomanic Episode DSM-V Criteria - DIGFAST At least 3 of (or 4 if mood is only irritable): Distractibility Indiscretion Grandiosity Flight of ideas Activity (goal-directed) or psychomotor agitation Sleep (Decreased need) Talkative (more than usual) or pressured speech These are not severe enough to impair function or necessitate hospitalization. Psychotic features should not be present. DSM-V Pharmacological management of acute hypomania Challenging to make evidence-based recommendations Treat as you would in acute bipolar I mania, especially if hypomania is frequent or debilitating Treatment options (See acute mania) Antipsychotics Anticonvulsants Lithium CANMAT 2018 Guidelines Acute Bipolar II Depression Mania Hypomania Euthymia Depression DSM-V Criteria for a Major Depressive Episode At least five of the following symptoms, with at least 1) or 2) being present daily in a 2-week period: 1) Depressed mood 2) Loss of interest or pleasure (anhedonia) 3) Significant, unintentional weight loss or weight gain 4) Insomnia or hypersomnia 5) Psychomotor agitation or retardation (observed and subjective) 6) Fatigue or low energy 7) Feelings of worthlessness or guilt 8) Poor concentration 9) Suicidal ideation +/- a specific plan, or a suicide attempt Symptoms must reflect a change from previous functioning and are not attributable to a substance or medical condition DSM-V Treatment in Acute Bipolar II Depression First line: Quetiapine Second line: Lithium Sertraline or venlafaxine XR (for non-mixed depression) Lamotrigine ECT CANMAT 2018 Guidelines Treatment in Acute Bipolar II Depression Third line: Fluoxetine (for non-mixed depression) Divalproex monotherapy Ziprasidone (only for mixed depression and hypomania) CANMAT 2018 Guidelines Antidepressants in Bipolar II Mood elevations may be less frequent in Bipolar II than Bipolar I, so benefit may outweigh risk Avoid in those with: History of treatment-emergent hypomania Mixed symptoms Rapid cycling Patient education on early warning signs of hypomania is key CANMAT 2018 Guidelines Maintenance Therapy in Bipolar II First line: Quetiapine Lithium Lamotrigine Second line: Venlafaxine XR Fluoxetine CANMAT 2018 Guidelines Maintenance Therapy in Bipolar II Third line: Divalproex Carbamazepine Other antidepressants (not named as first or second line agents) Risperidone (to prevent hypomania) CANMAT 2018 Guidelines Commonalities between treatment phases in Bipolar II Disorder Acute Acute Bipolar II Maintenance Hypomania Depression Quetiapine ✓ ✓ ✓ Lithium ✓ ✓ (2nd line) ✓ CANMAT 2018 Guidelines References American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th ed.). 2013. https://doi.org/10.1176/appi.books.9780890425596 Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet. 2016 Apr 9;387(10027):1561-1572. doi: 10.1016/S0140-6736(15)00241-X. Epub 2015 Sep 18. PMID: 26388529. Lappas AS, Helfer B, Henke-Ciążyńska K, Samara MT, Christodoulou N. Antimanic Efficacy, Tolerability, and Acceptability of Clonazepam: A Systematic Review and Meta-Analysis. J Clin Med. 2023 Sep 6;12(18):5801. doi: 10.3390/jcm12185801. PMID: 37762742; PMCID: PMC10531794. Leverich GS, Altshuler LL, Frye MA, Suppes T, McElroy SL, Keck PE Jr, Kupka RW, Denicoff KD, Nolen WA, Grunze H, Martinez MI, Post RM. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006 Feb;163(2):232-9. doi: 10.1176/appi.ajp.163.2.232. PMID: 16449476. Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, Friedman ES, Bowden CL, Fossey MD, Ostacher MJ, Ketter TA, Patel J, Hauser P, Rapport D, Martinez JM, Allen MH, Miklowitz DJ, Otto MW, Dennehy EB, Thase ME. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007 Apr 26;356(17):1711-22. doi: 10.1056/NEJMoa064135. Epub 2007 Mar 28. PMID: 17392295. Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, Sharma V, Goldstein BI, Rej S, Beaulieu S, Alda M, MacQueen G, Milev RV, Ravindran A, O'Donovan C, McIntosh D, Lam RW, Vazquez G, Kapczinski F, McIntyre RS, Kozicky J, Kanba S, Lafer B, Suppes T, Calabrese JR, Vieta E, Malhi G, Post RM, Berk M. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018 Mar;20(2):97-170. doi: 10.1111/bdi.12609. Epub 2018 Mar 14. PMID: 29536616; PMCID: PMC5947163 Monitoring and Follow-up in Bipolar Disorder Vanessa Hill, BSc(Hons), PharmD Pharmacist, Inpatient Mental Health Peter Lougheed Centre Southern Alberta Forensic Psychiatry Centre (SAFPC) [email protected] Lecture objectives Formulate a monitoring plan with respect to medication efficacy and safety in bipolar disorder Identify reasonable timelines for follow-up Recognize safety considerations of medications used in bipolar I disorder and use these to modify treatment plans Understand cardiovascular risk in bipolar disorder and integrate monitoring into the care plan Monitoring Efficacy in Bipolar Disorder When should I see an effect? Treatment of Mania Evaluate for some response at weeks 1 and 2. Modify therapy if required. Full response should be seen at 3 to 4 week mark Treatment of Bipolar (I and II) Depression Early response should be seen within 2 weeks If no response, consider switching medications CANMAT 2018 Guidelines Symptom monitoring Mood Sleep Cognitive symptoms Functioning (Work, relationships, daily activities) Quality of life Monitoring tips: Keeping a mood diary Having a follow-up contact CANMAT 2018 Guidelines Medication adherence Important to assess regularly to: Prevent neuroprogression and clinical progression Prevent recurrence of a mood episode Avoid inaccurate assessments and unnecessary treatment changes What are the safety implications? Medication adherence Strategies: Shared decision-making Psychoeducation Frequent follow-ups Blister packs LAIs Oral liquids, oral dissolving tablets (ODT), or sublingual formulations Treatment orders under the Alberta Mental Health Act Information about the Mental Health Act: https://www.albertahealthservices.ca/info/mha.aspx Medication assessments Can medications be simplified following a period of stability? Are there options with more acceptable side effect profiles? Rational Polypharmacy Medication regimens can become complex Ensure all medications have a part to play Rational Polypharmacy Example in Bipolar I Aripiprazole monohydrate 400 mg IM Q28days → Maintenance therapy Quetiapine 150 mg PO HS → Treatment of depressive episode; help with sleep Lithium 1250 mg PO with supper → treatment of depressive episode and prevention of mania Pregabalin 75 mg PO TID → Concurrent generalized anxiety disorder (GAD) Follow-up Risk of recurrence is high following discharge from hospital Important to arrange follow-up soon after discharge More frequent during medication changes and titrations In periods of stability, may have follow up every 2 to 6 months If a patient is on a LAI, follow-up will inherently be regular! CANMAT 2018 Guidelines Monitoring Safety Therapeutic Drug Monitoring Discussed in Lecture 1 When to consider drawing a level: Dose changes Changes in mental status Changes to renal and hepatic function As part of monitoring for signs of toxicity Cardiovascular risk in bipolar disorder Highest 10-year cardiovascular risk amongst severe mental illnesses (including schizophrenia and schizoaffective disorder) CVD risk in bipolar disorder has been documented even prior to the use of antipsychotics and mood stabilizers Bipolar I disorder is significantly associated with CV mortality HR=2.35, 95% C.I. 1.04–5.33, p=0.04 Rossom et al., J Am Heart Assoc 2022; Goldstein et al., Circulation 2015; Fiedorowicz et al., Psychosom Med 2009 Cardiovascular risk in bipolar disorder Known factors: Tobacco use High BMI Dyslipidemia Hypertension Diabetes Solution: Monitor both mental and physical health. Address cardiovascular risk early Rossom et al., J Am Heart Assoc 2022 Routine Metabolic Monitoring Weight, BMI Blood pressure Metabolic monitoring labs Fasting BG Hgb A1c Lipid Panel TSH Other recommended Interventions Smoking cessation Diet and lifestyle counseling Medications for antipsychotic-induced weight gain Psychotropic medication changes Bipolar Disorder in Older Age Drug metabolism is decreased Renal: decreased glomerular filtration rates Hepatic: decreased hepatic metabolism Drug doses can be markedly lower than in younger adults Pregnancy Considerations DO NOT USE: Divalproex - neural tube defects Carbamazepine - neurological and cardiac malformations Lithium Avoid in first trimester (cardiac malformations) Lamotrigine ↑↑↑↑ metabolism in pregnancy Dose adjustments may be required during pregnancy and immediately after delivery CANMAT 2018 Guidelines Pregnancy Considerations Antipsychotics, antidepressants In general, use risk/benefit assessment for selection Considerations for Women of Child-bearing Age Discuss options for contraception if started on teratogenic agents Pregnancy planning with community follow-up team References Goldstein BI, Carnethon MR, Matthews KA, McIntyre RS, Miller GE, Raghuveer G, Stoney CM, Wasiak H, McCrindle BW; American Heart Association Atherosclerosis; Hypertension and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young. Major Depressive Disorder and Bipolar Disorder Predispose Youth to Accelerated Atherosclerosis and Early Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. 2015 Sep 8;132(10):965-86. doi: 10.1161/CIR.0000000000000229. Epub 2015 Aug 10. PMID: 26260736. Fiedorowicz JG, Solomon DA, Endicott J, Leon AC, Li C, Rice JP, Coryell WH. Manic/hypomanic symptom burden and cardiovascular mortality in bipolar disorder. Psychosom Med. 2009 Jul;71(6):598-606. doi: 10.1097/PSY.0b013e3181acee26. Epub 2009 Jun 26. PMID: 19561163; PMCID: PMC2779721. Rossom RC, Hooker SA, O'Connor PJ, Crain AL, Sperl-Hillen JM. Cardiovascular Risk for Patients With and Without Schizophrenia, Schizoaffective Disorder, or Bipolar Disorder. J Am Heart Assoc. 2022 Mar 15;11(6):e021444. doi: 10.1161/JAHA.121.021444. Epub 2022 Mar 9. PMID: 35261265; PMCID: PMC9075298. Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, Sharma V, Goldstein BI, Rej S, Beaulieu S, Alda M, MacQueen G, Milev RV, Ravindran A, O'Donovan C, McIntosh D, Lam RW, Vazquez G, Kapczinski F, McIntyre RS, Kozicky J, Kanba S, Lafer B, Suppes T, Calabrese JR, Vieta E, Malhi G, Post RM, Berk M. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018 Mar;20(2):97-170. doi: 10.1111/bdi.12609. Epub 2018 Mar 14. PMID: 29536616; PMCID: PMC5947163 Sleep-Wake Disorders November 20, 2024 [RECORDED] Dylan Moulton, B.Sci., PharmD Assistant Clinical Professor Faculty of Pharmacy and Pharmaceutical Sciences Lecture Objectives Following the completion of this lecture, the learner should be able to: Describe the epidemiology and burden of sleep-wake disorders Describe risk factors, medications, and medical conditions associated with insomnia disorder Demonstrate how the DSM-5-TR diagnostic criteria can be used to support an insomnia diagnosis Recognize and use rating scales to screen, assess, and monitor patients with insomnia Describe the non-pharmacological and pharmacological treatment options for insomnia 2 Resources Clinical Practice Guidelines for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline Centre for Effective Practice: Management of Chronic Insomnia TOP Guidelines: Assessment to Management of Adult Insomnia: Clinical Practice Guideline 3 Sleep-Wake Disorders Sleep-Wake Disorders General Classiﬁcation Scheme (not DSM): Problems initiating and maintaining sleep Insomnia Problems of too much sleep Hypersomnia Excessive daytime sleepiness Circadian rhythm problems Parasomnias (“behavioural events” that dominate the clinical picture of poor sleep) sleep terrors, sleepwalking, nightmare disorder, sleep paralysis, etc The most common sleep-wake disorders seen in are: insomnia and excessive daytime sleepiness Psychiatry in Primary Care, 2nd Edition, CAMH 5 Sleep-Wake Disorders DSM-5-TR Classiﬁcation: Insomnia Disorder Hypersomnolence Disorder Narcolepsy Breathing-Related Sleep Disorders (e.g., Obstructive Sleep Apnea Hypopnea) Circadian Rhythm Sleep-Wake Disorders Non-Rapid Eye Movement (NREM) Sleep Arousal Disorders Rapid Eye Movement (REM) Sleep Behaviour Disorder Nightmare Disorder Restless Legs Syndrome Substance/Medication-Induced Sleep Disorder Patients with these disorders generally present with dissatisfaction regarding the quality, timing, and amount of sleep, which results in daytime distress and impairment. DSM-5-TR: Sleep-Wake Disorders 6 Sleep 4 Stages of Sleep These stages can be measured by polysomnography (multiple measurements) NREM Sleep N1 transition from wakefulness to sleep (~5% of time spent asleep) N2 speciﬁc EEG waveforms like sleep spindles and K complexes (~50% of time spent asleep) N3 slow-wave/delta sleep, deepest level of sleep (~20% of time spent asleep) REM Sleep majority of story-like dreams occur here (~20-25% of time spent asleep) Individuals cycle between NREM and REM phases approximately every 70-120 minutes (~4-6 cycles per night) DSM-5-TR: Sleep-Wake Disorders 8 Review Sleep Stages Video PRN https://www.youtube.com/watch?v=0LNdsTrQJCs 9 Sleep Architecture The amount and distribution of speciﬁc sleep stages (stages have a temporal organization across the night) N3 tends to occur in the ﬁrst ⅓ to ½ of the night REM occurs cyclically throughout the night, alternating with NREM sleep, and increases in duration toward the morning Human sleep varies characteristically across the lifespan As we age, sleep continuity and depth deteriorate (increased wakefulness and N1 sleep, decreased N3 sleep) This needs to be considered (age) when considering diagnosis DSM-5-TR: Sleep-Wake Disorders 10 Sleep Architecture https://www.psychdb.com/neurology/polysomnography 11 Insomnia Insomnia Disorder - Diagnostic Criteria DSM-5-TR Diagnostic Criteria: A. A predominant complaint of dissatisfaction with sleep quantity or quality, associated with one (or more) of the following symptoms: 1. Diﬃculty initiating sleep 2. Diﬃculty maintaining sleep, characterized by freq. awakenings or problems returning to sleep after awakenings 3. Early-morning awakening with inability to return to sleep B. The sleep disturbance causes clinically signiﬁcant distress or impairment in social, occupational, educational, academic, behavioral, or other important areas of functioning C. The sleep diﬃculty occurs at least 3 nights per week (i.e., chronic insomnia) D. The sleep diﬃculty is present for at least 3 months (i.e., chronic insomnia), < 3 months = “ST/acute” E. The sleep diﬃculty occurs despite adequate opportunity for sleep… what does this mean? DSM-5-TR: Sleep-Wake Disorders 13 Important Note About Criteria “E” Poor sleep quality/quantity in the setting of an inadequate opportunity for sleep, doesn’t mean insomnia disorder Insomnia must be distinguished from sleep deprivation attributable to inadequate opportunity or circumstance for sleep e.g., not sleeping well because of an emergency e.g., not sleeping well because of a professional or family obligation which forced the individual to stay awake e.g., not sleeping well because you have an exam the next morning and studied late and/or are anxious about it! DSM-5-TR: Sleep-Wake Disorders 14 Insomnia Disorder - Diagnostic Criteria DSM-5-TR Diagnostic Criteria: F. The insomnia is not better explained by and does not occur exclusively during the course of another sleep-wake disorder (e.g., narcolepsy, a breathing-related sleep disorder, a circadian rhythm sleep-wake disorder, a parasomnia) G. The insomnia is not attributable to the physiological effects of a substance (e.g., recreational, medication) H. Coexisting mental disorders and medical conditions do not adequately explain the predominant complaint of insomnia DSM-5-TR: Sleep-Wake Disorders 15 Insomnia Disorder - Complexity! How do you know what is causing what? How does this complicate a diagnosis? Insomnia may develop its own course with some anxiety and depressive features without those features meeting criteria for any one mental disorder Insomnia may manifest as a clinical feature of a more predominant mental disorder It is often impossible to determine the precise nature of the relationship between these clinical entities, and this relationship may change over time… therefore we don’t need to make a causal attribution between the two Rather, the diagnosis of insomnia disorder is made with concurrent speciﬁcation of the comorbid conditions. A concurrent insomnia diagnosis should only be considered when insomnia is suﬃciently severe to warrant independent clinical attention, otherwise, no separate diagnosis is necessary Although insomnia can be a symptom or an independent disorder, it is most frequently observed as a comorbid condition with another medical or mental disorder DSM-5-TR: Sleep-Wake Disorders 16 Insomnia Disorder - Manifestations Insomnia can have different manifestations during different times of the sleep period: Sleep-onset insomnia (initial insomnia) ○ Diﬃcult initiating sleep at bedtime ○ “Sleep latency” (time it takes to fall asleep) is sometimes deﬁned as taking > 20-30 minutes to fall asleep Sleep maintenance insomnia (middle insomnia) ○ frequent or prolonged awakenings throughout the night ○ most predominant manifestation (60% of those with insomnia), however, a combination of these manifestations is the most common presentation of all ○ “Diﬃculty maintaining sleep” is sometimes deﬁned as > 20-30 minutes awake after sleep onset Late insomnia ○ early morning awakening with an inability to return to sleep ○ “Early morning awakening” is sometimes deﬁned as waking >1 hr before intended and before 6 ½ hrs of total sleep DSM-5-TR: Sleep-Wake Disorders 17 Prevalence Approximately ⅓ of adults report insomnia symptoms 10 - 15% experience daytime impairments 4 - 22% have symptoms that meet criteria for insomnia disorder (10% average) Just because you have insomnia symptoms, does not mean you have insomnia disorder… Insomnia is the most prevalent of all sleep-wake disorders Prevalence rates are signiﬁcantly higher for those with medical or psychiatric conditions when compared to the general population 40 - 50% of individuals with insomnia disorder have a comorbid mental disorder AFAB > AMAB (1.3 : 1), as one ages (> 45), the ratio increases even more (1.7 : 1) Psychiatry in Primary Care, 2nd Edition, CAMH, DSM-5-TR: Sleep-Wake Disorders 18 Insomnia Disorder - Risk Factors Temperamental anxiety or worry-prone personality higher stress reactivity tendency to repress emotions Environmental noise, light, extremes of temperature, high altitude (from associated breathing diﬃculties) societal or individual stressors (e.g., unemployment, divorce, loss of loved ones) Genetic/Physiological AFAB, advancing age (insomnia prevalence is up to 40% in those over 65 yro) familial disposition (35 - 70% of those with insomnia have 1+ 1st degree relatives with a hx) heritability is highest with insomnia disorder without comorbidities Course Modiﬁers poor sleep hygiene practices (e.g., excessive caffeine use, irregular sleep schedules) DSM-5-TR: Sleep-Wake Disorders 19 Insomnia Disorder - Age Onset can occur anytime in life, but ﬁrst episode is most common in young adulthood less frequent in childhood or adolescence in menopause, the incidence of new-onset insomnia increases with menopause late-life onset can occur, but is most often associated with the onset of another medical condition Complaints often change with age! insomnia complaints are more prevalent among middle-age and older adults younger adults often complain of initiating sleep middle age/older adults more commonly complain of nighttime awakenings (maintaining sleep) DSM-5-TR: Sleep-Wake Disorders 20 Insomnia Disorder - Acute to Chronic It is not uncommon for a person to experience a triggering event that leads to an acute insomnia, which can develop into a chronic insomnia → especially if negative cognitive processes develop during this acute period… Insomnia can persist even when an initial precipitating event subsides… Why? The precipitating effects may differ from the perpetuating ones… How? Conditioning factors and/or hyperarousal e.g., an individual is bedridden due to a painful knee injury → diﬃculty sleeping → develop negative associations for sleep → conditioned arousal may then persist → persistent insomnia e.g., MDE → symptoms of insomnia become a major focus of attention during the episode → consequent negative conditioning → MDE resolves, but 40-50% of individuals have chronic insomnia e.g., having a fear of not sleeping DSM-5-TR: Sleep-Wake Disorders 21 Burden of Illness Inadequate sleep has many negative health implications: fatigue → often a more common complaint than “daytime sleepiness” cardiovascular complications (increased risk of CHF, HTN, stroke, MI, increased CV mortality) mood disturbances (irritability, mood lability, etc) rapid deterioration of multiple medical conditions sleep disorders can affect the pathophysiology of other medical conditions! higher risk of driving accidents compromised immune function impaired cognition (diﬃculties with attention, concentration, memory, complex manual skills) Psychiatry in Primary Care, 2nd Edition, CAMH, DSM-5-TR: Sleep-Wake Disorders 22 Burden of Illness Notice how many of the negative health implications listed on the slide previous could also impact your ability to: create/foster healthy interpersonal or social relationships with others meaningfully engage in your chosen occupation Insomnia is also a risk factor for numerous other medical conditions CVD (e.g., HTN, CAD, MI, congestive HF, CVA) Psychiatric (e.g., MDD, relapse of a MDE, anxiety disorders, SUD) DSM-5-TR: Sleep-Wake Disorders 23 Comorbidity / Other Medical Conditions Insomnia is a common comorbidity of many medical conditions (this list is NOT exhaustive) cancer, DM, coronary heart disease, COPD, arthritis, ﬁbromyalgia and other chronic pain conditions, degenerative brain diseases, TBI Insomnia is also highly comorbid with other sleep disorders sleep apnea (1 in 7 people is insomnia also have moderate to severe sleep apnea) rates of insomnia amongst people with narcolepsy are ~50% Insomnia is frequently comorbid with other mental disorders as well especially bipolar disorder, depressive and anxiety disorders SUD (many medications used in sleep-wake disorders can be misused - depressants/stimulants) The relationship is bidirectional, insomnia increases the risk of other medical conditions and vice versa Assess medical conditions to determine if another condition is causing or contributing to the insomnia DSM-5-TR: Sleep-Wake Disorders 24 Medications Associated with Insomnia DSM-5-TR: Sleep-Wake Disorders 25 Screening Insomnia Disorder - Screening Recall how sleep latency, diﬃculty maintaining sleep, and early morning awakening is often deﬁned... if you notice a patient exceeding these, it may be best to further assess! DSM-5-TR: Sleep-Wake Disorders 27 Insomnia Disorder - Screening Athens Insomnia Scale Patient-rated questionnaire ~5 minutes to complete Indicate how diﬃcult the following items were in the past month, provided that it occurred at least 3 times per week If a patient scores >10 on the screening tool, complete an assessment http://sleepontario.com/docs/scales/Athens-Insomnia-Scale/Athens-Insomnia-Scale-English.pdf 28 Insomnia Disorder - Screening Sleep Disorders Questionnaire Clinician-rated questionnaire Indicates which questions are being used to screen for (or rule out) different sleep-wake or other psychiatric disorders Rating on a scale of 1 - 5 (1 = Never, 5 = Always) Clear description of how to interpret scoring on the guidance page (2nd page of the document) https://actt.albertadoctors.org/media/5qlhhzfe/sleep-disorders-questionnaire.pdf 29 Assessment Insomnia Disorder - Assessment Sleep Schedule bedtime, sleep latency, #/duration of awakenings, ﬁnal awakening, time to leave bed, week vs. weekend beliefs about sleep and compensatory behaviours (excessive time in bed, use of hypnotics) bedtime routine and disturbing factors in the environment (e.g., devices, partners, noise, darkness, temp.) Anxiety/Worry at Night Daytime Functioning Psychiatric and Physical Disorders Medications CNS-stimulants, sleep-disrupting medications Substance Use Caffeine, recreational substances, alcohol withdrawal DSM-5-TR: Sleep-Wake Disorders 31 Insomnia Disorder - Assessment Insomnia Severity Index Patient-rated 7 Questions Assessing severity of insomnia in the last 2 weeks Questions are scored from 0 (none) - 4 (severe) Total score range is 0 - 28 0 - 7 suggests no clinically signiﬁcant insomnia 8 - 14 suggests subthreshold insomnia 15 - 21 suggests clinical insomnia of moderate severity 22 - 28 suggests clinical insomnia that is severe https://link.cep.health/mci3 32 Sleep Diary Record for ~1-2 weeks initially https://www.sleepfoundation.org/wp-content/uploads/2021/02/SF-23-127_Sleep_Diary_Interactive.pdf 33 Polysomnography (i.e., Sleep Study) The monitoring of multiple electrophysiological parameters during sleep (limited value in routine evaluation of insomnia) “Sleep Continuity” overall balance of sleep/wakefulness during a night of sleep speciﬁc sleep continuity measures include: “Sleep latency” - time required to fall asleep “Wake after sleep onset” - time awake between initial sleep onset and ﬁnal awakening (minutes) “Sleep eﬃciency” - ratio of time spent asleep to time in bed (higher % = better sleep continuity) You don’t refer to sleep specialists in the initial phases - refer when risk factors for other conditions (e.g., sleep apnea), or resistant/chronic cases and/or on long-term hypnotic therapy DSM-5-TR: Sleep-Wake Disorders, CPS: Insomnia [Therapeutic Choices], https://www.psychdb.com/neurology/polysomnography 34 Treatment Non-Pharmacological Psychoeducation Education about normal sleep average sleep need and individual variations in sleep need change in sleep need with age circadian rhythm and its importance in the patient’s ideal regular sleep schedule role of napping in compensating for lost sleep and its role in perpetuating chronic insomnia importance of sleep quality (vs. sleep duration only) consequences of sleep deprivation effects of caffeine, nicotine, medications and alcohol on sleep Psychotherapy Cognitive Behavioural Therapy for Insomnia (i.e., CBT-I) First-line standard treatment for insomnia → should be offered as initial treatment option to patients encompasses psychoeducation and dysfunctional beliefs that sustain insomnia Psychiatry in Primary Care, 2nd Edition, CAMH 36 CBT-I Short-term treatment (~3-6 sessions/weeks), but you can see improvements in sleep in 1-2 wks Beneﬁcial for more than 70% of patients Goal is to eliminate maladaptive behaviours and cognitions that are at the root of the condition, it provides beneﬁt even after termination of the treatment Often provided as individualized treatment from a trained clinician (e.g., psychologist, behavioural sleep specialist, nurses, social workers, pharmacists (special training), etc) If in-person is inaccessible, online CBT-I is available, in addition to self-guided CBT-I-based options (e.g., self-help books, websites, etc) in-person/clinician guided/full-program treatment is superior in effectiveness to these other options CBT-I is more effective (or “comparably eﬃcacious”) than pharmacotherapy, has longer lasting beneﬁts, is safer, and less costly over time Psychiatry in Primary Care, 2nd Edition, CAMH 37 CBT-I CEP: Management of Chronic Insomnia 38 CEP: Management of Chronic Insomnia Pharmacological To be considered for chronic insomnia when: CBT-I is unavailable (... there are many affordable, self-administered options) When past treatments with CBT-I (and other non-pharm) were ineffective As an adjunct to CBT-I (for short-term use only, 1 month 7. Disturbance causes clinically signiﬁcant distress or impairment in functioning 8. Disturbance is not attributable to the physiological effects of a substance or another medical condition Canadian Clinical Practice Guidelines for the Management of Anxiety, Posttraumatic Stress, and Obsessive-Compulsive Disorders (2014) 28 Post-Traumatic Stress Disorder (PTSD) - Diagnosis Canadian Clinical Practice Guidelines for the Management of Anxiety, Posttraumatic Stress, and Obsessive-Compulsive Disorders (2014) 29 Post-Traumatic Stress Disorder (PTSD) Presentation may be delayed > 6 or more months! PTSD can present in many different ways, this is partially related to the complexity of trauma and the different experiences people have had Canadian Clinical Practice Guidelines for the Management of Anxiety, Posttraumatic Stress, and Obsessive-Compulsive Disorders (2014) 30 Post-Traumatic Stress Disorder (PTSD) - Screening Brief Screening Questions “Do you ﬁnd it hard to stop thinking about a very diﬃcult event that has happened to you?” “Do you ﬁnd that you have nightmares related to the event?” “Do you ﬁnd that you have ﬂashbacks, and by that I mean very vivid daydreams or what we may call a “daymare” about the event?” “When something happens that reminds you of the event, does that trigger a very large response in you? “Do you generally avoid things that remind you of the event?” “Generally, do you feel anxious since the event and have trouble sleeping or startle easily?” “Do you feel that the memories of this, and the way it has left you feeling, still gets in the way of your life?” Psychiatry in Primary Care, 2nd Edition, CAMH 31 Post-Traumatic Stress Disorder (PTSD) - Treatment First line Psychotherapy CBT (exposure, TF-CBT) Eye movement desensitization and reprocessing (EMDR) Canadian Clinical Practice Guidelines for the Management of Anxiety, Posttraumatic Stress, and Obsessive-Compulsive Disorders (2014) 32 Post-Traumatic Stress Disorder (PTSD) - Treatment “Second Line” evidence is less clear surrounding eﬃcacy of psychotherapy vs. pharmacotherapy sv. combination therapy pharmacotherapy is an option, but psychotherapy would be ideal to trial ﬁrst or in combination Canadian Clinical Practice Guidelines for the Management of Anxiety, Posttraumatic Stress, and Obsessive-Compulsive Disorders (2014) 33 Post-Traumatic Stress Disorder (PTSD) - Treatment Prazosin → Off-Label Use alpha-1 antagonist (thought to reduce adrenergic activity in the CNS) may assist with sleep, reduce nightmares, and ease overall severity of PTSD takes up to 8 weeks to achieve full effect major dose-limiting SE is orthostatic hypotension and dizziness can see a profound initial dose effect, but there does not seem to be a sustained decrease in BP over time 1 mg PO QHS → titrate to effect (effective dose range varies - ~ 3 - 15 mg daily, can sometimes see daytime dosing too) Naltrexone → Off-Label Use small emerging body of evidence surrounding its use for dissociative symptoms in people with trauma Canadian Clinical Practice Guidelines for the Management of Anxiety, Posttraumatic Stress, and Obsessive-Compulsive Disorders (2014) 34 Post-Traumatic Stress Disorder (PTSD) Early treatment of PTSD may prevent chronicity Little data on early psychotherapy or pharmacotherapy as prevention of PTSD Evidence of worsening PTSD with early use of BZDs (high comorbid SUD) Mixed evidence regarding the use of propranolol to reduce physiological reactions to old and new traumatic memories Remission is achieved when diagnostic criteria are no longer met Often, long-term treatment is required Canadian

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