Choice of other psychotropics for BPSD 효자병원 한일우

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1 Choice of other psychotropics for BPSD 효자병원 한일우

2 Changing paradigm in diagnosis & treatment of signs and symptoms associated dementia Tariot PN, Daiello LA, Ismail MS.

3 General approach to the treatment of behavioral disturbances associated with dementia Define target symptoms in consensual manner with informants Establish or revisit medical diagnoses Establish or revisit neuropsychiatric diagnoses Assess and reverse aggravating factors Identify relevant psychosocial factors Educate caregivers Employ behavior management principles Use psychotropics for specific syndrome For remaining problems, consider symptomatic pharmacotherapy

4 Pharmacologic treatment of dementia Drug Neuroleptics Antidepressant Mood stabilizer Benzodiazepine BPSD suspiciousness, delusion, hallucination, aggression, hostility, belligerance, delusional agitated behavior depression, anxiety, simple agitated behavior not associated with delusion, insomnia agitation, disinhibited behavior, emotional lability Anxiety, insomnia

5 Antiepileptics AED Half life (hrs) Therapeutic L (mg/l) Adult dose (mg/day) Primary drug Phenytoin Carbamazepine Valproic acid Secondary drug Gabapentin Lamotrigine Topiramate NE Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed

6 Antiepileptics Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed

7 Carbamazepine Originally synthesized in 1957 Introduced into European market in the early 1960s as a treatment for epilepsy Use for bipolar disorder stems from the early 1970s in Japan 1 st drug for agitation or disinhibited behavior of dementia Mechanism of anti-agitation: Limbic kindling Direct neurochemical effect Electrophysiological effect Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed Tariot PN, Porsteinsson AP. Anticonvulsant to treat agitation in dementia. Int Psychogeriatrics 2000; 12(suppl 1)

8 Carbamazepine Am J Psychiatry 1998; 155: Randomized multi-site parallel group study during 6weeks Sample: 51 nursing home patients with agitation & dementia AD, VaD, Mixed type with MMSE score 6.8 Modal dose: 300mg/day, Mean serum level: 5.3μg/ml Primary outcome measure: BPRS, CGIC, OAS, BRSD

9 Carbamazepine Significant short-term efficacy of carbamazepine for agitation & aggression

10 Carbamazepine Randomized, double-blinded, placebo-controlled, parallel-group trial 6 weeks No of patients: 21 AD with MMSE score 6.0 Mean dose: 400mg/day Scale: BPRS, CGIC, Hamilton depression scale

11 Carbamzepine No difference between groups on BPRS, CGIC, Hamilton scale

12 Carbamazepine Dose Starting : mg at bed time for prevention of daytime oversedation Maintenance: (800)mg/day Serum level: 4-8(12) μg/ml Side effect Most serious: aplastic anemia or agranulocytosis Most common: Sedation, fatigue, nausea, dizziness At high dose: ataxia, diplopia, nystagmus, cognitive impairment Overdose: stupor, coma, death Elderly: osteoporosis or osteopenia Others: hyponatremia because of SIADH Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed Garnett WR. Optimizing ADE therapy in the elderly. ANN Pharmacother 2005; 39:

13 Carbamazepine Drug interaction: cytochrome P450 3A3/4 Drug that may increase CBZ level Drug that may decrease CBZ levels Drug whose blood level may be decreased by CBZ Cimetidine Diltiazem Doxycycline Erythromycin Fluoxetine Fluvoxamine Ketoconazole Phenobarbital Oral contracep. Phenytoin TCAs Neuroleptics Glucocorticoid Methadone Fentanyl Benzodiazepine Theophylline Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed

14 FDA approved in Valproate epilepsy (simple & complex absence attack, partial seizure) migraine prophylaxis FDA approved for treatment of acute mania in 1994 most commonly used in treatment of bipolar disorder in USA Other psychiatric indication: aggression, agitation, impulsivity explosive outburst, physical aggression, self-destructiveness Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed

15 Valproate Mechanism of anti-agitation Inhibition of metabolism & reuptake of GABA Inhibition of corticotropin-releasing factor Activation of central serotonergic system Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed

16 Valproate Randomized, multisite, placebo-controlled study 6weeks Sample: 56 nursing home patients with agitation AD, VaD, Mixed dementia with MMSE score 6.8 Mean dose: 826mg/day Primary outcome measure: BPRS, CGIC, OAS Am J Geriatr Psychiatry 2001; 9: 58-66

17 Valproate No difference in change in total scores on BPRS, OAS, CGIC Significant difference on BPRS agitation score(p=0.05)

18 Valproate Curr Ther Res Clin Exp. 2001; 62: Randomized, double-blinded, placebo-controlled, parallel group study Du: 6weeks Sample: 172 nursing home patients with dementia & secondary mania AD, VaD, Mixed Dementia with MMSE score 7.4 Median dose: 1000mg/day Primary outcome: Bech-Rafaelsen Mania scale(brms), CMAI, BPRS, CGI

19 Valproate No difference on BRMS or BPRS Change in CMAI total score slightly greater for drug group

20 Valproate Dose Starting: 125mg Maintenance: mg( )mg Serum level: μg/ml Side effect Most serious: hepatotoxicity, pancreatitis Common: sedation, weight gain, nausea, vomiting, cramp, diarrhea Others: tremor, ataxia, alopecia, coma, thrombocytopenia Curr Ther Res Clin Exp. 2001; 62:51-67 Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed

21 Valproate Drug interaction: cytochrome P 450 Drug that may increase valproate level Drug that may decrease valproate level Drug whose blood level may be decreased by valproate Cimetidine Erythromycin Fluoxetine Aspirin Ibuprofen Topiramate Rifampin Carbamazepine Phenobarbital Clinically significant metabolic induced with valproate not reported Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed

22 Gabapentin Released in US in 1994 as an adjunctive treatment for complex partial seizure Indication: Anxiety disorder, bipolar disorder, substance abuse Agitation and aggression in dementia Trigeminal neuralgia, post-herpetic neuralgia, diabetic neuralgia Neuroleptic induced movement disorder: Blepharospasm, oromandibular dyskinesia Miller LJ. Gabapentin for treatment of BPSD. Ann Pharmacother 2001; 35: Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed

23 Gabapentin Mechanism: Increase GABA synthesis in brain Decrease release of monoamine neurotransmitters GABA GABA activity is related to sensitization-kindling model Disturbance is result of accumulation of bioelectric discharge(kindling) in limbic area of the brain These discharges result in disrupted neuronal sensitization with psychiatric manifestation Miller LJ. Gabapentin for treatment of BPSD. Ann Pharmacother 2001; 35:

24 Gabapentin Study Dis No Design Regan(1997) AD 1 Case Sheldon(1998) AD 1 Case Goldenberg(1998) DOS 1 Case Low(1999) AD 2 Case Dallochio(2000) AD 2 Case Roane(2000) AD, VaD 4 Open-label Hermann(2000) AD, VaD,AlcD 12 Open-label FTD Dosage (mg/day) ,400 1,200 Response Some efficacy in geriatric patients with BPSD Average daily therapeutic dose: 900mg/day Advantage: superior adverse effect profile, fewer drug interaction Miller LJ. Gabapentin for treatment of BPSD. Ann Pharmacother 2001; 35:

25 Dose Starting: 300mg/day Gabapentin Maintenance : 900-1,200mg/day Side effect Common: somnolence(20%), dizziness(18%), ataxia(13%) High dosage: cognitive impairment Others: nystagmus, tremor, nausea, diplopia, headache, weight gain Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed

26 Special consideration Gabapentin Completely eliminated by renal excretion Increasing age decreases renal function and alters elimination of clearance Elimination correlates with creatinine clearance, which may be used as a guideline for dosing Short half life, so frequent dosing Drug interaction Not metabolized in the liver & Not protein bounded Few drug interaction: cimetidine reduce serum level of gabapentin by 10-15% Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed Miller LJ. Gabapentin for treatment of BPSD. Ann Pharmacother 2001; 35:

27 Lithium In psychiatry, Australian state hospital, 1949 FDA approved for treatment of acute mania & as maintenance therapy Other Psychiatric indication: Mood lability, impulsivity, episodic violence or anger Borderline personality disorder Neurological indication: Cluster headache, Huntington s disease, Spasmodic torticollis Coffey CE, Cummings JL. Textbook of geriatric neuropsychiatry 2 nd ed. 2000; Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed

28 Lithium Mechanism: Modulate balance between excitatory & inhibitory effects of NT such as serotonin, epinephrine, glutamate, GABA, & dopamine Effect neural plasticity through its effects on glycogen synthetase kinase-3β, cyclic AMP-dependent kinase, & protein kinase C Adjust signaling activity via effects on 2 nd messenger activity Enhance serotonergic transmission Short term use: increase synthesis of serotonin by increasing tryptophan reuptake in synaptosome Long-term use: enhance release of 5-HT from neuron Chronic use: down-regulation in 5-HT1A, 5-HT1B, 5-HT2 receptor Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed

29 Mechanism Lithium Increase synthesis of NE Reduce excretion of NE in manic patient Increase excretion of NE in depressed patient Block postsynaptic dopamine receptor s supersensitivity Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed

30 Lithium 2006; 30: Lithium may block accumulation of Aβ peptides & inhibit hyperphosphorylation of tau via inhibition of GSK-3α

31 Lithium Prevalence between 66 elderly euthymic patients with bipolar disorder who were on chronic lithium therapy & 48 similar patients without recent lithium therapy AD prevalence: 5% of patients on lithium therapy 33% of patients without recent lithium therapy

32 Dose Lithium 1/2-2/3 of usual adult dose because of age-related reduction of renal clearance & volume distribution Lithium half-life in increased to about 40 hours in elderly Starting: mg Maintenance: 600-1,200mg/day Serum level: mEq/L Coffey CE, Cummings JL. Textbook of geriatric neuropsychiatry 2 nd ed. 2000;

33 Lithium Side effect Type Neuro-muscular Cognitive Intracranial EEG Endocrine Renal Gastrointestinal Manifestation tremor, ataxia, dysarthria, incoordination, myoclonus, parkinsonism amnesia, aphasia, confusion, impaired concentration, flat affect pseudotumor cerebri generalized slowing, seizure hyperparathyroidism, hypothyroidism polyuria, polydypsia, nephrogenic diabetes insipidus Nausea, vomiting, diarrhea Coffey CE, Cummings JL. Textbook of geriatric neuropsychiatry 2 nd ed. 2000; Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed

34 Special consideration Lithium Lower seizure threshold & induce seizure in nonepileptic patients Cause extrapyramidal side effect Cognitive side effect are poorly tolerated by dementia pts Neurotoxic interaction between lithium & neuroleptics Cardiac monitoring due to slowing of depolarization of sinus node & conduction through AV node Coffey CE, Cummings JL. Textbook of geriatric neuropsychiatry 2 nd ed. 2000;

35 Benzodiazepine Psychiatric indication: anxiety, panic disorder, insomnia, alcohol withdrawal Neurological indication: generalized seizure, myoclonic seizure, absence seizure trigeminal neuralgia, choreoathetosis, akathisia, myoclonus Coffey CE, Cummings JL. Textbook of geriatric neuropsychiatry 2 nd ed. 2000;

36 Benzodiazepine Short half life or intermediate half life: Oxazepam, lorazepam, alprazolam, triazolam No active metabolite Metabolic pathway not affected by aging, so less or no accumulation Quicker to reach a steady state Long half life: Diazepam, chlordiazepoxide, flurazepam, halazepam Active metabolites such as desmethyldiazepam via hepatic oxidative metabolism Accumulation(+) Long elimination half life: prolonged 2 or 3 times in elderly Coffey CE, Cummings JL. Textbook of geriatric neuropsychiatry 2 nd ed. 2000;

37 Benzodiazepine Medication Starting (mg) Therapeutic(mg) Half-life(hrs) Midazolam Lorazepam Alprazolam Oxazepam Clonazepam >100 Diazepam Chlordiazepoxide Prazepam Clorazepate Halazepam Coffey CE, Cummings JL. Textbook of geriatric neuropsychiatry 2 nd ed. 2000;

38 Benzodiazepine Neuropsychiatric side effect increased sensitivity of benzodiazepine receptor in older CNS sedation, memory impairment, confusion, fall, paradoxical reaction Special consideration Dependency & withdrawal Frequent side effect especially in dementia or cbll disease Coffey CE, Cummings JL. Textbook of geriatric neuropsychiatry 2 nd ed. 2000;

39 Drug interaction Benzodiazepine Manifestation CNS depressant Opioid Cimetidine Anticonvulsant Interaction Increased sedation, confusion, amnesia, psychomotor impairment Increased respiratory depression Increased benzodiazepine level Decreased benzodiazepine level Coffey CE, Cummings JL. Textbook of geriatric neuropsychiatry 2 nd ed. 2000;

40 Buspirone Characteristics Lower affinity to benzodiazepine and GABA receptors Effect on chloride channel coupled to the benzodiazepine- GABA receptor complex Antianxiety effect Dopaminergic properties or Partial agonist on 5-HT 1A receptor Nearly absent withdrawal Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed

41 Dose Buspirone Starting: 10mg/day Maintenace: 20-30mg/day Side effect Headache, nausea, dizziness No ataxia or cognitive impairment Schatzberg AF, Cole JO, Battista CD. Manual of clinical psychopharmacology 4 th ed

42 Propranolol Dose Starting: 10mg/day Maitenance: mg/day Side effect Bradycardia, hypotension, fatigue, impotence, bronchospasm