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T. Lau, MD, FRCPC [psych], MSc., Assistant Professor, Faculty of Medicine, UNIVERSITY OF OTTAWA Royal Ottawa Mental Health Centre Geriatrics •Updated Jan 2008 Mood • Anxiety MDD • BAD Dysthymia Cycothymia Adjustment • Bereavement SCZ-A/SCZ Substance- • GMC PD S-GMC • • SAD, SP, GAD, PTSD, OCD, Panic+/-A, Separation AD Associated w depression / psychosis Somatoform / Dissociative disorders PD S-GMC Psychosis • Personality • Substance Mood D/O – Traits and • (MDD or BAD) disorders • SCZ – 3 Clusters • BPE – MAD • Dissociative – BAD • D/O – SAD Delusional – Different disorder Domains Delirium – Extroversion, introversion PD – Harm S-GMC avoidancenovelty seeking Cognition: Delirium, Dementia, NOS, Psychosis, Dissociative, Mood or anxiety d/o [performance], MR-PDD, S-GMC ETOH Uppers Downers Mixed Rx Proportion of population aged 80 years (%) Aged 80 years in 1994 Aged 80 years in 2020 AGE DEPENDENCY RATIO Comorbid medical illness / cognitive disorders Sensory loss Financial worries Retirement Dependency Dying and death Bereavement 3 D’s Depression Dementia Delirium (check the pee, poop etc) 2 Extra D’s Drugs Delusional sx (Psychosis in the Elderly) Overview and cases of DEPRESSION MANIA ANXIETY PSYCHOSIS DELIRIUM DEMENTIA “I want to die in my sleep like my grandfather, not like the people kicking and screaming in the backseat of his car.” Sue McKay Geriatric Psychiatrist 73 year old woman who presents with 2 month history of tearfulness, loss of energy, apathy, inability to get out of bed in the morning, and insomnia with early morning awakenings. She describes increasing anxiety, an inability to cope, forgetfulness, problems reading or even watching TV, a 30 lb weight loss and feels very constipated. She expresses a concern that something is wrong with her stomach. Her lower back has also been bothering her more. She lost her husband 8 months ago and one of her children a little over 1 year ago. She has a remote history of resected breast cancer and a more recent history of thyroid cancer which was resected 3 years ago. She also has a history of atrial fibrillation. She has no past psychiatric history and has always been able to cope with difficulties until recently. She is on coumadin and a beta blocker. What is in your differential diagnosis? What kind of investigations would you order? Assuming you believe her to be depressed what would be your plan of treatment? Is there a reason for suggesting one antidepressant over another? Assuming she does not have any response to treatment after 3 weeks what would you do? Psychological Depressed mood Loss of interest or pleasure Feeling worthless or guilty Problems thinking or concentrating Suicidal ideas or plans Vegetative Change in appetite or weight Change in sleep Loss of energy Psychomotor changes – Associated (non-DSM IV) – Anxiety (brooding, obsessive ruminations) or phobias – Irritability – Excessive worry about physical health – Pain – Tearfulness Response (50% reduction in HAMD or MADRS) Remission (2/12 completely free of sx) plus functional recovery Relapse (reoccurance before 2/12) Recurrence (reoccurance after 2/12) Initiate treatment with SSRI, SNRI, NRI, other Partial or no response after 4-6 wks of tx at adequate dosages R/A Diagnosis. Optimize dose Switch to new antidepressant from a different class Consider psychotherapy at any point particularly with early childhood trauma Inadequate response 2nd Augment 1st Lithium atypical antipsychotic 3rd Lamotrigine 4th Thyroid T3 Combine 2 antidepressants from different classes Consider ECT at any time particularly when Very severe depression Not eating or drinking Catatonia Psychosis Suicide Risk Med Intolerance / Pregnancy BIO: SIMILAR EFFICACY SSRI’s (~equal DBPC trials (70/40% D/P response), SNRI’s (?lower remission rates, faster response), SARI’s, NaSSA’s, TCA’s, MAOIs, RIMA’s, NDRI’s. COMPARE pooled [n-33 DBPC] remission rates [SSRI/SNRI/P= 35/41/24%; n=3355/3410/932] Nemeroff 2004 WJP. Comparison trials have higher response and remission rates. ADEQUATE TRIALS Adequate trial 4-6 weeks (look for some response @ 2 weeks as a predictor of success). Switching amongst the same class may also work. Effective (Response: 70% w 1st, 70% w 2nd, 90% overall). BUT 50% discontinue in first 3/12, <30% complete full course of tx. Watch for adherence. SPECIAL POPULATIONS Some evidence for > efficacy in severe depression with TCA’s (Clomipramine study group although HAMD favors sedative ADs over celexa). Atypical features: Better efficacy with MAOI’s. Recurrent & FHx of BAD consider Li. Psychotic features: ECT vs add AAP to antidepressant. ECT (particularly psychotic depression 95% RR). Consider especially if situation is urgent, not eating.drinking, taking medication, suicidal, medication intolerance AUGMENTATION Augmentation: Li (11 w TCA’s studies (n=135), RR 52%, ? w SSRI’s), T3 (w TCA’s), MPH, tryptophan, low dose atypical neuroleptics (Nemeroff JCP 2005). Consider also DA agonists-pramipexole (Aiken JCP 2007), strattera, pindolol, buspar, tryptophan, lamictal. Combos: Buproprion (2D6 inhibition), NaSSA’s (Carpenter 99, Debonnel 2000), SARI’s (watch for SS), SSRI w Des (Nelson 99, 2000). Caution with MAOIs and SSRIs. MAOI can be combined with a noradrenergic agent b/o COMT. STAR*D augmentation in TRD. See next slide. MEDICALLY UNWELL Comorbid medical conditions, consider stimulants, which are relatively safe and work faster. Methylphenidate, dextroamphetamine, and modafinil (less inc in BP, also helpful with narcolepsy). NEW OPTIONS Novel agents on the horizon: duloxetine (balanced dual 5HT/NA agent with affects on pain), agomelatine (agonist MT1/MT2 antagonist 5HT2C helps with sleep few ASEs), Ketamine, Selegiline transdermal system (STS), released this year in the US, reduced risk of dietary restrictions at lower doses compared with standard MAOIs. Rates of recovery vary with duration of unremitted symptoms Kindling Decrease in precipitators Number of episodes increases risk of reoccurence Thase-Rush Criteria: Stage 1: Failure of an adequate trial of 1 class of major antidepressant Stage 2: Failure of adequate trials of 2 distinctly different classes of antidepressant Stage 3: Stage 2 plus failure of a third class of antidepressant, including a tricyclic antidepressant (TCA) Stage 4: Stage 3 plus failure of an adequate trial of a monoamine oxidase inhibitor (MAOI) Stage 5: Stage 4 plus failure of an adequate course of electroconvulsive therapy (ECT) Options Switch antidepressants Different or same class Augmentation Another antidepressant Mood stabilizers: Li, Lamictal Atypical antipsychotic Dopaminergic agents Stimulants Psychotherapy ECT Experimental: TMS, VNS See slide on reasons for tx resistance LEVEL Interventions Remission Rate % Cumulative Remission % Step 1 N=3671 Citalopram 36.8 36.8 Step 2 N=1439 Switch VEN/BUP/SER Combine BUP/BUS Switch/Combine CT 30.6% 56.1% Step 3 N=390 Switch NOR/MIR Augment Li/T3 13.7% 62.1% Step 4 N=123 Switch TCP/VEN+MIR 13.0% 67% Rush AJ AJP 2006 Controversy exists still about whether depression in late life is assoc with poorer outcome Post Hoc analysis of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D). Early onset age<55. Late onset age 55-75. (n=574) with non psychotic MDD with baseline HAMD>14. Citalopramx14 weeks. Outcome: 16 item Quick Inventory of Depressive Sx-self rated score. Time to remission, remission rates did not differ between the groups. Am J Geriatr Psychiatry 2008 (Next 2 slides for details….) In the Elderly Community studies have shown that 25% of elderly persons report having depressive symptoms, but only 1% to 9% meet the criteria for major depression Lebowitz BD JAMA 1997. Prevalence varies according to the population. Higher prevalence rates are reported in the hospitalized elderly (36% to 46%), those who receive homecare 13.5% (Hybels Clinics in Ger Med 2003) and those in long-term care facilities (10% to 22%) Teresi J. Soc Psychiatry Psychiatr Epidemiol 2001 More likely to have somatic complaints, anxious, melancholic and psychotic features. Therefore ECT often used and is effective. Similar response rates (although may take longer to tx), high relapse rates. Only 10-20% are tx resistant. With aging, more frequent episodes and longer untreated episodes (duration to spontaneous remission is longer) or may change to chronic course. May have comorbid cognitive impairments. Non-compliance and physical disability often lead to chronicity. More often confronted by death, grief may be a complicating feature Depression Persistent mood state Poor self esteem (from Mourning and Melancholia, Freud: introjected lost object w negative assoc feelings experienced as part of self) Fxnal impairment beyond 2/12 Suicidal thoughts with desire to die Acute despair/protest, denial (numbness, outbursts, anger) Yearning / searching for deceased (restlessness, preoccupation w deceased) Disorganization + despair (going through the motions, withdrawn, apathetic) Reorganization (can think of loved one w joy/sadness Grief Dysphoria, sadness comes in waves with marked fluctuation, often w triggers No fxnal impairment > 2/12 No psychomotor retardation, active suicidality, psychosis (although transient phen may occur) Bowlby Phases of Uncomplicated Grief (PSDR) Grief in Children Protest, Despair, Detachment Kubler Ross 1) Shock/denial, 2) anger, 3) bargaining, 4) depression, 5) acceptance The following is true regarding depression a) it is a treatable condition that with antidepressants has a remision rate of 30-40% and response rates of 67-90% b) the neurotransmitters serotonin and noradrenaline are involved c) Psychotherapy is effective in severe depression d) an association between early life trauma, hippocampal atrophy and depression can be seen e) it often presents with multi-system physical complaints f) it is associated with coronary artery disease, stroke, diabetes, cancer, Parkinson’s, and MS. g) ECT should be considered only when all other treatments have failed Depression in old age: a) b) c) d) e) f) g) Is more prevalent in women than men Prevalence rates rise sharply with age Is accompanied by a much lower suicide risk than in younger adults Is unresponsive to treatment in half of cases. Is often precipitated by a loss Both b) and d) Both a) and e) Psychotic Depression: a) Is more frequent in elderly. b) Remits with antidepressants in 50% of cases c) Remits with antidepressants + antipsychotics in 75% of cases d) Responds and remits best with ECT e) Should prompt thorough search for symptoms of bipolar illness in pt and family members. f) All of the above except b) g) All of the above except b) and c) MCQs a) b) c) d) e) “Nerves” Excessive fatigue Hypersomnia (sleeping too much) Digestive problems Fear of Alzheimer’s disease MCQs a) Active suicidal ideation b) Prominent psychotic symptoms c) Crying spells when she thinks of her deceased husband. d) Being less active socially e) Being unable to attend to her usual daily activities 3 months after the death of her husband 76 year old who presents with decreased sleep, increased activity, mood lability with both tearful episodes and euphoria, 20 lb weight loss, irritability, circumstantiality, ruminations about perceived injustices in the past, and a concern over a conspiracy that involves his family physician, friends and neighbours. He was started on Prednisone for a skin condition two weeks preceding these changes. Because he is convinced he is invincible and his behavior started to include reckless and dangerous activities he was admitted to hospital. MANIC/HYPOMANIC EPISODE E with 3/7 or I with 4/7 for 1 week Hypomania same but for 4 days no psychosis, no severe impairment, no hospitalization Mixed episode criteria met simultaneously for MDE and ME nearly every for at least 1 week. G grandiosity I increased goal directed activity D decreased judgment D distractibility I irritability N need for sleep decreased E euphoria S speedy thoughts S speedy talk DDx: ME GMC Substance induced MDE w irritable mood Mixed episode ADHD Psychosis BAD specifiers Type I [Mania] Type II [No hx of mania but episodes of hypomania] Most recent episode Rapid cyclers (>4 mood episodes per yr) B- Determine phase of illness MDE,M, ME, E Mania: start or optimize monotherapy: Li or VPA, consider augment w AP (particularly w psychotic features), benzo. If no response combine other (Li or VPA). Mixed or dysphoric (?comorbid subs abuse): VPA may be better. Usually depressive sx are residually present. Another option is OLZP (2 large RCT’s- Tohen 10 mg, AJP 1999, Tohen 15 mg AGP 2000) w comparable efficacy to Li, VPA, Haldol. > than VPA in comparison trial. Risp and Zip studied in PCT as add ons to Li or VPA w efficacy comparable to Haldol>PCB. Depression: do not start an antidepressant without a mood stabilizer. Lithium monotherapy should be considered. Lithium (8 PCT’s 79% response) or Lamotrigine (Calabrese JCP 1999: MADRS 200>50mg/d>PCB , n=195 BAD-I). AD monotherapy not recommended b/o switch +/- rapid cycling. Buproprion (2 controlled add on studies 1st = efficacy to Des but less manic switch, RIMA (comparable to IMI w less ASE), Paxil 3 double blind add on studies, 1st good response=add on of other (ie. of either VPA or Li), no difference if Li > 0.8, sim to Effexor but less manic switch. AAP improve depression subscales in tx of Mania and extension trials. B- Determine phase of illness DE,M, ME, Maintenance: Only Lithium supported by RPCT’s although some design limitations. One negative PC comparison trial w VPA (Bowden AGP 2000). VPA studied in comparison w Li but no PC. Specific Meds: Lithium (Cade’s disease: for mania, depression, relapse prevention 5 PCTs >25y ago), Epival (rapid cycling, dysphoric, mixed episode, efficacy in mania but prophylaxis data lacking). Alternatively monotherapy w AAP. Lamotrigine appears helpful w depression (Calabrese JCP 1999) , rapid cycling (BAD-II) (Calabrese JCP 2000), but not mania). Topimax (no PCT, studied as add on cf buproprion: McIntyre Acta Neuropsychiatr 2000), GABApentin. OLZP and more atypical studies pending. Also consider Clozapine in tx resistant cases. ECT for tx resistant acute mania or depression (particularly w psychotic features). Generic Name Mania Lithium X Valproate X Carbamazepine X Mixed X X X X X X Lamotrigine Olanzapine Maintenance Depression X X Olanzapine + Fluoxetine X Quetiapine X X Risperidone X X Aripriprazole X X Chlorpromazine X X P- Establish therapeutic alliance, individual psychoed intervention, interpersonal and social rhythm therapy [helps correct sleep] which decreases relapse risk. Prelim studies suggest that CBT may help reduce depressive sx, improve longer term outcomes and adherence. Supportive therapy may also be helpful (social skills help, coping skills, problem solving. S- Involve family. Family interventions and focused therapy can helping to accept illness, identifying precipitating stressors inside and outside of family, examining family interactions that produce stress in the pt, developing management plan: these all lead to reduced relapse rates. Housing, work/vocational support. Collaborate to address comorbidity. Case management, ACT, rehab, should be considered. More secondary mania (less often +FHx). More mixed/dysphoric features with irritability but lithium response rate similar in young and old. Longer acute episodes. Increased frequency, higher prevalence of neurological abnormalities Less hyperactivity, grandiosity, less euphoria, flight of ideas although may have disorganization and circumstantiality as well as delusions. Secondary Causes of Mania in Elderly Extrapyramidal disease, subcortical dementias, HIV, CNS infections, tumors, Demyelinating disease, Temporal lobe epilepsy, Systemic illness, Hyperthyroidism, uremia, pellagra Drugs: steroids, L-dopa, amphetamines, cocaine, cyclobenzaprine (Flexeril), yohimbine (Aphrodyne), clarithromycin (Biaxin) C-L service: steroids, HIV, TLE Rundell JR, Wise MG (1989), J Neuropsychiatry Clin Neurosci Which of the following is true of Bipolar disorder a) Depression is the most debilitating and treatment resistant phase of the illness b) Lithium has the best evidence for the treatment of depression, mania, suicide risk reduction and maintenance c) Their exists double blind placebo controlled evidence for the use of Epival in depression and for the maintenance phase of the illness d) Lamotrigine has been shown to be an effective antimanic agent e) There is evidence for the use of atypical antipsychotics in mania f) Olanzapine and Seroquel have been studied in a placebo controlled fashion for the depressive phase. g) Clozapine can be used for treatment refractory cases MCQs a) b) c) d) e) Less hyperactivity More mixed (depressive/manic) clinical presentations More disorganised speech with flight of ideas. More irritability and less euphoria Less paranoid delusions Anxiety Disorder Mood Disorder Depressed / irritable mood Anhedonia Euphoria Weight gain/loss Loss of interest Fear Apprehension Panic attacks Chronic pain GI complaints Excessive worry Agitation Difficulty concentrating Sleep disturbances Hypervigilance Agoraphobia Compulsive rituals APA 1994; Keller MB 1995; Clayton PJ et al 1991; Coplan JD, Gorman JM 1990 As many as 90% of depressed patients suffer from anxiety symptoms1-3 More severe illness at baseline More psychosocial impairment Greater likelihood of chronic illness Poorer, slower response to treatment Greater likelihood of committing suicide 1. Richou H. et al. Human Psychopharmacol 1995; 10:263-71 2. Coplan JD et al. J Clin Psych 190; 51(Suppl 10):9-13 3. Kasper S. et al. Primary Care Psych 1997; 3:7-16 Secondary anxiety disorders more common in elderly Primary anxiety disorders, like personality disorders, generally do not have an onset in the elderly High comorbidity with depression Overally less common in the elderly. Phobias and GAD are the most common. Panic disorder is relatively rare, less than the 1-3% described in younger populations (Flint AJP 1994). Caution with anxiolytics can cause paradoxical disinhibition Diphenylhydramine (Benadryl), Dimenhydrinate (Gravol), Chlorpromazine, Amitriptyline, chloral hydrate and barbiturates are not good anxiolytics for older patients due to their side effects Elderly are more sensitive to benzodiazepines. Associated with an increased risk for falls and MVAs Cognition Amnesia specially in alcoholics with benzos Memory and visuospatial impairment Psychomotor Accentuate postural sway and coordination Increase risk for MVAs and falls Paradoxical dysinhibition Respiratory Depression avoid benzos in sleep apnea Sleep Decreased sleep latency but also decreased stage 3 and 4 sleep with Benzos The following is true of anxiety disorders in old age a) It is more often secondary to another axis 1 condition like depression or medical condition b) Anxiolytics can worsen not only anxiety but can cause sleep disruption, falls, and MVAs. c) Benzodiazepines are safe in the elderly d) Benadryl, Gravol, Chlorpromazine, Amitriptyline and other anticholinergic medications can be dangerous in the elderly because of delirium and associated other receptor effects (orthostatic hypotension) e) Primary anxiety disorders and personality disorders, including dependent personality disorder, do not begin in old age The following is true of anxiety disorders in old age a) It is more often secondary to another axis 1 condition like depression or medical condition b) Anxiolytics can worsen not only anxiety but can cause sleep disruption, falls, and MVAs. c) Benzodiazepines are safe in the elderly d) Benadryl, Gravol, Chlorpromazine, Amitriptyline and other anticholinergic medications can be dangerous in the elderly because of delirium and associated other receptor effects (orthostatic hypotension) e) Primary anxiety disorders and personality disorders, including dependent personality disorder, do not begin in old age MCQs a) Prevalence rates increase with ageing. b) Phobias are the most common anxiety disorder c) Overall prevalence rates for all anxiety disorders in old age is around 10% d) Panic disorder affects approx. 5% of elderly. 85 year old woman who lives alone, never married and has no children. She is hard of hearing and visually impaired. She has become increasingly seclusive and withdrawn. Her hydro and water stopped being paid and was cut off. A nephew who was concerned called the CCAC to ask if someone could check in on her and help her at home. She refused to allow anyone in and talked about a how people were trying to break into her house and kill her. She was convinced the mail man was delivering messages from the devil. In the Elderly ALL Schizophrenia Psychosis Late onset 25% Early onset grown old 75% Substance - GMC Delusional Disorder Mood D/O (MDD or BAD) SCZ, SCZ-A 0.03% but 1-2% of hospital admissions Paraphrenia MOOD DISORDERS Depression BPE (33% of severe subtype cf 15% mild to moderate) Dissociative D/O Delusional disorder PRIMARY PSYCHOTIC DISORDERS Mania Delirium COGNITIVE DISORDERS Dementia (~50% have psychotic symptoms) Personality disorders Delirium Substance-GMC PRIMARY Schizophrenia Bizarre delusions Absence of memory problems, disorientation Schizoaffective Delusional disorder MOOD Depression Mood, somatic (often bowel), anxious sx, real or perceived losses, phx/FHx of depression Mania More mixed states in the elderly, dysphoria, less grandiosity COGNITIVE Delirium Reversed sleep cycle, marked variation, hallucinations, recent drugs, ETOH, intox/withdrawal Dementia By history Cortical / subcortical syndromes Neuropsych Which of the following are not true of psychotic disorders in late life? a) b) c) d) e) Most paranoid disorders of old age are due to schizophrenia [Jeste 2000]. More women develop late onset schizophrenia [Jeste 2000]. With ageing, schizophrenia tends to give less severe positive symptoms [Jeste 2000]. Patients with schizophrenia live 10-30 years less on average [Harris BJP 98, Colton Prev Chron Dis 2006, Hennekens Am Heart J 2005] There is some evidence that the elderly are less likely to experience the same metabolic side effects as younger patients do with atypical antipsychotics [Herrmann Drug Safety 2006] 68 year old woman who you, as her family physician have followed over many years, presents with increasing confusion, gait instability, falls, and incontinence. The change appears abrupt. She is now sleeping much of the day and is up at night. She is on several medications including beta blockers, diuretics and Mobicox for arthritis. She continues to have some brandy after supper. When she last came to the clinic you were away and a locum prescribed some clonazepam to help her sleep better and relieve some of her anxiety. She is admitted to the hospital under your care. What is in your differential diagnosis? What tests would you order? A urine C&S and CT head were normal. Routine blood work was also normal. She is now extremely agitated at night. Falling frequently and is distressed with the belief that people are trying to kill her and she has to escape out of this prison. The nurses on the floor are requesting sedation or restraints for safety. What are your next steps and why? Disturbance of 4Cs C Consciousness (focus, sustain or shift attention) C Cognition (memory, disorientation, language) or perceptual disturbance C Course C Consequence of GMC Delirium in the elderly patient is associated with increased mortality, longer hospital stays, and increased risk of institutional placement. Subcategories: due to GMC, substance intoxication/withdrawal, multiple etiologies Prevalence: 10-15% of those hospitalized. Under recognized. in those >65 higher (1040%). Independent risk factor for mortality 40% @ one yr. Lab features: EEG generalized slowing Meagher (1996), BJP Hypo: dec Ach in nucleus basilis & RAS, associated with CVA, metabolic disorders, late sepsis, aspiration, pulmonary embolism, decubitus ulcers and other complications related to immobility. Characterized by: Unawareness, inattention, decreased alertness, sparse or slow speech, lethargy, decreased motor activity, staring, apathy. Liptzin (1992) BJP Hyper: withdrawal states, acute infection, mediated by LC-NA. Etiology: Hyper and hypactive delirium Ach in RAS (dorsal tegmental pathway). Risk factors Medical illness, sensory impairment, hx of delirium, ETOH, pre-existing brain damage (eg. Dementia), malnutrition Reversible causes of delirium Intoxication or substance abuse Adverse drug side effects Infections (urinary, pneumonia, etc.) Metabolic disorders (including diabetic complications) Systemic Illnesses Anticholinergics, antidepressants, mood stabilizers, antipsychotics, antiparkinsonians, antihistamines, narcotics, benzodiazepines Generalized infections (Tb, HIV, secondary to transfusions) Vascular (cardio, cerebral, hypoperfusion) Constipation or fecal impaction Sensory deprivation Sleep disorders Pain of any kind (eg. Dental pain) Environmental changes Treatment Biological Determine cause if possible and treat (eg. infection, med ASE’s, metabolic d/o, pain, renal/hepatic failure, drug intoxication/withdrawal, SOL, CVA, NPH, etc). Manage sx (low dose neuroleptics), watch for AC ASE of meds (Breitbart AJP 1996). Psychological Establish calm and safe environment. Develop trust and provide reassurance Place near NS station with adequate lighting, reorientation, familiar faces, voices. Social Support family, may be helpful in decreasing distress and reorientation Environmental interventions Noise reduction Diurnal variation in noise and lighting Frequent reorientation Day/date in room, big clock in room Keep familiar items in room e.g., family pictures Early mobilization, physical therapy Limit use of restraints Early recognition and treatment of dehydration Ozbolt J Am Med Dir Assoc 2008 Risperidone most studied, 80-85% effective doses 0.54 mg/day Olanzapine 70-76% effective doses 2.5-11.6 mg/day Few studies with Quetiapine AAP vs. Haldol, limited number of trials, higher EPS additional 10-13% No DBPCT exist Lonergan el al. Cochrane Database Syst Rev. 2007 Apr Not significantly different: low dose haloperidol (< 3.0 mg per day) with the atypical antipsychotics olanzapine and risperidone (Odds ratio 0.63 (95% CI 10.29 - 1.38; p = 0.25). Low dose haloperidol did not have a higher incidence of adverse effects than the atypical antipsychotics. High dose haloperidol (> 4.5 mg per day) in one study was associated with an increased incidence of EPS, compared with olanzapine. Low dose haloperidol decreased the severity and duration of delirium in post-operative patients, although not the incidence of delirium, compared to placebo controls in one study. There were no controlled trials comparing quetiapine with haloperidol. Small studies of limited scope. Haldol remains the generally accepted gold standard although there is emerging evidence for atypicals. Potency and Half-Life of Various Benzodiazepines High-potency benzodiazepines Drugs with a short half-life Alprazolam (Xanax) Lorazepam (Ativan) Triazolam (Halcion) Drugs with a long half-life Clonazepam (Klonopin) Low-potency benzodiazepines Drugs with a short half-life Oxazepam (Serax) Temazepam (Restoril) Drugs with a long half-life Chlordiazepoxide (Librium) Clorazepate (Tranxene) Diazepam (Valium) Flurazepam (Dalmane) Liabilities Toxicity and drug interactions Synergy with CNS depressants Fatal overdoses w ETOH Psychomotor retardation Drowsiness, poor concentration, ataxia, falls, dysarthria, motor incoordination, diplopia, muscle weakness, vertigo, confusion. Slowed reaction times, impaired driving. Memory impairment anterograde amnesia separate from sedation Paradoxical Disinhibition Depression and emotional blunting more incapable of tolerating their emotions and life stressors Class D Teratogens fetal transmission, birth and withdrawal effects Tolerance Dependence Short term withdrawal effects Protracted withdrawal The following is true of delirium a) It is characterized by problems and fluctuations with attention and consciousness b) It is most often completely reversible c) Hypoactive subtypes are more often missed d) Environmental interventions do not help e) It is a significant independent risk factor for death f) It can be superimposed on dementia or depression g) It is rare in the elderly h) It is better to use benzodiazepines than neuroleptics for psychotic and behavioural symptoms A 78-year-old widow who lives alone and whom you have seen infrequently is brought to your office by her daughter. Although the patient has no complaints, her daughter indicates that for the past 2 years she has become more forgetful. Her behaviour is repetitive, and she sometimes calls her daughter several times a day to ask the same question. The quality of her housework is beginning to decline (her house is untidy, food is left to spoil in the refrigerator, she is limiting food preparation to simple, familiar items, and she has to check recipes even for easy dishes). Her personal hygiene is also declining, and some bills are not being paid on time. What is in your differential diagnosis? What tests would you order? What are your next steps? You see her several years later in a nursing home. She is more confused and no longer recognizes you. She is frequently exit seeking and is resistive with care at times. She has injured staff and co residents during periods of anger and agitation. What would you do? What is Dementia? Memory problems with difficulties in another cognitive area (aphasia, apraxia, agnosia, executive dysfunction) together with a loss of function x3 x2 Canadian Study of Heath and Aging Working Group. CMAJ 1994;150:899-913. Alzheimer’s Vascular Dementia with Lewy Bodies Frontotemporal Dementia Others Parkinson’s with dementia PSP Prion Huntington’s In 1901, Alzheimer tended to patient in Frankfurt named Mrs. Auguste D. The 51-year-old patient had strange behavioral symptoms, including a loss of short-term memory. In April 1906, Mrs. D. died and Alzheimer had the patient records and the brain sent to Munich where he was working at Kraepelin's lab. Together with two Italian physicians, he would use the staining techniques to identify amyloid plaques and neurofibrillary tangles. A speech given on 3 November 1906 to the 37th Meeting of the Southwest German Psychiatrists in Tübingen would be the first time the pathology and the clinical symptoms of presenile dementia would be presented together. Mild cognitive impairment • Memory impairment • Absence of ADL deficits • Apathy, anxiety, irritability AD Progression Mild - MMSE >20 • Forgetfulness • Problems with shopping, driving and hobbies • Depression Moderate - MMSE 10-20 • Marked memory loss • Require help with ADLs • Wandering • Insomnia • Delusions Severe - MMSE <10 Adapted from Galasko D. Eur J Neurol. 1998;5:S9-S17. • Very limited language • Loss of basic ADLs • Incontinence • Agitation Nursing home placement, death from pneumonia and/or other comorbidities Activities of Daily Living Bars show 25th to 75th %ile of patients losing independent performance. EAT WALK CLEAR TABLE DISPOSE LITTER MAINTAIN HOBBY GROOM DRESS SELECT CLOTHES FIND BELONGINGS USE HOME APPLIANCES TRAVEL ALONE OBTAIN MEAL/SNACK TELEPHONE KEEP APPOINTMENTS MMSE 30 25 Mild AD 20 15 Moderate AD Adapted from Galasko. Eur J Neurol. 1998;5(suppl 4):S9-S17; Galasko et al. Alzheimer Dis Assoc Disord. 1997;11(suppl 2):S33-S39. 10 Severe AD 5 0 Detection Latency .Traumatisms . Vascular risk factors Symptoms Induction .Genetic/hereditary Pathogenesis Disease Primary Prevention Vaccine Estrogen NSAID Ginkgo Secondary Prevention (“Mild cognitive Impairment”) Antioxydants Anti-inflammatories Neurotrophic factors Estrogens Vascular Prevention Symptomatic Treatment Cholinergic replacement Therapy Glutamate Modulation Mood and Behaviour Management Key Symptom Areas – – – – – A B C D E ADL’s Behaviour Cognition Depression Effect on others May improve A. ADLs- activities of daily living, CIBC/FAST/CGItime to institutionalization B. Behaviour/Mood- decreased concomitant psychotropics, NPI total score reductions, CMAI C. Cognitive enhancement, SIB, MMSE Types Acetylcholine-esterase inhibitors Donepezil, Rivastigmine, Galantamine NMDA antagonists Memantine Pivotal Trials: Cognition (6 months) Change in ADAS-cog score vs. placebo Reference ChEI Daily dose Donepezil 10 mg 2.9 Rogers et al., 1998 10 mg 2.8 Burns et al., 1999 6-12 mg 2.6 Rösler et al., 1999 6-12 mg 4.9 Corey-Bloom, 1998 24 mg 3.6 Tariot et al., 2000 24 mg 3.9 Raskind et al., 2000 Rivastigmine Galantamine ADAS-Cog: Alzheimer’s Disease Assessment Scale on Cognition Memantine • • • Glutamate excitatory neuronal balance is NB in the progression of dementia Memantine is an uncompetitive, NMDA receptor antagonist with moderate affinity and fast receptor kinetics. Evidence from animal models of AD suggests that memantine has anti-ischemic and anti-excitatory properties, and recent clinical trials have demonstrated statistically significant efficacy in the treatment of moderate to severe AD [MBEST & NEJM] and mild to moderate vascular dementia [Stroke 2002 MMM300, MMM 500]. Long Term Treatment of Moderate to Severe Alzheimer‘s disease with Memantine Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, and Möbius HJ (2006), Arch Neurol Effects of Memantine on behavioural symptoms in Alzheimer´s disease patients: An Analysis of the neuropsychiatric Inventory (NPI) data of two randomised, controlled studies. Gauthier S, Wirth Y, Möbius HJ (2005) International Journal of Geriatric Psychiatry 20:1-6 Memantine in Moderate-to-Severe Alzheimer’s Disease Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ (2003). New England Journal of Medicine, 348 (14): 1333-41. 51 y-old ♀ with cognitive impairment and: delusions of sexual infidelity, paranoid delusions, hallucinations, hiding objects inappropriately, screaming and agitation, physical aggression Alois Alzheimer 1906 Key Symptom Areas – – – – – A B C D E ADL’s Behaviour Cognition Depression Effect on others O'Donnell M, Molloy DW, Rabheru K. Dysfunctional behaviour in dementia: a clinician's guide. Dundas, Ontario: New Grange Press; 2001. Often the most distressing symptom to caregivers Correlates with placement, inability to drive, morbidity and mortality Incidence 90% Prevalence 60-90% NSG home Community 60% Tariot 1999 Lyketsos 2002 70-90% Ballard 2001 Lysketsos 2000 Physical: DELIRIUM, diseases, drugs, discomfort, disability Intellectual: dementia – cognitive abilities/losses Emotional: depression, psychosis Capabilities:environment not too demanding yet stimulating enough, balancing demands and capabilities Environment: noise, relocation, schedules… Social, cultural, spiritual: life story, relationships family dynamics, personality traits…… Herrmann and Lanctot Canadian Journal of Psychiatry Oct 2007 Atypicals Remain the best studied and most effective but side effects limit their use Antidepressants Some evidence for Trazadone and Celexa but effect size may limit use in urgent situations Anticonvulsants Tegretol can be effective but poorly tolerated. Negative studies with Epival. Not as thoroughly studied as atypicals Benzodiazepines Short term use only The following is true of Alzheimer’s a) Insidious, gradual and progressive decline b) Motor symptoms are absent until later in the disease c) A dramatic presentation is not the same as an abrupt onset d) Behavioural symptoms are often the most distressing symptom for families and caregivers e) The ‘head turning sign’ refers to sexual disinhibition f) Vascular events may co-occur and cause cognitive dysfunction 65 year old woman who presents with a two year history of strange behaviour and sleeping problems and one year history of resting tremor, falls and increasing mental and physical slowness. As her family physician you diagnosed Parkinson’s disease and initiated L-Dopa. The L-Dopa helped with her motor symptoms. Periods of confusion became evident as were well formed visual hallucinations. Because of your suspicion of delirium and some urinary symptoms you treated her for a UTI. Despite this, the fluctuations and hallucinations continue. Her daughter who is the primary caregiver feels she is at her wits end and is asking you what to do. Diagnosis Dementia Plus >2/3 (probable, 1/3 possible) • Clinical Features Fluctuating cognition VH’s well formed + delusions Parkinsonism Pathologically identified with Ubiquitin Stain. LB seen in PD in SN. a-synnuclein stain better ie. No NFT staining LBD and Delirium Fluctuating LOC/attention. LBD has attn to do months in reverse Parkinson’s and DLB wrt to PD hallucinations and depression but not delusions suggesting cortical pathology for delusions. Louis’97 reported rest tremor lower in DLB but myoclonus higher. – – – – – – – – – – Repeated falls Syncope w transient LOC Neuroleptic sensitivity Systematized delusions (>50%) Hallucinations in other modalities Increased rates of depression (4050%) Misidentification syndrome v. common Tx Seems to respond well to AchEI Extreme caution with neuroleptics Which of the following is true regarding Dementia with Lewy Bodies a) It is common b) Associated with severe neuroleptic sensitivity, REM sleep disorders, and falls c) PET/SPECT shows decreased Dopamine uptake in the basal ganglia d) Can occur in patients who have had the motor symptoms of Parkinson’s for over one year e) Comorbid Depression is common f) Response to Acetylcholinesterase inhibitors is poor g) There is mixed subcortical and cortical features 82 year old married man who you have followed over several years having treated him for hypertension, diabetes and peripheral vascular disease. He has a history of paroxysmal atrial fibrillation and is on Coumadin. He has not been as steady while walking lately and had some recent falls. His wife and family have become increasingly concerned that something is wrong. He is forgetful and needs constant reminders even to change and get dressed. The family have also observed that he seems very emotional at times. He has been getting lost while driving. Memory problems + one of: Agnosia, Apraxia, Aphasia Executive dysfxn Vascular Focal si/sx or lab evidence Impairment Not during delirium Clinical features: Cognitive changes: executive dysfxn with few language impairments, often motor, gait abnormalities. Memory problems often retrieval related: working memory. Neurological: dizziness, focal motor, pseudobulbar palsy Subtypes: Multiinfact&Bingswangersmall vessel subcortical deep white matter Risk Factors: M, age, apo E4, race=black / asian, HTN, CAD, DM, Hyperchol, smoking TREATMENT B Clarify diagnosis: timing wrt to vascular event. Optimize management of vascular risk factors for future events. Consider antiplatlet agents for stroke prevention. AChEI, Memantine. Management of BPSD P establish therapeutic alliance with patient and family S advance planning (financial, housing, personal care directives), support for family, driving. Collaboration w other health care professionals and community agencies (H/C, MOM, support groups, respite) Cardiovascular Risk Factors Sandra Black U of T HTN, NIDDM, Genetics, Hyperlipidemia, CAD •Ischemic damage to cerebral vasculature Multiple Distinct Pathologies Large Vessel •Single Strategic infarct •Multiple infarcts Damage to critical cortical and subcortical structures Small Vessel •Multiple lacunae •Binswanger’s •CADASIL Hemorrhage Hypoperfusion •cSDH •SAH •ICH •Global (eg. After cardiac arrest) Decreased cholinergic transmission •Hypotension Damage/interruption of subcortical circuits and projections Erkinjuntti T. CNS Drugs, 1999 Which of the following are characteristics of Vascular Dementia a) Lateralizing findings b) Gait changes c) Step wise deterioration d) Neuroimaging or clinical evidence of CVA e) White matter hyperintensities and microvascular changes on CT are part of the diagnosis f) Retrieval > encoding deficits on neuropsych testing g) Easy to distinguish from Alzheimer’s 60 year old married mother of 2 who presents with a 2 year history of increasingly strange and uncharacteristic behaviour. She was caught shoplifting and has become surprisingly disinhibited. Her awareness of her social inappropriateness was negligible and quite embarassing for her family who feel she seems like a different person. Her language also has changed where she has experienced increasing difficulties speaking clearly. She often mutters and has been persisting in rigid patterns of behaviour, for instance, ruminating over a routine of watching TV and eating. FTLD Landmark case: Arnold Pick 1892, “aphasia and senile atrophy” Neary and Snowden [case reports, UK] outlined a syndrome with initial symptoms that were suggestive of psychiatric illness. However, the following frontal lobe behavioral abnormalities appeared over time: disinhibition, impulsivity, impersistence, inertia, loss of social awareness, neglect of personal hygiene, mental rigidity, stereotyped behavior, and utilization behavior (ie, tendency to pick up and manipulate any object in the environment). These descriptions included language abnormalities such as reduced speech output, mutism, echolalia, and perseveration. Recently, the condition described in the North American literature as PPA and that described in the European literature as frontal dementia have been combined under the diagnosis frontotemporal dementia (FTD). Neary Neurology 1998. Core diagnostic features. (need all) Early loss of insight Early decline in social interpersonal conduct Breaches of etiquette, decline in manners and social graces, disinhibition [speech, gestures, sexual behaviour, shop lifting], violation of interpersonal space Early emotional blunting Emotional shallowness with unconcern, loss of emotional warmth, indifference to others, loss of empathy and sympathy Early impaired regulation of personal conduct Inactivity, passivity, inertia, pacing, wandering, increased talking, laughing, sexuality, singing, hyperorality [overeating, food fads, oral exploration of objects], sterotyped behaviours [repetitive clapping, singing, dancing, hoarding], utilization behaviours [unrestrained exploration of objects], declining in hygiene and grooming, and aggression Insidious onset and gradual progression Mendez J Neuropsychiatry Clin Neurosci. 2002 All five at initial presentation 17/53 (33%), All five at two years (83%) Clinical features F>M, onset often before 65 Early personality changes Kluver Bucy Apathy, mental rigidity, inertia-restlessness, obsessions Disinhibition/aggression Loss of empathy Frontal executive dysfunction R sided sx: depression, psychosis, OCD, stereotypy, prosody L sided: early non-fluent aphasia (early descriptions of Pick’s disease) PPA Three different neurobehavioral syndromes: FTD [most common], Primary Progressive Aphasia, Semantic Dementia. Latter 2 have language impairment. Pathology Same pathologies different sites of lesions. Early anatomical lesions: orbital frontal, superior medial frontal, hippocampus Broe Neurology 2003 Neuronal loss, Pick bodies (25%)(Argentophilic), Gliosis O/E: look for frontal release signs, fasiculations, primitive reflexes Tx B- SSRI’s, low dose atypical AP’s. Benefit with Trazadone on NPI, DBPC no change MMSE or CGIC. Paxil negative study. Kertesz ANA 2005. Caution with acetylcholine-esterase inhibitors less cholinergic deficit, Feldman-no worsening. P- supportive, social skills training, behavioural treatment S- build social scaffold, plans for placement, behavioural management. Frontotemporal Dementia is characterized by a) b) c) d) e) f) g) Personality changes early, disinhibition Early loss of insight, decline in social interpersonal conduct with impaired regulation, emotional blunting, executive skills deficits, frontal signs Visuospatial and memory impairment early on Characteristic functional neuroimages with frontal cerebral hypometabolism High rates of family history Aphasia in certain subtypes of FTD minimal cholinergic deficit AD insidious onset, gradual progression memory, language, and visuospatial defects indifference, delusions Normal B/W Subcortical Vascular CVS risk factors, step wise decline Gait changes, EP signs Recall, executive skills deficits Depression, apathy MRI subcortical lacunes or hyperintensities DLB visual hallucinations fluctuating course parkinsonism Frontotemporal Degeneration Personality changes early, disinhibition Executive skills deficits, frontal signs, preserved visuospatial early on Characteristic functional neuroimages Complicated because Different receptors for same ligand Different effects at dendritic soma and axon Receptor desensitization and localization Different pathways and function Psychomotor activation Psychosis Sedation/Drowsiness Weight gain Blurred vision Dry mouth Constipation Sinus tachycardia Urinary retention Memory dysfunction DA reuptake ` inhibition 5HT2 Stimulation Sexual dysfunction Activating side effects Insomnia Nausea Ach block Antidepressant 5-HT reuptake inhibition Priapism Alpha2 block Postural hypotension Dizziness Reflex tachycardia GI disturbances Activating effects NE reuptake inhibition Dry mouth Urinary retention Activating effects Tremor Adapted from Richelson E. Current Psychiatric Therapy. 1993;232-239 other Relative Importance of Cytochrome p450 in Drug Metabolism - adapted from Shimada T J Pharmacol Exp Ther 1994 3A ¾ (50%) SUBSTRATES • 2D6 (20-25%) B benzos • SUBSTRATES E effexor • E effexor S sertraline • A AP’s, T tertiary amine, trazadone antiarrhythmics C clozaril • T trazadone L luvox • C clozaril, codeine O OCP • R risperidone N Nefazadone • O olanzapine E Erythromycin • P prozac, paxil INHIBITORS • S secondary amines N nefazadone, norfluoxetine • INHIBITORS F fluoxetine • P2 paxil, prozac L luvox • B buproprion • S sertraline R retrovirals A antifungals G grapefruit E erythromycin • 1A2 (10-15%) • • SUBSTRATES • C clozaril, coumadin, caffeine • H haldol • A acetaminophen • T tertiary amines, theophyline INHIBITORS • L luvox • • • E erythromycin C cipro, cimetidine G grapefruit juice Drugs Withdrawn For Excessive Adverse Drug Reactions Terfenadine (Seldane)—February 1998 Mibefradil (Posicor)— June 1998 Astemazole (Hismanol)—July 1999 Cisapride (Propulsid)— January 2000 Fluvoxamine (Luvox)— 2005 All relate to P450 enzymatic interactions with other drugs Drug Interactions (2006) Most Dangerous Psychotropic Drug Interactions Meperidine and phenelzine Libby Zion reaction (serotonin syndrome) Paroxetine and buspirone SSRIs,TCAs, divalproex, metoclopramide, sumatriptan, tramadol (Ultram), mirtazapine (Remeron) Serotonin syndrome Lamotrigine (Lamictal) and valproate (Depacon) Stevens Johnson syndrome Overlooked Causes of Drug Toxicity and Interactions P450 enzyme competition (2D6)—inducers, inhibitors Drug/diet interactions Grapefruit juice, tobacco, St. John’s Wort Drug/OTC interactions Dextromethorphan (Dexedrine) and SSRIs Additive side effects anticholinergic Orthostatic hypotension due to TCAs, metoclopramide, BPH medications and haloperidol (Haldol) Abused Drugs Alcohol (mood effects. Withdrawal and alcoholic hallucinosis), Amphetamines, Cocaine (especially free-base or crack), Marijuana (panic reaction), Phencyclidine (PCP) and hallucinogens (acute intoxication and flashbacks), Sedative-hypnotics (withdrawal) Analgesics Opiods and delirium Meperidine (toxic metabolite) Pentazocine and other opiate mixed agonistantagonists Anticholinergics Can produce an acute confusional state +/- urinary retention/constipation Interactions with opiates and synergy in anti alpha adverse side effects Anticholinergic antiparkinsonians Antihistamines (e.g., diphenhydramine) Atropine and derivatives Cyclic antidepressants Low-potency antipsychotic drugs (e.g., thioridazine, clozapine) Meclizine Scopolamine Memory impaired in Elderly Tune et al. Am J Psychiatry 1992;149:1393-4. Miller et al. Am J Psychiatry 1988; 145: 342-5 Elderly often take multiple medical medications Greater sensitivity exists to a given drug concentration Increase in neuronal sensitivity to sedative drugs (eg. 2o to reductions in Ach, Histamine) Pharmacokinetic changes result in higher and more variable drug concentrations Reduced lean body mass, increased fat Reduced hepatic blood flow (? metabolism) Decreased glomerular filtration Decreased creatinine clearance Increase in brain MAO-B (decreased amines) Decrease in Plasma Proteins May Affect Free Drug Fraction, Not Concentration—Rarely of Clinical Importance but May Affect Lab Interpretation Beer’s List of inappropriate medications in the Elderly http://www.dcri.duke.edu/ccge/curtis/beers.html
