Pharmacologic Management of Mood and Behavioral Changes in

Transcription

1 Pharmacologic Management of Mood and Behavioral Changes in Dementia James E. Galvin, MD, MPH Professor of Neurology and Psychiatry New York University Langone Medical Center

2 CADASIL MRI scan showing leukoencephalopathyon T2-weighted images Filleyet al, J NeurolSci1999 Punch skin biopsy demonstrating granular osmiophilicmaterial deposits of the vascular smooth muscle cells

3 Clinical Manifestations Cardinal clinical manifestations: migraine with aura, transient ischemic attacks (TIAs) fixed focal neurologic deficits caused by lacunarinfarctions, cognitive decline (subcortical dementia) In some patients, mood disorders, especially depression, may predominate. In the long run the disease always worsens, but in shorter periods - two years, for example - evolution is much variable Time to death is also highly variable -10 to 30 years. Death occurs around 65 (men) 70 years (women) on average, from accumulation of morbidities and clinical complications related to infection and immobility.

4 Clinical Stages of CADASIL Del Rio-Espinola, et al Exp Rev Nerother 2009

5 Mood and Behavioral Disturbances Traditionally, cognitive function has been the main focus of interest in treatment and research for people with dementia. It is becoming increasingly recognized, however, that non-cognitive symptoms are those that are most disturbing to families and caregivers, and may seriously impact not only the patient s wellbeing, but also the family s, caregivers and providers approaches to managing the patient. These common symptoms have been grouped together under the umbrella term behavioraland psychological symptoms of dementia (BPSD) As the disease progresses, BPSD symptoms become predominant problems and impose an enormous toll both emotionally and financially. They are also a common reason for institutionalization of people with dementia and they increase the burden and stress of caregivers A common measurement tool is the Neuropsychiatric Inventory (NPI)

6 NPI Developed by Cummings and colleagues Asked to informant to rate presence, severity and distress caused by a behavioral symptom 12 domains Hallucinations, delusions, agitation/aggression, disinhibition, irritability/lability, depression, anxiety, apathy, elation/euphoria, aberrant motor behaviors, appetite changes, sleep disturbances A shorter version the NPI-Q is appropriate for office use

7 Prevalence of BPSD in CADASIL At least 20 to 40% of patients with CADASIL exhibit psychiatric disorders. Typically develop during the course of disease rather than at onset In a report of 454 patients, 106 (24%) had mood disorders. Depression is the most common manifestation -at least half of the cases. The incidence and severity varies widely in different families Ischemic lesions in specific locations -such as basal ganglia and frontal white matter - may facilitate the emergence of mood disorders. Mood changes and other psychiatric manifestations -adjustment disorders and anxiety, psychotic events and rarely schizophrenia, usually appear after diagnosis, from 40 years on, in patients with previous ischemic episodes or cognitive disorders. Most studies did not use defined clinical criteria Valentiet al Act NeurolScand 2008;

8 Prevalence of Psychiatric Disturbances Poggesiet al Act NeurolScand 2008

9 Prevalence of Mood Disturbances Poggesiet al Act NeurolScand 2008

10 Why look for psychiatric manifestations? Psychiatric manifestations in CADASIL are important in clinical practice for different reasons when making a CADASIL diagnosis, it is important to look for psychiatric disturbances as their treatment may improve quality of life; psychiatric disturbances might also represent the onset of CADASIL, especially in young patients, and thus should be valued in the differential diagnosis.

11 Reyes, S. et al. Neurology 2009;72: Effect of Apathy on NPI

12 Effect of Apathy on Quality of Life Reyes, S. et al. Neurology 2009;72:

13 Treatment of Mood and Behavior At the present time, there are no approved therapies for the treatment of the cognitive, mood, or behavioral disturbances associated with Dementia (in general) or CADASIL (specifically)

14 What evidence exists? In 2003, Mesulamand colleagues studied the brain of a 36 year-old patient and showed that cortical cholinergic deficit exclusively attributable to small subcorticalinfarcts was present even in the absence of pathology suggestive of Alzheimer-type dementia. In vitro study of the brains of patients with CADASIL detected a large reduction of both the activity of acetylcholine transferasein frontal and temporal neocortex and its distribution Together, therefore, several research lines point to the presence of a cholinergic deficit in patients with CADASIL MesulumM et al, Neurology 2003; KeverneJS et al, Stroke 2007

15 Effect of Galantamine on Behavioral Symptoms: NPI 3 Dose increments 2 Improvement Mean (±SE) Change From Baseline e in NPI Placebo Galantamine 16 mg/d Galantamine 24 mg/d Months * Deterioration *p<0.05 vs. placebo (galantamine 16 and 24 mg); p<0.05 vs. baseline Adapted from Tariot PN et al. Neurology. 2000;54:

16 Memantine: Behavior (NPI) Worsening Improvement Delusions P=.0386 Hallucinations Agitation/Aggression P=.0083 Depression/Dysphoria Anxiety Elation/Euphoria Apathy/Indifference Disinhibition Irritability/Lability Aberrant Motor Behavior Nighttime Behavior Appetite/Eating Change Memantine Placebo *LOCF analysis at Week 28 Source: Gauthier S et al. Presented at: 24th Collegium Internationale Neuro-Psychopharmacologicum; June 20-24, 2004; Paris, France.

17 Clinical trial of Donepezil Multinational study, involving researchers in 10 countries. Enrolled 168 patients Primary outcome: vascular dementia - the Vascular- Alzheimer's Disease Assessment Scale-cognitive subscale (V-ADAS-cog) The study failed to demonstrate beneficial effects of the use of donepezil-10 mg/day -on the V-ADAS-cog scale (p=0.956) or MMSE after 18 weeks of use. The use of donepezilwas associated with improved performance in some tests that assess executive functions. Treatment did not influence positively the ability to perform activities of daily living or a number of other secondary outcomes. DichgansM, et al Lancet Neurol2008

18 Strategic Management of Behavioral Disturbances The following approaches are recommended in the order mentioned: Identify and limit behavioral triggers Underlying causes and medications Environmental modifications Nonpharmacologic interventions Address the underlying behavioral deficits Antidementia therapy Treat existing behavioral symptoms Prevent emergence of new symptoms Psychoactive therapy for acute behavioral issues Identify the behaviors that respond to therapy Source: Sink KM, et al. JAMA. 2003;293:

19 Non-Pharmacological Approaches Non-pharmacologic interventions are recommended as the most appropriate initial strategy for managing inappropriate behaviors in dementia for the following reasons: they address the psychosocial/environmental underlying reason for the behavior they avoid the limitations of pharmacologic interventions, namely, adverse side effects, drug drug interactions, and limited efficacy

20 The Premise of Nonpharmacologic Interventions in AD Majority of behavioral symptoms result from cognitive and functional impairments of dementia Unmet psychosocial needs Sensory deprivation, boredom, loneliness Loss of learned behavior and consequences Progressively lowered stress threshold Loss of coping abilities, greater vulnerability to the environment Nonpharmacologic interventions address the underlying deterioration from a patient s former level of intellectual function Source: Cohen-Mansfield J. Am J Geriatr Psychiatry. 2001;9:

21 Nonpharmacologic Approaches Music therapy Reminiscence therapy Montessori-based therapies Simulated presence therapy Pet therapy Multisensory stimulation Aromatherapy Touch therapy Therapeutic massage Therapeutic communication Light therapy Sources: Forbes DA, et al. Geriatrics Aging. 2005;8: Desai AK, Grossberg GT. Primary Care Companion J Clin Psychiatry. 2001;3:

22 Music Therapy Music therapy has been shown to decrease a range of challenging behaviors including agitation, aggression, wandering, repetitive vocalizations, and irritability Randomized, controlled trial Nursing home AD patients (n=39) Crossover design: 6 weeks individualized music, 2 weeks washout, 6 weeks classical music or reverse Agitation measured by CMAI for 30 minutes during and for 30 minutes after music CMAI = Cohen-Mansfield Agitation Inventory. Sources: Sherratt K, et al. Aging Ment Health. 2004;8:3-12. Gerdner LA. Int Psychogeriatr. 2000;12: Frequency of Agita ation Music No Music Time (Minutes) Baseline Classical Individual

23 Reminiscence Therapy for Dementia Reminiscence therapy is highly rated by staff and participants Discussion of past activities, events and experiences With the aid of tangible prompts, eg, photographs, familiar household items, sound or video recordings In a group setting encouraged to talk about past events once a week Individual sessions guided chronologically through life experiences Randomized, controlled trials (4 trials, total of 144 patients) Statistically significant benefits for cognition, mood and general behavioral function Significant decrease in caregiver stress Source: Woods B, et al. Cochrane Database Syst Rev. 2005;CD

24 Montessori-Based Activity Programming Montessori: Individual-based, aesthetically pleasing materials from everyday environment Regular: Large group activities, games, exercise, movies, discussion groups Montessori-Based Programming Regular Programming Mean Time Spent in State of Engage ement (s)* P<.001 P<.03 Mean Time Sp pent in State of Affe ect*, P<.001 P< *As measured over the course of a 10-minute observation period. Time spent in each state was evaluated using the following scoring system: 1 = none; 2 = <16 seconds; 3 = seconds; 4 = 1-5minutes; 5 = >5 minutes. CE PE NE SE CE = constructive engagement; PE = passive engagement; NE = nonengagement; SE = self-engagement; PLE = PLE pleasure; ANG ANG = anger; ANX = anxiety/fear; ANX SAD = sadness. Engagement Measure Key: CE: constructive engagement, P: passive, NE: non-engagement, SE: self-engagement 1 Affect Measure Key: PLE: pleasure, ANG; anger, ANX: anxiety/fear, SAD; sadness SAD Orsulic-Jeras S, et al. Gerontologist. 2000;40:

25 Psychotropics and Behavior in AD No FDA-approved orally administered agents for behavioral disturbances in AD/dementia Agitation Psychosis Depression Atypical antipsychotics* Mood stabilizers/ anticonvulsants Antidepressants, anxiolytics, etc Atypical antipsychotics* SSRIs SSRNIs *FDA Public Health Advisory (April 2005): Clinical trials of antipsychotic drugs to treat behavioral disorders in elderly patients with dementia have shown a higher death rate compared to placebo. SSRIs = selective serotonin reuptake inhibitors; SSRNIs = selective serotonoin and noradrenergic reuptake inhibitors. Source: TariotPN. J Am GeriatrSoc. 2003;51(S2):S305-S313.

26 Antipsychotic Safety FDA Public Health Advisory (April 2005): Clinical trials of atypical antipsychotic drugs to treat behavioral disorders in elderly patients with dementia have shown a higher death rate compared to placebo Specific causes of death were primarily due to: Heart-related events (eg, heart failure, sudden death) Infections (mostly pneumonia) Wang PS, et al. N Engl J Med. December, 2005 Conventional antipsychotics were associated with higher risk of death than atypical antipsychotics in elderly patients. Risk is highest: Soon after therapy is initiated At high doses Sources: Schneider LS, et al. JAMA. 2005;294: ; Wang PS, et al. N Engl J Med. 2005;353: ; FDA Public Health Advisory. Available at: Accessed December 19, 2005.

27 Atypical Antipsychotics Atypical antipsychotic agents Recommended uses: control of problematic delusions, hallucinations, severe psychomotor agitation and combativeness General cautions: diminished risk of developing extrapyramidal symptoms and tardive dyskinesia compared with typical antipsychotic agents Risperidone (Risperdal) Olanzapine (Zyprexa) Quetiapine (Seroquel) Initial dosage: 0.25 mg per day at bedtime; maximum: 2 3 mg per day, usually twice daily in divided doses Initial dosage: 2.5 mg per day at bedtime; maximum: 10 mg per day, usually twice daily in divided doses Initial dosage: 12.5 mg twice daily; maximum: 200 mg Comments: current research supports use of low dosages; extrapyramidal symptoms may occur at 2 mg per day Comments: generally well tolerated Comments: more sedating; beware of transient Sadowsky and Galvin, In Press 2010 twice daily orthostasis

28 Classic Antipsychotics Typical antipsychotic agents Recommended uses: control of problematic delusions, hallucinations, severe psychomotor agitation and combativeness; second-line therapy in patients who cannot tolerate or who do not respond to atypical antipsychotic agents General cautions: current research suggests that these drugs should be avoided if possible, because they are associated with significant, often severe side effects involving the cholinergic, cardiovascular, and extrapyramidal systems; there is also an inherent risk of irreversible tardive dyskinesia, which can develop in 50% of elderly patients after continuous use of typical antipsychotic agents for 2 years Haloperidol (Haldol), fluphenazine (Prolixin), thiothixene (Navane) Trifluoperazine (Stelazine), molindone (Moban), perfenazine (Trilafon), loxapine (Loxitane) Sadowsky and Galvin, In Press 2010 Dosage: varies by agent Dosage: varies by agent Comments: anticipated extrapyramidal symptoms; if these symptoms occur, decrease dosage or switch to another agent; avoid use of benztropine (Cogentin) or trihexyphenidyl (Artane) Comments: agents with inbetween side-effect profile

29 Mood Stabilizers Mood-stabilizing (anti-agitation) drugs Recommended uses: control of problematic delusions, hallucinations, severe psychomotor agitation and combativeness; useful alternatives to antipsychotic agents for control of severe agitated, repetitive and combative behaviors General cautions: see comments about specific agents Trazodone (Desyrel) Initial dosage: 25 mg per day; maximum: mg per day in divided doses Comments: use with caution in patients with premature ventricular contractions Carbamazepine (Tegretol) Initial dosage: 100 mg twice daily; titrate to therapeutic blood level (4 8 mcg per ml) Comments: monitor complete blood cell count and liver enzyme levels regularly; carbamazepine has problematic side effects Divalproex sodium (Depakote) Initial dosage: 125 mg twice daily; titrate to therapeutic Comments: generally better tolerated than other mood blood level (40 to 90 mcg per stabilizers; monitor liver ml) enzyme levels; monitor platelets, prothrombin time and partial thomplastin time Sadowsky and Galvin, In Press 2010 as indicated.

30 Anti-Anxiety Drugs Anxiolytic drugs Benzodiazepines Recommended uses: management of insomnia, anxiety and agitation General cautions: regular use can lead to tolerance, addiction, depression and cognitive impairment; paradoxic agitations occurs in about 10% of patients treated with benzodiazepines; infrequent, low doses of agents with a short half-life are least problematic Lorazepam (Ativan), oxazepam (Serax), temazepam (Restoril), zolpidem (Ambien), triazolam (Halcion) Dosage: varies by agent See general cautions Non-benzodiazepines Buspirone (BuSpar) Initial dosage: 5 mg twice daily; maximum: 20 mg three times daily Comments: useful only in patients with mild to moderate agitation; may take 2 4 weeks to become effective Sadowsky and Galvin, In Press 2010

31 Antidepressants Antidepressant drugs (SSRIs) General cautions: full therapeutic trial requires 4 8 weeks; as a rule, dosage is increased using increments of initial dose every 5 7 days until therapeutic benefits or significant side effects become apparent; after 9 months, dosage reduction is used to reassess the need to medicate; discontinuing an antidepressant over days limits withdrawal symptoms. Note: patients with depression and psychosis require concomitant antipsychotic medications. General cautions: sweating, tremors, nervousness, insomnia, somnolence, dizziness and GI/sexual disturbances Fluoxetine (Prozac) Initial dosage: 10 mg every other morning; maximum: 20 mg every morning Comments: activating, very long-half life; side effects may not manifest for a few weeks Paroxetine (Paxil) Initial dosage: 10 mg per day; maximum: 40 mg per day (morning or evening) Comments: less activating but more anticholinergic than other SSRIs Sertraline (Zoloft) Initial dosage: mg per day; maximum: 200 mg per day (morning or evening) Comments: well tolerated; compared with other SSRIs, sertraline has less effect on metabolism of other medications Citalopram (Celexa) Initial dosage: 10 mg per day; maximum: 40 mg per day Comments: well tolerated; some patients experience nausea and sleep disturbances Fluvoxamine (Luvox) Initial dosage: 50 mg twice daily; maximum: 150 mg twice daily Comments: exercise caution when using fluvoxamine with alprazolam or triazolam Sadowsky and Galvin, In Press 2010

32 Citalopram vs Perphenazine Pollack, BG, Am J Psych 2002

33 Citalopram vs.risperidone Source: Pollock BG et al, Am J Geriatr Psych 2007;

34 Treatment of Apathy Thirty-five studies were included: 2 meta-analyses, 13 randomized controlled trials (RCTs), 14 open-label studies, 5 case series, and 1 single case study. Eight studies included apathy as a primary outcome. A cholinesterase inhibitor was investigated in 24 studies, methylphenidate in 5, and other medications in 6 studies. Cholinesterase inhibitors reported statistically significant effect but with small effect size A single RCT provided evidence for a positive effect of Ginkgo biloba extract suggested benefit 1 small RCT and 3 case reports suggested that methylphenidate was beneficial.

35 Repetitive TranscranialMagnetic Stimulation Stimulation at Left Dorsolateral PreFrontal Cortex 5/11 patients were treatment responders Jorge RE et al, Arch Gen Psych 2008

36 Summary Mood and behavioral disturbances are common in CADASIL Depression and Apathy are the most common symptom Diminish quality of life for patient May lead to greater behavioral disturbances No approved treatments and to date cholinesterase inhibitors have not shown efficacy Non-pharmacological approaches should be considered SSRI antidepressants should probably be first line therapies with addition of an atypical antipsychotic as necessary More studies are needed using standardized diagnostic criteria General principle #1: START LOW, GO SLOW General principle #2: RE-ASSESS, RE-EVALUTE, REPEAT