Behavioral and Psychological Symptoms of Frontotemporal : A Review

Frontotemporal dementia (FTD) is commonly diagnosed in people younger than 65 years, and presents with various behaviors which could be unsafe for the patient and their caregivers. Many studies have been conducted to determine the behaviors’ source and the possible treatments for the varied psychological symptoms, from agitation and aggression to eating disturbances.

By Ryan D. Rajaram, MSc; Nathan Herrmann, MD, FRCPC; and Krista L. Lanctôt, PhD

nce thought to be an infrequent behavior, personality and/or language trials in FTD patients have been con- Ocause of dementia, it is now esti- ability.4 Symptoms may worsen to the ducted, using interventions including mated that FTD is found in 4% of the point of a loss of independence5 and antidepressants,11-14 antipsychotics15 general dementia population,1 and is inappropriate social functioning.6 There and cognitive enhancers.16-18 present in 20% to 30% of dementia have been multiple attempts to clearly The numerous consensuses have patients younger than 65 years.2,3 This outline the key diagnostic features of the outlined the typical neuropsychiatric early-onset dementia can initially pres- clinical variants.7-9 Three distinct clini- symptoms occurring in patients with ent in a variety of phenotypes, most cal variants have arisen: the behavioral- FTD.7,9 At early onset of the disease, commonly as a gradual change in based (bv-FTD), and the language- many of the behavioral symptoms are based primary progressive aphasia present in the bv-FTD variant, and to a Ryan D. Rajaram, MSc (PPA) and semantic dementia (SD). lesser extent in SD and PPA.19,20 The Department of Bv-FTD is defined by an impair- most common neuropsychiatric symp - Sunnybrook Health Sciences ment in social functioning and emo- toms associated with FTD, their neu- Centre tional blunting in the patient, but may robiological correlates and the treat- Toronto, Ontario also include a decline in personal ment options currently available are hygiene and mental rigidity, and dis- outlined below. Nathan Herrmann, MD, FRCPC tractibility.7,9 PPA patients initially Professor, University of Toronto present with a progressive loss of Neuropsychiatric Symptoms Head of the Division of Geriatric speech without cognitive or behavioral Associated with FTD Psychiatry impairment, while SD patients’ fluen- . This behavior is often mistak- Sunnybrook Health Sciences Centre cy is intact (though the quality of en for , but is considered a Toronto, Ontario speech is compromised and behavioral hallmark of FTD as it is present in 21,22 Krista L. Lanctôt, PhD symptoms may be present at the onset 95% to 100% of FTD patients. 7,10 Associate Professor of Psychiatry of the disease). Typically, apathetic individuals pres- and Pharmacology/Toxicology, Although improvements have been ent with a lack of effort for performing University of Toronto made in the diagnosis of FTD, treatment routine activities or starting new activ- Department of Psychiatry, options remain limited and have focused ities, indifference to their own person- Sunnybrook Health Sciences Centre on the management of neuropsychiatric al problems and flat , a symptom Toronto, Ontario symptoms. Only a handful of treatment where individuals do not respond

The Canadian Review of Alzheimer’s Disease and Other • 9

Table 1 Treatment of Behavioral Symptoms in FTD

Study Intervention(s) Outcomes Comments

Antidepressants Swartz et al 1997 • Fluoxetine (20 mg/d) • NPI: 9/11 patients “improved,” • AEs: 2 withdrawals 3-month open-label • Sertraline (50-125 mg/d) not statistically significant (1 sertraline-diarrhea, (n = 11) • Paroxetine (20 mg/d) 1 paroxetine-agitation, psychomotor agitation) Morreti et al 2003 • Paroxetine (20 mg/d) • Behavioral improvements • AEs: No dropouts 14-month open-label compared to • Reduced caregiver (n = 8) (1200 mg/d) Lebert et al 2004 • Trazodone (titrated to • NPI: 10/26 “responder” to drug • MMSE score unchanged after 6-week placebo- a max 300 mg/d) • Improvement in , treatment controlled (n = 26) agitation, depression and • AEs: 5 withdrawals (signifi- eating disorders cantly greater in drug group vs. placebo) • 11 patients reported AEs (fat- igue, dizziness, hypotension) Lebert et al 1999 • Trazodone (titrated to • NPI: Significant decrease • MMSE score unchanged 6-week open-label a max 300 mg/d) from baseline in • One AE reported: transient (n = 14) in bv-FTD aggression, and faintness (300 mg/d) irritability with 150 mg/d • Significant decrease in depression, disinhibition and aberrant motor behavior Huey et al 2008 • Quetiapine (150 mg/d) • NPI: Significant decrease in • AEs: 1 patient reported 3-week open-label compared to score from baseline only sedation with quetiapine. (n = 8) in bv-FTD dextro amphetamine with dextro amphetamine Sleep disturbance with both (20 mg/d) drugs Gafoor et al 2003 • (27.5 mg/d) • Manic symptoms improved • Secondary a rare 2 case studies of + (0.5 mg/d) with all treatments occurrence FTD + mania • (5 mg/d) • Involvement of the right frontal lobe? Curtis et al 2000 • Risperidone (6 mg/d) • Psychotic symptoms • AEs: and mild 1-week case study improved after 1 week treatment. (n = 1) of Pick’s • After 3 months of treatment, no Disease + delusions/hallucinations Cognitive Enhancers Mendez et al 2007 • Donepezil (10 mg/d) • No significant improvement on • AEs: Caregivers reported 6-month case-control any outcome: MMSE, CDR, increased disinhibition, study (n = 12) in FTD checklist. compulsions bv-FTD Moretti et al 2004 • Rivastigmine (3-9 mg/d) • NPI: Significant improvement • AEs: Nausea, muscle 12-month open-label vs. control (matched in total scores from baseline cramps, blood pressure (n = 20) in bv-FTD FTD patients taking and vs. control on most items changes antipsychotics, of NPI , • Reduction in caregiver burden selegiline) Lampl et al 2004 • Donepezil (10 mg/d) • 4/9 patients demonstrated • AEs: None reported 3-month open-label • Rivastigmine (6-12 mg/d) clinical significant improvement (n = 9) + improvements on SPECT imaging

10 • The Canadian Review of Alzheimer’s Disease and Other Dementias Behavioral and Psychological FTD Symptoms

Treatment of Behavioral Symptoms in FTD (continued)

Study Intervention Outcomes Comments

All FTD subtypes Kertesz et al 2008 • Galantamine (mean • NPI: No significant improvement • AEs: nausea, diarrhea, 18-week open-label 21.5 ± 4.9 mg/d) in behavioral or language (5 withdrawals) (n = 36) in bv-FTD + PPA outcomes (PPA patients showed trend) • Subjects demonstrated improvement in the withdrawal phase over placebo on CGI-S, results not significant after correction Diehl-Schmid et al 2008 • Memantine (20 mg/d) • NPI: No significant improvement • AEs: Depression, other 6-month open-label in scores from baseline reported but deemed (n = 16) in bv-FTD + SD • SD subgroup improved unrelated to the significantly in FBI score from medication baseline Swanberg M et al 2007 • Memantine (20 mg/d) • NPI: Improvement in apathy, •AEs: None reported 3-month open-label agitation and anxiety (n = 3) in bv-FTD • No improvements in cognition emotionally.23 While not considered nent in bv-FTD, it is also present in SD lism in the right anterior temporal lobe, an immediate danger to the patient, manifesting as an inability to behave in consistent with the previous finding that apathy may have significant negative a socially acceptable manner.33 this region was responsible for “social” implications. In addition to the decline Behaviors indicative of a loss of cognition, while another PET study sin- of activities of daily living (ADL), inhibition are wide ranging, with one gled out the orbitofrontal cortex.35-37 poor quality of life and an increased study reporting shoplifting, exhibition- Agitation and aggression. The probability of developing Parkinson- ism, inappropriate contact with presence of agitation and aggression like symptoms,24-26 patients may strangers and extramarital affairs has been previously reported in FTD cease all social interactions and neg- among others. Of note, patients exhibit- patients and poses a great risk not only lect personal hygiene.27,28 ing moderate to severe disinhibition to the patient, but also to care- Apathetic behaviors have been demonstrated hypoperfusion in the givers.38,39 It is not uncommon to see most commonly linked to bv-FTD, but a significant portion of patients who While not considered an immediate danger to the patient, initially present with PPA may devel- op this symptom as the disease pro- apathy may have significant negative implications. gresses.29,30 Reports have suggested that SD patients may also present with right temporal lobe.34 Neuroimaging more dangerous behaviors, such as apathy, possibly linked to bilateral data supports the right temporal lobe as aggression, in severe cases, which amygdala atrophy.31 A recent MRI an important site of degeneration, lead- could lead to incarceration or institu- study, examining 62 FTD patients, ing to a loss of inhibition. One MRI tionalization.20,40 A comparative study linked the severity of apathy to the study associated increased disinhibition found a greater proportion of FTD right dorsolateral prefrontal cortex.32 with grey-matter loss in the nucleus patients (45%) than Alzheimer’s dis- Disinhibition. Although less fre- accumbens and the right mediotempo- ease (AD) patients (5%) exhibiting quently reported at the onset of FTD ral region of the brain.32 A recent PET antisocial behaviors, such as assault than apathy, disinhibition remains a imaging study, looking at 29 socially and death threats, which could be prevalent symptom and is found in impaired FTD subjects (all three vari- linked to hypoperfusion in the anterior 52% of FTD patients.21 Most promi- ants), found decreased glucose metabo- frontal and temporal regions of the

The Canadian Review of Alzheimer’s Disease and Other Dementias • 11 Tauopathies

brain.41 A genetic study found a rela- symptoms may be present but may not There is a good rationale for SSRI use tionship between the apolipoprotein necessarily represent true core features in FTD, as studies have indicated a E4 allele and agg re ssion in FTD, of FTD. Repetitive behaviors or obses- disruption of the serotonergic system, where patients homozygous for the sive-compulsive features have com- including losses of 5HT-1A and 5HT- allele displayed a significantly greater monly been reported within the FTD 2A receptors.56,57 Significant losses of score in aggression outcomes.42 An population.49 A study examining these these receptors in key brain regions increase in dopaminergic neurotrans- behaviors found that, within a popula- may decrease the response to sero- mission and a disruption of the sero- tion of 90 FTD subjects, 21% dis- tonin, which may confer the need for tonergic pathway were recently sug- played complex compulsive behavior replacement and limit treatment effec- gested as contributors to aggression and this was associated with temporal tiveness of SSRIs.58 and agitation in FTD patients.43 lobe atrophy, a degenerative pattern A three-month open-label study Eating disturbances. Dramatic common to SD.50 Another study found examined fluoxetine, sertraline or parox- changes in diet may occur with high that both the frontal and the temporal etine treatment in 11 FTD patients and frequency at the onset of FTD and variants of FTD demonstrated a signif- found that more than half the subjects may steadily get worse as the disease icant number of stereotypical/repeti- exhibited impro vement in behaviors progresses. Such changes early in the tive behaviors, including verbal perse- such as disinhibition, depression and presentation may help differentiate veration, hoarding and rituals.51 compulsions.59 Another open-label trial examined 20 mg/d of paroxetine in eight Dramatic changes in diet may occur with high frequency FTD subjects and found a significant at the onset of FTD and may steadily get worse as the improvement in behavioral symptoms following 14 months of treatment.11 disease progresses. In contrast, a randomized control trial (RCT) found no benefits in FTD from other neurodegenerative Psychotic symptoms have also been behavioral symptoms, and even wors- diseases like AD.44 reported in FTD, although they are an ened cognitive performance, in eight A comparative study between FTD uncommon occurrence. A study com- bv-FTD subjects who were titrated to subjects and AD patients found that paring the prevalence of psychotic a maximum of 40 mg/d paroxetine.14 79% of FTD patients reported carbo- symptoms in FTD and AD found that Two trials evaluating the efficacy of hydrate craving, while no AD patients fewer FTD patients reported symp- trazodone in FTD have been conduct- exhibited this behavior.45 Another toms (2% vs. 17.4%), with both ed, one a placebo-controlled crossover study examining the eating patterns of patient groups reporting delusions and trial and the other an open-label study. bv-FTD and SD patients found that .52 A number of case studies In the six-week crossover trial of tra- both subgroups had similar eating have also reported the presence of psy- zodone vs. placebo, 26 FTD patients behaviors with both experiencing chosis in FTD patients.53-55 with neuropsychiatric symptoms changes in food preferences and improved significantly on behaviors appetite at onset, and a decreasing Treatment Options for FTD of irritability, agitation, depression and swallowing ability as the disease pro- There are few effective treatment eating disorders.12 The open-label gressed.46 In an epidemiologic study options for FTD, and the majority of study of trazodone in 14 FTD subjects of bv-FTD patients, eating disorders, clinical trials aim to treat symptoms found a dose-dependent improvement including overeating, bulimia and associated with the disease, rather than in delusions, irritability, aggression food fads, were among the most com- focusing on disease modification. A and disinhibition.60 A recent review mon symptoms that progressed within number of pharmacologic interven- evaluated the drug trials that have been a four-year period.47 A recent study tions have been used in clinical trials conducted for the management of examining binge eating in the bv-FTD and have demonstrated variable behavioral symptoms in FTD. Those variant was linked to atrophy in the results. These data are summarized authors concluded that there was mod- right ventral insular cortex, striatum below and in Table 1. est evidence to support the efficacy of and the orbitofrontal cortex.48 Antidepressants. The selective paroxetine, fluvoxamine, selegiline Other behavioral features. A serotonin reuptake inhibitor (SSRI) and trazodone, as FTD patients were number of other neuropsychiatric drug class has been the most studied. more likely to improve while taking

12 • The Canadian Review of Alzheimer’s Disease and Other Dementias Behavioral and Psychological FTD Symptoms

these medications.61 These results study of donepezil in FTD (n = 24) What’s the next step? must be interpreted with some caution, found conflicting evidence, suggesting The behavioral symptoms associated as only two of the studies were ran- no significant differences in cognition with FTD appear wide-ranging and domized clinical trials. were observed between the drug and may overlap with other neurodegener- Antipsychotics. A number of case control groups, with the drug group ative diseases. This may contribute to reports have shown variable results experiencing significantly greater misdiagnoses and leave patients with antipsychotics. Potential therapeu- worsening of symptoms following untreated until behavioral symptoms tic effects of this drug group may be treatment.66 reach an unmanageable level. A related to dopaminergic antagonism, as A 12-month open-label study of recent study in Norway and Sweden one study found an association between rivas tigmine found that subjects taking found that, on average, it took two to increased dopaminergic neurotransmis- the drug experienced a significant three years for a clinical diagnosis of sion and agitated and aggressive behav- improvement in behavioral symptoms FTD to be confirmed from the first iors in 25 FTD patients.43 One small and caregiver burden when compared physician visit.70 It is for this reason study demonstrated imp ro vement with to age-matched controls.16 Similarly, that further research is warranted, olanzapine and haloperidol in the treat- an 18-week open-label study followed with the goal of effective treatment at ment of manic symptoms associated by an eight-week RCT (n = 36) look- an early stage. with FTD.62 Another study (n = 8), ing at galantamine in the treatment of A number of therapeutic options found significant improvement in bv-FTD and PPA found no significant have shown efficacy in the treatment behavioral symptoms with dextroam- phetamine treatment but not quetiap- There are few effective treatment options for FTD, and ine.15 A single case study reported the the majority of clinical trials aim to treat symptoms effectiveness of one week of risperi- associated with the disease, rather than focusing on done 3 mg bid for an FTD patient with psychotic symptoms.63 disease modification. Cognitive enhancers have also been investigated as possible treat- improvement in behavior or language, of neuropsychiatric symptoms asso- ment options. A deficit in cholinergic but the language performance of PPA ciated with FTD, but more must be transmission has been a hallmark con- subjects taking the drug remained sta- done. An epidemiologic study has tributor to AD, yet a link to FTD is less ble compared to subjects taking place- found that it would be feasible to con- convincing. Only one study has shown bo.17 Evidence for another cognitive duct large-scale multi-centred clinical a disruption of this system, with enhancer, the N-methyl-D-aspartate trials, since all the factors for a suc- decreases of muscarinic acetylcholin- (NMDA) receptor antagonist, meman- cessful trial, including a large, ergic recep tors in the temporal cortex of tine, is contradictory with regard to testable FTD population and appro- five SD patients.64 Within the efficacy. The rationale for its use as a priate standardized outcomes, are cholinesterase inhibitor (ChEI) class, treatment option remains somewhat readily available.71 The potential of studies have looked at treatment with scarce, with a handful of studies sug- disease-modifying therapies are cur- donepezil, rivastigmine and galan - gesting a disruption of the glutamater- rently being investigated in AD and it tamine. A small open-label study (n = 9) gic system, with decreased NMDA is hoped that this will spread to the of recently diagnosed FTD patients receptors and glutamatergic neurons FTD field. In theory, drugs targeting found that four of the subjects taking in the frontal and temporal brain tauopathies or ubiquitination of TDP- either donepezil or rivastigmine regions of FTD patients.67,68 A small 43 proteins may prove beneficial in showed clinically significant improve- case series suggested benefits in reversing the localized damage to the ments after three months of treatment, behavior and cognition,69 while an frontal and temporal lobes of the and improvements in their SPECT open-label study (n = 16) found no sta- brain. Until this happens, more thera- scans after six months, although out- tistically significant improvement in peutic options to treat the debilitating comes for this study were vaguely behavioral outcomes and a decline in neuropsychiatric symptoms of FTD defined.65 A six-month case-controlled cognitive performance.18 are urgently required.

The Canadian Review of Alzheimer’s Disease and Other Dementias • 13 Tauopathies

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13.1 • The Canadian Review of Alzheimer’s Disease and Other Dementias Behavioral and Psychological FTD Symptoms

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The Canadian Review of Alzheimer’s Disease and Other Dementias • 13.2