Psychiatric Annals

CME Article 

Management of Psychiatric Features in Frontotemporal Dementia

Jamie Starks, MD; Michael Rosenbloom, MD, FAAN

Abstract

Frontotemporal dementia (FTD) refers to a group of neurodegenerative disorders that affects the frontotemporal cortices, resulting in progressive decline affecting cognitive and behavioral function. FTD is most commonly divided into three clinical syndromes: behavioral variant frontotemporal dementia (bvFTD) and two language variants, semantic variant primary progressive aphasia and nonfluent/agrammatic variant primary progressive aphasia. bvFTD may present with symptoms that overlap with psychiatric disorders. Treatment in FTD is symptomatic rather than disease-modifying, consisting of both nonpharmacological behavioral interventions as well as pharmacological treatments such as selective serotonin reuptake inhibitors and neuroleptics. This review discusses a diagnostic approach to FTD followed by a review of the literature on both pharmacological and nonpharmacological interventions for the commonly observed psychiatric symptoms in this patient population. [Psychiatr Ann. 2017;47(5):246–257.]

Abstract

Frontotemporal dementia (FTD) refers to a group of neurodegenerative disorders that affects the frontotemporal cortices, resulting in progressive decline affecting cognitive and behavioral function. FTD is most commonly divided into three clinical syndromes: behavioral variant frontotemporal dementia (bvFTD) and two language variants, semantic variant primary progressive aphasia and nonfluent/agrammatic variant primary progressive aphasia. bvFTD may present with symptoms that overlap with psychiatric disorders. Treatment in FTD is symptomatic rather than disease-modifying, consisting of both nonpharmacological behavioral interventions as well as pharmacological treatments such as selective serotonin reuptake inhibitors and neuroleptics. This review discusses a diagnostic approach to FTD followed by a review of the literature on both pharmacological and nonpharmacological interventions for the commonly observed psychiatric symptoms in this patient population. [Psychiatr Ann. 2017;47(5):246–257.]

Frontotemporal dementia (FTD) is a heterogenous neurodegenerative process that affects the frontotemporal cortices, resulting in progressive decline affecting cognitive and behavioral function. In 1892, Arnold Pick first described FTD in a patient with young onset dementia presenting with aphasia and lobar atrophy. This condition is the third most common cause of dementia across all age groups, accounting for 5% to 10% of all pathologically confirmed cases1 and the second most common cause of young onset dementia in people age 45 to 65 years.2 The prevalence is approximately 15 to 22 per 100,000 within the US population3 and survival ranges from 6 to 11 years from symptom onset.4

FTD is unique from other neurodegenerative processes resulting in dementia such as Alzheimer's disease (AD) and Lewy body dementia (LBD) in that the condition affects patients earlier in life, affecting people age 65 and younger, and has a genetic association in 40% of cases.

FTD is most commonly divided into three separate, but occasionally overlapping clinical syndromes: behavioral variant frontotemporal dementia (bvFTD) and two language variants, semantic variant primary progressive aphasia (svPPA) and nonfluent/agrammatic variant primary progressive aphasia (nfvPPA). In general, clinical presentation is driven by the regional atrophy: right hemisphere predominant atrophy results in behavioral symptoms whereas left hemisphere predominant atrophy results in language symptoms.5 In certain cases, FTD-related neurodegeneration may progress to involve motor neurons and extrapyramidal structures, leading to motoric dysfunction. When neurodegeneration extends beyond the focal regions within the frontotemporal cortex, these three FTD subtypes clinically converge, ultimately becoming indistinguishable from each other.

A diagnosis of definitive FTD, like most neurodegenerative processes, requires a postmortem neuropathological confirmation. In contrast to AD, which has a single pathological signature of amyloid plaques and neurofibrillary tangles, FTD has a broader spectrum of associated neuropathologies that can be subsumed under the umbrella category of frontotemporal lobar degeneration (FTLD). The three abnormal protein aggregates described in FTLD include tau, transactive response DNA-binding protein (TDP-43), and fused-in-sarcoma (FUS).3 Clinical presentation may provide some insight into the underlying pathology (eg, svPPA is almost exclusively associated with TDP-43 pathology), but most commonly no specific conclusions about underlying molecular abnormalities can be made from a clinical evaluation.

This review is divided into two sections: first, we describe the clinical phenotype associated with the three FTD subtypes, all of which result in frontotemporal atrophy or neurodegeneration (Figure 1). In the second portion, we outline both pharmacological and nonpharmacological strategies addressing the most common presenting neuropsychiatric symptoms observed in the spectrum of FTD.


The frontotemporal dementias are characterized by preferential atrophy of the frontotemporal lobes (blue arrow) with relative sparing of the parieto-occipital cortex (red arrowhead). Courtesy and used with permission of Suzee Lee, MD (University of California, San Francisco Memory and Aging Center).

Figure 1.

The frontotemporal dementias are characterized by preferential atrophy of the frontotemporal lobes (blue arrow) with relative sparing of the parieto-occipital cortex (red arrowhead). Courtesy and used with permission of Suzee Lee, MD (University of California, San Francisco Memory and Aging Center).

Clinical Subtypes of Frontotemporal Dementia

Behavioral Variant Frontotemporal Dementia

Behavioral variant frontotemporal dementia (bvFTD) is the most common FTD clinical subtype, responsible for slightly more than one-half of cases and more commonly found in men.6 Among the FTD variants, bvFTD has the least favorable prognosis with an average survival ranging from 3 to 4 years from diagnosis.4,7 Patients frequently present with early changes in social behavior and comportment that ultimately affect both social and occupational relationships. Based on the international consensus criteria,8 there are six core clinical features associated with possible bvFTD. If patients have neuroimaging evidence for frontotemporal neurodegeneration and functional decline, they would meet criteria for probable FTD. These core clinical features are described below8:

  • Early behavioral disinhibition: Behavioral disinhibition is the most widely recognized clinical characteristic of bvFTD with early loss of social boundaries (eg, approaching strangers), poor impulse control (eg, excessive spending), and compromised judgment (eg, petty theft, public urination, sexually inappropriate comments).3 There is clear loss of manners or decorum. Often, behavioral disinhibition can be immediately observed when interacting with the patient during the mental status examination.
  • Early apathy or inertia: Apathy is characterized by a loss of motivation as well as interest in work, hobbies, social interactions, and personal hygiene.3 In addition, this condition may be further described as inertia. Consequently, patients may experience social isolation and reduced emotional range.
  • Early loss of sympathy or empathy: Because of damage involving the frontotemporal lobes, patients may exhibit the inability to emotionally respond to friends and family members in times of grief or sadness. Patients may further exhibit a loss of interrelatedness, reduced social interest, and/or decreased personal warmth.8 A typical example of a patient losing the ability to exhibit empathy includes the patient who had to rush a sick family member to the hospital for a medical emergency, but only expresses frustration about driving through rush hour traffic, disregarding any suffering on the part of his wife.
  • Early perseverative, stereotyped, or compulsive/ritualistic behavior: bvFTD further leads to progressive dysfunction of the frontal networks that regulate repetitive behaviors, producing repetitive movements, ritualistic behaviors, or speech stereotypy.8 Compulsive motor symptoms such as clearing the throat, rubbing, picking, pacing, or wandering may be observed.9 There may be more complex manifestation of compulsive symptoms including collecting, hoarding, shoplifting, and rummaging. In contrast to obsessive-compulsive disorder, obsessive thoughts typically do not accompany compulsive behaviors in FTD.9
  • Hyperorality or dietary changes: An increased predilection for sweets occurs frequently but is nonspecific (and observed in other neurodegenerative disorders); more specific to bvFTD are impaired satiety and hyperphagia, both symptoms that develop as result of atrophy involving the right ventral insula, striatum, and orbitofrontal cortex. Habits such as binge eating or increased consumption of alcohol or cigarettes may develop. Consequently, patients have frequently been observed to exhibit weight gain in the earlier stages of the disease. In addition, there may be an alteration in food preferences and attempted consumption of inedible objects.
  • Neuropsychological deficits that are predominantly executive in nature, sparing episodic memory and visuospatial function: Cognitive symptoms reflect prominent executive dysfunction with relative sparing of memory and visuospatial function, which are more often affected in AD.8 Specific cognitive deficits are found on frontal-based tasks such as attention, working memory, set shifting, mental flexibility, response inhibition, problem solving, and abstract reasoning.10 Poor attention often manifests as distractibility and impulsiveness. Studies have further shown that letter fluency (eg, generation of words beginning with a certain letter within a 1-minute time frame) is a particularly effective way to distinguish bvFTD from AD. Such frontal lobe dysfunction will result in a patient who is unable to engage in complex decision-making or problem solving, resulting in an inability to partake in complicated tasks.
  • Imaging results indicating structural or functional abnormalities within the frontotemporal lobes: The presence of either frontotemporal atrophy (Figure 1) on brain magnetic resonance imaging or frontotemporal hypometabolism on fluorodeoxyglucose positive emission tomography may further be used to support a diagnosis of bvFTD. The atrophy pattern that is most commonly associated with bvFTD involves the anterior cingulate and frontoinsular cortex5 (Figure 2). A diagnosis of definitive bvFTD requires postmortem neuropathological confirmation.

From the perspective of the psychiatrist, accurate recognition of FTD is particularly challenging due to overlap in age of onset (eg, <65 years) as well as shared neuropsychiatric symptoms of disinhibition, apathy, stereotyped movements that may be seen as other psychiatric conditions including depression, bipolar disorder, and obsessive-compulsive disorder. In addition, patients with bvFTD may present with increased consumption of food and alcohol,3 thus complicating distinguishing this neurodegenerative process from patients with dual diagnosis. Features that may be helpful in differentiating bvFTD from an Axis I psychiatric disorder include (1) mid-life age-at-onset of behavioral symptoms, (2) progressive cognitive decline and impairment in executive dysfunction on neuropsychological testing, (3) focal frontotemporal cerebral atrophy or hypometabolism on neuroimaging, and (4) family history of FTD.

Furthermore, patients with FTD suffer significant decline, compromising social and occupational function.3,8

Primary Progressive Aphasia

Primary progressive aphasia (PPA) was first described by the behavioral neurologist, Marcel Mesulam, who defined a clinical syndrome characterized by progressive language decline over 2 years with relative preservation of memory and visuospatial function. Recent clinical observations have demonstrated that PPA is a disorder with heterogenous pathologies including both FTLD and Alzheimer's-specific findings.11 The PPA cases resulting from FTLD pathology include two distinct clinical phenotypes: progressive nonfluent/agrammatic variant and semantic variant of PPA.

Nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) is a progressive, primary language disorder resulting from motor speech dysfunction and characterized by effortful, nonfluent speech.12 There is a female predominance for nfvPPA.6 In contrast to bvFTD, patients with nfvPPA have relative sparing of social comportment. However, it should be noted that neuropsychiatric symptoms in these patients are not emphasized in the diagnostic criteria for nfvPPA, but have been increasingly recognized by clinicians. Depression, irritability, and apathy are particularly common in nfvPPA, possibly related to relatively retained insight. Early in the disease course, patients initially develop frustrated, effortful speech with shortened phrase lengths. In addition to effortful speech, the other key clinical feature is agrammatism, with omissions of articles and other syntactic words, leading to speech sometimes being described as telegraphic.12 Patients further exhibit apraxia of speech, a motor impairment resulting in an inability to accurately produce sounds secondary to impaired planning or programming of speech movements. Consequently, pronouncing complex words such as “catastrophe” or “huckleberry” is challenging in this patient population. Comprehension is relatively spared compared to speech production, yet patients may struggle to interpret syntactically complex sentences.12 Over time, there is progressive deterioration of language leading to mutism. This condition localizes within the left-hemispheric prefrontal-perisylvian region of the cerebral cortex12 (Figure 3). Neuropsychological testing reveals primary expressive language impairment, but may also show minor working memory and executive deficits.11 At autopsy, nfvPPA is frequently associated with FTLD-tau pathology. Of all the FTD variants, nfvPPA has the strongest association with extrapyramidal symptoms, progressing in certain instances to either progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS) (described below).


The nonfluent/agrammatic variant of primary progressive aphasia leads to dominant (left) hemispheric atrophy involving the inferior frontal gyrus (red arrowhead) and insular cortex (blue arrow). Courtesy and used with permission of Suzee Lee, MD (University of California, San Francisco Memory and Aging Center).

Figure 3.

The nonfluent/agrammatic variant of primary progressive aphasia leads to dominant (left) hemispheric atrophy involving the inferior frontal gyrus (red arrowhead) and insular cortex (blue arrow). Courtesy and used with permission of Suzee Lee, MD (University of California, San Francisco Memory and Aging Center).

Semantic Variant Primary Progressive Aphasia

Compared to nfvPPA, svPPA is a relatively fluent aphasia localizing to the left anterior temporal pole resulting in patients presenting with early symptoms of word-finding difficulty. Patients may have initial problems coming up with the specific words such as “pomegranate,” substituting more vague, categorical terms such as “fruit” in its place.5 Over time, there is progressive loss of word meaning and single-word comprehension. Thus, patients not only struggle with naming an object such as “pencil,” but also lose any semantic knowledge relating to the object. Family members may also witness confusion on the use of simple objects such as a pen due to this fund of knowledge loss.

svPPA most commonly results in neurodegeneration of the anterior temporal lobes in which asymmetric atrophy is more pronounced in the left hemisphere in about three quarters of cases13 (Figure 4). However, the disease may progress to the right anterior temporal lobe or in rare cases originates within the right hemisphere. In such instances, presenting symptoms will have more of a behavioral quality consisting of emotional detachment, lack of empathy, strict routines, food fads, clock watching, and/or dieting. In addition, cognitive symptoms of prosopagnosia (impaired facial recognition) relating to both acquaintances as well as celebrities may be observed.14 At autopsy, svPPA is frequently associated with FTLD-TDP pathology.15


The semantic variant of primary progressive aphasia is characterized by left greater than right atrophy of the anterior temporal pole and amygdalae (blue arrow). Courtesy and used with permission of Suzee Lee, MD (University of California, San Francisco Memory and Aging Center).

Figure 4.

The semantic variant of primary progressive aphasia is characterized by left greater than right atrophy of the anterior temporal pole and amygdalae (blue arrow). Courtesy and used with permission of Suzee Lee, MD (University of California, San Francisco Memory and Aging Center).

Motor Symptoms

In addition to cognitive and behavioral impairment, FTD may result in motor neuron and extrapyramidal disease. Approximately 10% to 15% of patients with bvFTD will develop amyotrophic lateral sclerosis (ALS) and experience dysphagia, dysarthria, limb weakness, or loss of dexterity.16 Respiratory weakness and impaired swallowing are frequently life-limiting manifestations. ALS is almost exclusively found in bvFTD and only in rare instances has it been described in nfv-PPA and svPPA. In a separate group of patients with bvFTD or PPA, Parkinsonian symptoms may develop, including tremor, rigidity, slowness, or imbalance. The nfvPPA of FTD can evolve into “Parkinson plus” syndromes of PSP and CBS.5 Whereas Parkinson's disease presents with tremor and limb rigidity, PSP is classified as an atypical parkinsonian condition characterized by axial ridigity with relative sparing of the limbs. In addition, patients experience disruption in vertical eye movements, increased falls, and pseudobulbar palsy. CBS presents with asymmetrical parkinsonism, limb dystonia, ideomotor apraxia, myoclonus, and in certain instances, alien limb phenomenon (involuntary movements of an affected limb).

Management of Frontotemporal Dementia

In this section, we outline a pragmatic and rational approach to management of psychiatric symptoms in patients with FTD based on the existing literature and our clinical experiences. We begin with a discussion of general management principles followed by a review of the literature on both pharmacological and nonpharmacological interventions for commonly observed psychiatric symptoms in this patient population.

Although profiles of behavioral symptoms are helpful in defining each of the FTD syndromes, the psychiatric manifestations of these clinically heterogeneous conditions frequently overlap in clinical practice. Furthermore, clinical phenotypes may demonstrate evolution over time; for example, patients initially meeting diagnostic criteria for nfvPPA frequently evolve into a CBS or a PSP presentation, both of which are associated with a different set of neuropsychiatric symptoms. From a pragmatic standpoint, we suggest approaching treatment of the individual psychiatric symptom rather than according to the FTD clinical syndrome.

There is currently a paucity of research specifically investigating treatment of psychiatric symptoms in FTD. A recent systematic review17 found only nine randomized controlled, double-blinded clinical trials investigating medications for treatment of behavioral and/or cognitive symptoms in FTD patients. Similarly, reviews of randomized controlled trials of nonpharmacological interventions yield limited conclusive data.18 In part, the lack of data may reflect the heterogeneous factors influencing manifestation of behavioral symptoms in FTD, limiting the ability to study interventions on a broader scale and also signaling the need for an individualized approach to symptom management in FTD.

Nonpharmacological Interventions

Nonpharmacological interventions should be the cornerstone of management of psychiatric symptoms in FTD, with drug therapy serving an adjunctive role or reserved for refractory or dangerous symptoms.18 Not only is there more risk associated with pharmacological therapies, but literature suggests that nonpharmacological interventions are comparable to, if not more efficacious for management of psychiatric symptoms in patients with dementia.18 Ideally, a multidisciplinary approach should be used that involves a physician or advanced practice provider, occupational therapists, speech-language pathologists, social workers, and other specialists experienced with FTD to meet individuals' needs.18 The most effective interventions often entail creative yet simple solutions based on careful observation with an emphasis on environmental modifications, communication strategies, and caregiver education. Theoretical models to inform strategies for such interventions in dementia include the Unmet Needs Model and the Progressively Lowered Stress Threshold (PLST) model. The Unmet Needs model postulates that problematic behaviors arise due to patients' diminished capacity to communicate new needs that arise with changes in functionality occurring with disease progression.18 The PLST model proposes that behavioral problems in dementia are a result of environmental demands exceeding a patient's cognitive abilities to cope.18

Pharmacological Interventions

Strategies for pharmacologic intervention largely seek to address neurotransmitter deficiencies in FTD. Evidence from autopsy, cerebrospinal fluid, and neuroimaging studies indicate a prominent and relatively selective serotonergic deficit.19–21 Accordingly, serotonergic drugs are the best studied and most widely used medication class in FTD, although robust clinical trial data are limited. The only serotonergic drug showing positive results in a double-blind, placebo-controlled trial is trazodone at a dose of 300 mg in 26 patients with bvFTD.17 Several selective serotonergic reuptake inhibitors (SSRIs) including fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram have been studied in FTD, but only paroxetine has been examined in randomized, controlled trials, which have yielded conflicting results.19,20,22–24 From a theoretical standpoint, SSRIs with a relatively specific serotonergic effect, such as citalopram, may be preferable due to the relative preservation of noradrenergic and cholinergic systems in FTD.20

Evidence for dysfunction of the dopaminergic system in FTD19–21 has prompted investigation of the use of stimulants in FTD, particularly to address symptoms of apathy.17 There is suggestion that methylphenidate may reduce risk-taking behavior in eight patients with bvFTD from a laboratory-based study19 and a small randomized-controlled trial of eight patients with bvFTD demonstrated behavioral improvement with dextroamphetamine in comparison to quetiapine.17 Although patients in both studies tolerated the medications well, more data about the safety of stimulants in FTD patients are needed before clinical recommendations can be made.

Dopaminergic deficits in FTD also limit the usefulness of antipsychotic medications, as patients with FTD appear to be exceptionally sensitive to extrapyramidal side effects.21 Although they are sometimes necessary for treatment of more difficult or dangerous behaviors, neuroleptics should be used with great caution in this population.

In contrast to AD, the cholinergic system is relatively preserved in FTD. Although cognitive enhancers such as donepezil, galantamine, and memantine are commonly used in patients with bvFTD,17 they have failed to demonstrate benefit in FTD patients and, in some cases, may worsen behavioral and/or cognitive symptoms.17, 22

Addressing Caregiver Burden

In addition to relieving symptoms for patients, therapeutic interventions in dementia should also aim to relieve caregiver burden. Caregiver interventions have been shown to both increase caregiver quality of life and postpone institutionalization of patients with FTD.25 Caregiving in FTD is uniquely challenging due to a combination of factors including the prominence of behavioral changes, patients' lack of insight, relatively early onset of disease, financial challenges related to young patient age, lack of public awareness and delayed diagnoses,26 as evidenced by higher levels of caregiver distress, depression, and burden in comparison to caregivers for AD.27 Arriving at a correct diagnosis is an essential first step for allowing caregivers to understand, accept, and adapt to the behavioral changes occurring in their loved one.25 Unfortunately, the diagnosis of FTD is often delayed, with a mean interval of 3.6 years between symptom onset and diagnosis, as many of the early symptoms are initially attributed to marital problems or primary psychiatric disorders.28 Education is also an important tool for empowering caregivers and reducing their distress. Programs providing caregivers training in strategies for behavioral management have been demonstrated to improve behavioral symptoms and caregiver outcomes.18,26

Symptom-Specific Treatment Strategies

Disinhibition and impulsivity. Social dysfunction resulting from these symptoms can be a major source of caregiver distress.25 Strategies for mitigating public embarrassment include limiting outings to places where the patient is well-known and providing an explanatory letter for caregivers to carry in public.26 Case reports have also demonstrated success in reducing disinhibition and inappropriate behaviors by introducing old hobbies or tasks that use the preserved procedural memory in patients with bvFTD, such as knitting.18 These symptoms also create serious concerns about safety, financial, and occupational risks. A home safety evaluation, environmental modifications, and removal of access to items such as motorized vehicles, credit cards, or mail are important measures to consider in all patients exhibiting such symptoms.18

There is suggestion that bolstering serotonergic systems may improve disinhibition in FTD studies. A randomized, placebo-controlled study of 12 patients with bvFTD indicated a positive physiologic response to a single dose of 30 mg of citalopram resulting in improved response inhibition on a laboratory-based task.24 Open-label studies have demonstrated decreases in symptoms of disinhibition with SSRIs including citalopram,20 fluoxetine, sertraline, and paroxetine.22 Limited evidence also suggests that stimulants such as methylphenidate and dextroamphetamine may be helpful for improving response inhibition, although more data are needed.17

Apathy. Apathy affects nearly all patients with FTD at some point in their illness29 with major consequences on caregiver burden26,27 due to increased physical care needs26 and the emotional effect of having a loved one become disengaged and disinterested. Paradoxically, apathy is also positively correlated with disinhibition, impulsivity, and other difficult to manage behaviors.30

Acceptance of a patient's apathy enables caregivers and family members to explore different activities that allow for more passive participation by the patient, avoiding the frustration that results for both parties by maintaining expectations of prior activity levels.31 Offering limited choices and telling rather than asking may also facilitate more participation by patients in activities. For example, rather than asking the patient if they would like to take a walk, it may be more effective to take them by the hand and say, “Let's take a walk.”26 Structured activities and routine are also more likely to keep patients active and engaged. Use of dietary or monetary rewards may be effective for encouraging certain desired behaviors.18

Frontosubcortical dopaminergic dysfunction has been postulated as a major component underlying apathy. Accordingly, the limited research on pharmacologic interventions for FTD in apathy has focused on targeting the dopaminergic system. The only recent pharmacological trial showing significant improvement of apathy in individuals with FTD suggested a beneficial effect of agomelatine, a structural analog of melatonin that increases prefrontal dopaminergic and adrenergic tone.32 The efficacy of stimulants such as dextroamphetamine for apathy in FTD remains primarily theoretical, and clinical use needs to be weighed against potential cardiovascular side effects.17

Loss of empathy. Loss of empathy is a devastating symptom for loved ones of FTD patients, as patients appear to become cold-hearted and uncaring toward others.9 Loss of empathy results in part from an impaired ability to accurately recognize and interpret facial emotional cues (particularly in semantic and bvFTD) and may also be due to dysfunction of complex frontal-based cognitive processes. This symptom is perhaps the most difficult FTD symptom to treat. Therefore, many interventions focus on providing psychological support and education to caregivers and family members. Given the unique challenges of FTD caregiving in comparison to more common dementia syndromes, support groups for caregivers should be specific to FTD. Caregivers may also benefit from grief counseling, as behavioral and emotional dysfunction in patients with FTD often causes caregivers to feel as though they have lost their loved one.9,33

Minimization of environmental distractions (eg, reducing noise, simplifying social situations) may help enhance a patient's ability to respond to salient emotional cues.18 Development of communication strategies by speech-language pathologists or other providers experienced with FTD may also help caregivers adapt to deficits in emotional expression resulting from primary language impairments in all forms of FTD including PPA.34

Compulsive behaviors. Caregivers should be counseled to accept or ignore compulsive behaviors that are not problematic, as performance of these actions may contribute to a sense of purpose for the patient. Some compulsions may be transformable into a useful activity, such as folding laundry over and over. For compulsions that are more troublesome, distraction can be a simple but effective strategy to abort behaviors. Another strategy is to encourage substitution of a more benign behavior in place of problematic compulsions; for example, by providing a squeeze ball to replace compulsions to touch strangers.18

As with obsessive-compulsive disorder, serotonergic deficits are speculated to underlie compulsive behaviors in FTD22, 29 and treatments have similarly targeted serotonergic augmentation. Open-label studies of SSRIs have suggested efficacy of sertraline and fluvoxamine in decreasing stereotypical and compulsive motor behaviors in FTD.22,35 Behaviors in three bvFTD patients responded well to treatment with clomipramine, a tricyclic antidepressant with predominantly serotonergic properties.22

Irritability, agitation, and aggression. Nonpharmacological strategies that have been shown to reduce aggression in FTD patients include avoidance of triggers, identification of unmet needs, and environmental adjustments based on individual patients' strengths and deficits.18 Frustration over communication difficulties may result in irritability being the prominent psychiatric symptom of patients with PPA and may be improved with speech-language therapy, communication augmentation, and caregiver communication strategies.34

Serotonergic medications may be helpful in reducing agitation that is refractory to nonpharmacological interventions. In a randomized-controlled trial, trazodone resulted in substantially reduced agitation and aggression in FTD patients.17 Preliminary evidence also suggests efficacy of citalopram for these symptoms.20 Although atypical antipsychotics appear to be effective for decreasing agitation in FTD,19,36 their use should be reserved only for management of more severe, refractory behaviors due to the risk of extrapyramidal side effects and increased mortality in elderly patients.21 When neuroleptic use is necessary, atypical antipsychotics with minimal D2 receptor antagonism such as quetiapine may be preferred.21 Literature regarding use of specific antipsychotics in FTD is particularly scant. One open-label study of 17 FTD patients demonstrated reduction in behavioral symptoms including irritability and social misconduct with olanzapine at an average dose of 5 to 10 mg daily, with a good safety and tolerability profile.19 In one case series, quetiapine at a dose of 250 mg every morning plus 500 mg every night decreased agitation in 3 of 3 patients with FTD but failed to show significant behavioral benefits at a dose of 75 mg twice per day in a double-blind crossover trial of eight patients with FTD.17,19 Evidence for use of aripiprazole or risperidone is limited to a handful of case reports.22

Mood stabilizing antiepileptic medications may be another strategy for these symptoms. There is one case report of a patient with FTD with severe aggression refractory to numerous medications who had a striking positive response to lamotrigine.37 Lamotrigine appears to be safe and well-tolerated for elderly patients with dementia based on a few small studies.38) Valproic acid reduced agitation in an open-label study of three patients with FTD but has failed to show significant benefit in larger placebo-controlled studies of dementia patients.19,39

Furthermore, its safety and side-effect profile must be weighed against any potential benefit. The potential for weight gain with valproic acid or antipsychotics such as olanzapine must also be considered, as patients with FTD are already at risk for obesity and metabolic syndrome related to the hyperphagia and physical inactivity due to apathy.

Depression and anxiety. Symptoms of depression and anxiety appear to be common in all types of FTD.40 There is sparse literature on nonpharmacological interventions for mood disturbances, perhaps due to the hindrance of traditional psychotherapeutic interventions by the cognitive deficits of FTD. Although cognitive behavioral therapy (CBT) in dementia has been considered, a randomized-controlled trial assessing CBT for anxiety in dementia demonstrated no measurable effect.18 Serotonergic medications such as citalopram and trazodone appear to be helpful in reducing symptoms of depression or anxiety in FTD.17,20

Conclusion

FTD is a complex set of neurodegenerative disorders characterized by cognitive and behavioral decline. Due to the early onset of this dementia and the prominence of neuropsychiatric symptoms, it is expected that most behavioral health providers will eventually be faced with the diagnosis and management of these conditions. The key historical and clinical elements that would be more suggestive of frontotemporal degeneration rather than a psychiatric condition includes middle age onset, progressive cognitive decline, family history of similar processes, abnormal neuropsychological profile, and regional atrophy within the frontotemporal lobes. Once FTD has been confirmed, we have outlined a symptom-based therapeutic method that begins with a nonpharmacological approach focusing on behavioral interventions for both the patient and caregiver. Pharmacological-based strategies consist of using many of the available treatments for psychiatric conditions, including SSRIs and neuroleptics (Table 1). Although there is a paucity of class I/II data supporting the use of these agents in FTD, it is our practice to initiate patients on an SSRI as a result of the prominent serotonin deficit followed by a neuroleptic for refractory behavioral symptoms. Further clinical trials are necessary to better inform an evidence-based therapeutic approach toward neuropsychiatric symptoms in this unique set of neurodegenerative disorders.


Evidence-Based Pharmacotherapy for Behavioral Symptoms Associated with Frontotemporal Dementia
Evidence-Based Pharmacotherapy for Behavioral Symptoms Associated with Frontotemporal Dementia

Table 1.

Evidence-Based Pharmacotherapy for Behavioral Symptoms Associated with Frontotemporal Dementia

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Evidence-Based Pharmacotherapy for Behavioral Symptoms Associated with Frontotemporal Dementia

SymptomMedicationsDoseStudy DesignPatientsResult
Disinhibition and impulsivitySSRIs   Citalopram   Sertraline   Fluoxetine   Paroxetine Stimulants   Methylphenidate   Dextroamphetamine20–40 mg/day 30 mg (single dose) 50–125 mg/day (mean 75 mg/day) 20 mg/day 20 mg/day 50–125 mg/day (mean 75 mg/day) 20 mg/day6-week open-label study Laboratory-based, randomized controlled study 3-month open-label study Laboratory-based study Randomized, double-blind crossover study15 FTD patients (12 bvFTD, 2 PPA, 1 SD) 12 bvFTD patients 5 FTD patients 5 FTD patients 1 FTD patient 8 FTD patients 8 FTD patientsDecreased NPI-D (F = 4.030, P= .029) and FBI-D (F = 7.138, P= .003) scores20Improved response inhibition24Disinhibition improved in 67% of patients (per CGI change scale)41Reduced risk-taking behavior43Mean NPI-D scores decreased 2.4 points47
ApathyAgomelatine Dextroamphetine50 mg/day 20 mg/dayRandomized, double-blind crossover study Randomized, double-blind crossover study24 bvFTD 8 FTD patientsDecreased NPI-A (P= .002) and NPI-A-distress (P= .02) scores; improved AES-C scores (P= .006)32Mean NPI-A scores decreased 2.8 points47
Compulsive behaviorsSSRIs   Sertraline Fluoxetine   Paroxetine   Fluvoxamine Clomipramine50–100 mg/day 50–125 mg/day (mean 75 mg/day) 20 mg/day 20 mg/day 50–150 mg/day (mean 110 mg/day) 20–175 mg/day6-month open-label study 3-month open-label study 12-week open-label study Case series8 FTD patients with stereotypical movements 5 FTD patients 5 FTD patients 1 FTD patient 16 FTD patients 3 FTD patientsMean AIMS scores decreased 4.38 points (P< .01)23Compulsions improved in 57% of patients (per GCI change scale)41Mean SRI scores decreased 12 points (P= .002)41,44Improved compulsive behaviors41
Irritability, agitation, aggressionTrazodone Citalopram Atypical antipsychotics   Quetiapine   Olanzapine   Risperidone Mood stabilizers/antiepileptics   Lamotrigine   Divalproex sodium150–300 mg/day 20–40 mg/day 250 mg every morning plus 500 mg every night 2.5–10 mg/day (mean 4.42 mg/day) 1 mg BID 100 mg/day (titrated up from 25 mg/day) 1,125 mg/dayRandomized, double-blind, placebo-controlled crossover study 6-week open-label study Open-label case series 24-month open-label study Open-label case series Case report Open-label case series16 FTD patients 15 FTD (12 bvFTD, 2 PPA, 1 SD) 3 FTD patients 17 FTD patients 3 FTD patients 1 FTD patient 3 FTD patientsDecreased NPI irritability and aggression scores48Decreased NPI irritability scores (F = 7.497, P= .0025)20Decreased agitation in all three patients45Decreased NPI irritability (P< .01) andBEHAVE-AD scoress (P< .05)46Decreased agitation in one patient45Decreased agitation37Decreased agitation in all three patients45
Depression and anxietySSRIs   Citalopram Sertraline   Fluoxetine   Paroxetine Trazodone20–40 mg/day 50–125 mg/day (mean 75 mg/day) 20 mg/day 20 mg/day 150–300 mg/day6-week open-label study 3-month open-label study Randomized, double-blind, placebo-controlled crossover study15 FTD patients (12 bvFTD, 2 PPA, 1 SD) 5 FTD patients 5 FTD patients 1 FTD patient 16 FTD patientsDecreased NPI depression scores (F = 3.467, P= .045)20Depression improved in 64% of patients (per CGI change scale)41Decreased NPI depression scores48
Authors

Jamie Starks, MD, is a Clinical Fellow, University of California, San Francisco, Memory and Aging Center. Michael Rosenbloom, MD, FAAN, is a Clinical Director, HealthPartners Center for Memory and Aging; and the Department Chair, HealthPartners Neuroscience Center – Neurology.

Address correspondence to Michael Rosenbloom, MD, FAAN, 401 Phalen Boulevard, Mail Stop, 41104C, Saint Paul, MN 55130; email: Michael.H.Rosenbloom@HealthPartners.com.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/00485713-20170411-01

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