Identifying and Managing Behavioral Disturbances in Those Living with Frontotemporal Dementia

Frontotemporal dementia (FTD) refers to a group of clinically, pathologically, and genetically heterogeneous neurodegenerative disorders characterized by progressive atrophy of the frontal or temporal lobes of the brain.¹ FTD is associated with 3 distinct clinical syndromes (ie, phenotypes): 1) behavioral variant frontotemporal dementia (bvFTD), 2) semantic variant primary progressive aphasia (PPA), and 3) nonfluent/agrammatic variant PPA.¹

The underlying pathology of FTD is diverse, and key molecular features linked to the clinical syndromes include abnormal accumulations of tau, TDP-43, and FUS proteins. In addition, sequence variations in 3 genes—C9orf72 (chromosome 9 open reading frame 72), GRN (progranulin), and MAPT (microtubule-associated protein tau)—along with other, less common genetic variants contribute to the phenotypic diversity of FTD, particularly its neuropsychiatric manifestations.¹

Neuropsychiatric Manifestations of FTD 

bvFTD diagnosis is based on established clinical criteria that include core behavioral features, such as disinhibition; apathy or inertia; loss of empathy or sympathy; perseverative, stereotyped, or ritualistic behaviors; and hyperorality or dietary changes. Language impairment is the hallmark feature of PPAs. PPA is associated with depression, apathy, agitation, anxiety, appetite change, and irritability. Neuropsychiatric symptoms (NPS) such as hallucinations and delusions are virtually absent in PPA. Nighttime behavior is not significantly associated with PPA.² These symptoms reflect the frontal lobe dysfunction characteristic of the syndrome and the overlap between cognitive and behavioral dysfunction across the FTD spectrum.²

A systematic and longitudinal assessment is essential to accurately characterize FTD behavioral and cognitive manifestations. This approach incorporates formal and nonformal tools and is critical for distinguishing FTD from phenocopy syndrome (ie, similar symptoms seen in bvFTD, but without the characteristic brain atrophy or other signs of neurodegeneration), primary psychiatric disorders, and other neurodegenerative conditions, such as Alzheimer disease. The emergence of late-onset psychiatric and behavioral symptoms, particularly when they evolve over time, is an important clue, and should prompt thorough evaluation for an underlying organic etiology. 

The “DICE framework” is a systematic approach that can be used for the evaluation of behavioral symptoms and includes the following:³

Describe (context, environment, patient and caregiver perspective, degree of distress)

Investigate (potential iatrogenic causes, pain, fear, boredom)

Create (a plan for intervention with a discrete follow-up time)

Evaluate (evaluate the intervention and plan continuation or withdrawal)

Formal assessment tools also play a critical role in the evaluation of behavioral symptoms. The Neuropsychiatric Inventory Questionnaire (NPI-Q) is widely used for global neuropsychiatric assessment. It offers both severity ratings and caregiver distress scores which enhance clinical understanding of symptom burden.⁴ The NPI-Q can be combined with tools that target specific symptom domains, such as the Geriatric Depression Scale, the Cohen-Mansfield Agitation Inventory, and the Brief Psychiatric Rating Scale.⁵ Neuropsychiatric manifestations in FTD often present as clusters of co-occurring symptoms.⁶ We highlight key abnormalities of these symptom clusters in this article, but a detailed discussion is beyond the scope of the article. 

Hyperactive Cluster

The hyperactive cluster includes agitation and aggression as the most commonly reported symptoms. Agitation is defined as an inappropriate and disruptive increase in activity; it may manifest as motor (eg, pacing, fidgeting, picking), verbal (eg, shouting, cursing, grunting), or affective (eg, anger, laughing, crying) symptoms. Aggression refers to verbal or physical actions that may cause or threaten harm to oneself or another (eg, physical assault, property damage, sexual harassment or assault, self-mutilation, suicidality) and includes physical acts as well as ideation and plan formation. 

Mood Cluster

The mood cluster most commonly presents as depression and apathy, particularly in individuals with bvFTD. The relationship between depression and FTD is complex due to the fact that depression may present as a risk factor, comorbidity, or consequence of the disease.⁷ Diagnosing depression in individuals with FTD is challenging due to overlapping symptoms, cognitive decline, reduced independence, and impaired communication ability. Several symptoms of depression (eg, reduced interest, low motivation, fatigue, impaired concentration) closely resemble core features of bvFTD, further complicating the diagnosis. Major depression may present with anhedonia (ie, the inability to experience joy or pleasure) in the absence of persistent sadness, which may be difficult to distinguish from apathy, a hallmark feature of bvFTD. Apathy (ie, a lack of goal-directed thought and behavior) is closely associated with increased caregiver burden, reduced functional independence, and worsening cognitive decline. Apathy is generally unresponsive to antidepressant treatment, whereas anhedonia may indicate an underlying depressive episode that could benefit from pharmacologic or psychotherapeutic intervention.⁴

Psychotic Cluster

Symptoms of psychosis, although less common in those with FTD compared with other neuropsychiatric clusters, can be disruptive to both patients and caregivers. The core features of the psychosis cluster include hallucinations, delusions, and delusional ideation. Patients may also exhibit internal preoccupation and disorganized thought processes. Certain types of delusions that are more characteristic of neurodegenerative dementias include delusions of infidelity, theft, or phantom boarders (the belief that an uninvited person is living in their home); misidentification delusions, including Capgras syndrome (the belief that an imposter has replaced a loved one) and Fregoli syndrome (the belief that a persecutor is disguising themselves as different people); and reduplicative paramnesia (the belief that a familiar location has relocated elsewhere).

Sudden onset or worsening of symptoms of psychosis should prompt evaluation for an acute medical cause of hyperactive delirium, such as infection, stroke, or metabolic disturbance. Visual or hearing impairment may exacerbate symptoms of psychosis in patients with FTD and should be addressed as part of a comprehensive management plan.

Management

Management of NPS requires a multidisciplinary approach which  emphasizes caregiver education and nonpharmacologic interventions to reduce symptom burden and minimize medication use. The Table below includes a summary of management options for NPS in individuals with FTD.

Nonpharmacologic strategies^8,9,15 include the following:

• Identifying and managing triggers
• Modifying the environment
• Treating underlying conditions
• Reviewing and discontinuing medications that may exacerbate symptoms
• Exploring alternative therapies and activities (eg, aromatherapy, animal-assisted therapy, exercise, music therapy, art therapy, reminiscence therapy)
• Providing caregiver education and support

Pharmacotherapy

Psychotropic medication use in individuals with FTD has substantial limitations^9,10 including the following:

• Limited efficacy in managing NPS 
• Adverse effects; all medications used to treat NPS are associated with increased risks of cognitive decline, falls, and serious cardiovascular events^10,11
• Significantly increased risk of death in people with dementia, prompting a black box warning from the Food and Drug Administration for antipsychotic medications
• Compounding of these risks with drug interactions

If nonpharmacologic interventions prove ineffective or if any of the previously described situations exists, then use of pharmacologic therapy may be warranted. Pharmacotherapy may be considered first-line treatment after a thorough risk/benefit assessment in the following situations:

• Substantial risk of harm to the patient or others due to psychosis or aggression
• Severe distress in the patient or caregivers
• Major depression with or without suicidal ideation

Specific medication recommendations for the treatment of NPS in individuals with dementia vary, but a consistent principle is the judicious use of psychotropics in older adults.

Key considerations include the following:

• Regular reassessment: these medications should not be prescribed indefinitely.
• Trial period and discontinuation: if no substantial improvement is observed after a 4-week trial at an adequate dose, the medication should be tapered and discontinued. 
• Antipsychotic tapering attempts should be made within 4 months of initiation.
• The guideline to “start low and go slow” to the target effective dose as tolerated should be followed.
• Before starting any new medication, current prescriptions and over-the-counter medications should be optimized and reviewed to minimize anticholinergic burden.

Agitation or Aggression

Identifying and addressing triggers for NPS, such as pain, infection, medication side effects, environmental changes, and boredom, is crucial. Pharmacologic intervention should be reserved for persistent, severe agitation unresponsive to nonpharmacologic strategies.

Treatment with selective serotonin reuptake inhibitors (SSRIs) (eg, citalopram) combined with psychosocial interventions may reduce agitation in individuals with mild cognitive impairment and moderate agitation, but they carry risk of cognitive decline and cardiac adverse effects. 

Antipsychotic medications offer modest benefits for agitation and aggression but increase mortality risk. Quetiapine has a potentially lower mortality risk compared with risperidone and haloperidol and should be considered only for cases of severe aggression posing a risk of harm, and used at the lowest effective dose for a short duration (with reevaluation at 8 weeks). 

Antiepileptic medications (eg, carbamazepine) have shown some efficacy in small studies,¹² require slow titration, and carry considerable drug interaction risks. Valproic acid is generally ineffective and poorly tolerated. Data on newer antiepileptics (eg, levetiracetam, lamotrigine) are lacking. Despite widespread use, benzodiazepines have limited evidence of benefit for NPS in those with FTD and are associated with cognitive decline and falls. 

Dextromethorphan-quinidine¹³ is approved for the treatment of pseudobulbar affect and has shown promise in reducing agitation in a clinical trial, offering a potential alternative to antipsychotics. However, falls and urinary tract infections were noted as side effects.

Depression

Depression is common in people with FTD, affecting ~33% of patients. The evidence supporting the efficacy of antidepressants for managing depression in patients with dementia is mixed. The use of antidepressants is warranted when major depression, especially with suicidal ideation, substantially affects quality of life. Low-dose SSRIs are recommended as a first-line treatment.¹⁴ Tricyclic antidepressants and SSRIs with strong anticholinergic properties, such as paroxetine, should be avoided due to potential adverse effects. 

Psychosis

Although episodes of psychosis are not as frequent as depression or agitation, they can still be distressing for individuals with FTD and their caregivers and may contribute to increased risk of institutionalization.

Reassurance and redirection are sufficient management strategies when symptoms are mild. The presence of hallucinations does not automatically necessitate treatment with antipsychotic medication. Reviewing current medications and reducing or discontinuing those that might exacerbate psychosis, such as sedatives or anticholinergics, should be considered. 

People with FTD are susceptible to adverse reactions to antipsychotic medications, especially extrapyramidal and behavioral side effects. However, atypical antipsychotics can improve psychiatric and behavioral symptoms in some peopAle with FTD. Therefore, potential risks and benefits of antipsychotics need to be assessed case-by-case.¹⁵

If symptoms are severe, dangerous, or distressing, a low-dose antipsychotic medication may be prescribed. The American Psychiatric Association only recommends treatment with antipsychotic medications for such cases and advises against using haloperidol as a first-line medication.¹⁶ Any antipsychotic medication should be tapered and discontinued once symptoms are controlled.

Conclusion

All types of FTDs are associated with substantial NPS, leading to distress for both patients and caregivers. It is vital to define and quantify each symptom to establish a baseline to assess the effectiveness of interventions. Nonpharmacologic interventions and caregiver education are the mainstay for most symptoms. Medications (eg, SSRI, atypical antipsychotics, other psychotropic medications) have limited efficacy and substantial side effects. Efforts should be made to use the smallest possible dose and discontinue medication when feasible. It is important to avoid concomitant medication use to help minimize side effects, especially cardiovascular events and associated mortality risk.