Association for Frontotemporal Dementias

Treatment

DISEASE MODIFYING TREATMENTS

There are no treatments approved by the Food and Drug Administration (FDA) for FTD at present.  Research is leading to greater understanding of the molecular basis of disease and informing new strategies for the development of potentially disease modifying treatments.  Advances are being made in the design of clinical drug trials in FTD and the first drug studies are now becoming available.

SYMPTOMATIC TREATMENTS

Although currently no medication will prevent, slow decline or cure FTD, many of the symptoms can be treated.  Both pharmacologic and behavioral interventions are available for symptomatic benefit of specific cognitive and behavioral features.

In practice, clinicians do best by families if it is clear to the primary caregiver what target symptom any prescribed drug is meant to treat. Such clarity helps to manage expectations and facilitates the family’s understanding of whether the clinician is attempting to treat a symptom that is directly related to FTD (e.g., obsessive-compulsive behaviors) or that is a responsive behavior (e.g., patient is bored and seeking stimulation). Educating the caregivers in this way helps them to be better partners in monitoring the medications for their effects.

A limited number of open-label studies and placebo controlled studies have researched the use of psychiatric, Alzheimer’s and other medications in FTD (Boxer and Boeve, 2007; Huey et al., 2006).  While pharmacological intervention is expected to improve with advancing research, existing agents can be used to address symptoms and contribute to patient and caregiver quality of life (Jicha and Nelson, 2011).

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors (SSRIs), other antidepressants and antipsychotics have all been studied in FTD (Boxer and Boeve, 2007; Huey et al., 2006).  Specialists have the most experience with the selective serotonin reuptake inhibitors including sertraline and trazodone.  SSRIs are often useful treating a wide range of behavioral symptoms in FTD including apathy, depression, agitation, anxiety and obsessive compulsive behaviors. These agents are considered relatively safe in the dementia population.  Nuedexta has gained popularity as a treatment for emotional lability, but definitive studies regarding its use in FTD are lacking.

Antipsychotic agents

Aggressive and agitated behavior can be difficult to treat, and are problematic for caregivers.  Antipsychotic medications should be avoided when possible due to the increased mortality, stroke and cardiac complications of these medications in (elderly) dementia patients.  The risk of these life threatening complications in our younger FTD patients is not known but florid psychotic features and other safety-related behaviors that do not respond to SSRIs require the use of this class of agents.  However, other serious adverse responses may also occur.  Similar to patients with other non-AD dementias, FTD patients may be overly sensitive to adverse responses with these agents, especially those involving motor functioning (parkinsonism and tardive dystonia).

Clinicians must weigh the pros and cons of using neuroleptics in general, which class to use (typical and atypical), and which specific agent to use at which dose. There are no evidence-based analyses to assist the clinician in making these decisions.  Side-effects (sedation, parkinsonism, tardive dyskinesia) are far more common in the typical neuroleptics, but this class and specifically haloperidol may be a reasonable choice if cost associated with medication use is a major concern. Most clinicians nowadays use the atypical neuroleptics as they tend to be better tolerated, have reasonable efficacy (based purely on anecdotal experience) and are not cost-prohibitive for most patients/families. The usual dictum is critical: “start low and go slow” when any medication in the antipsychotic class is commenced and titrated upward as necessary and tolerated.

Cholinesterase inhibitors

Several medications are approved for symptomatic treatment of the cognitive symptoms of AD.  These are sometimes prescribed, off label, for FTD patients. Cholinesterase inhibitors provide temporary stabilization or modest improvement in attention/memory, activities of daily living and global functioning in AD because AD patients have reduced CNS acetylcholine levels. FTD patients do not have cholinergic loss, however, these agents may help temporarily stabilize cognitive symptoms, including aphasic symptoms, apathy and executive functioning. Although cholinesterase inhibitors help with behavioral symptoms (including apathy) in AD, FTD patients may have adverse responses, including worsening impulsivity and disinhibition, so care should be taken in using these agents in FTD patients with prominent behavior problems. Many doctors prescribe these medications as a trial, especially when the etiology of disease is not definitive.

Cholinesterase inhibitors include donepezil (Aricept), rivastigmine (Exelon) and Galantamine (Reminyl and Razadyne).  There are differences in the route, timing and indications for cholinesterase inhibitors. Donepezil is indicated for all stages; the latter two agents are for mild to moderate symptoms.  Rivastigmine comes in a transdermal form, and there is an orally disintegrating form of donepezil.

These agents work by enhancing cholinergic function, so side effects include GI upset (nausea, vomiting, diarrhea, abdominal cramping, loss of appetite/weight loss).  Rivastigmine also inhibits butyrocholinesterase activity (present in the GI tract) so GI side effects are more common and severe.  Transdermal administration and strategic oral dosing (taking the medication with food) may help; however, since cholinesterase inhibition leads to increased GI motility, problems may still occur. Cholinesterase inhibitors also may cause bradycardia so they should be used with caution in those with cardiac sinus disease, cardiac conduction defects, or severe cardiovascular disease.   Donepezil may also cause vivid dreams/insomnia; sometimes early day dosing helps with this.

Memantine

The N-methyl-D-aspartate receptor antagonist memantine (Namenda) is the other FDA approved cognitive enhancer for AD.  However, research on the use of this drug in FTD using a placebo-controlled, double-blind approach has not shown it to be efficacious. Some studies suggest that this agent may actually have a detrimental effect on cognition in some individuals with FTD.  (Boxer, et al., 2013).

Aphasia, parkinsonism and motor neuron disease

Bromocriptine (Parlodel), has been used for aphasia, with occasional FTD subjects noting improved verbal fluency.  However, a single, small randomized, placebo control study did not demonstrate a benefit in the PPA patients. (Reed, et al., 2004) Unfortunately, parkinsonism in FTD is not very treatable. Patients are minimally responsive to L-DOPA (van Swieten, et al., 2010). However, a trial is usually worthwhile. Management of patients with FTD-ALS is particularly difficult because of non-compliance issues. The patient should be referred to an ALS specialty clinic.

Psychostimulant agents

Another class of medications that needs to be used with extreme caution for behaviors in FTD are the psychostimulant agents [e.g., methylphenidate (Ritalin), dextroamphetamine (Dexedrine), etc.]. Adverse outcomes are not rare and these drugs should be a last resort (Dolder, Davis and McKinsey, 2010).

SUMMARY

Since the medication management of this patient group is complicated, primary care physicians may want to refer FTD patients with behavior problems to academic centers specializing in FTD. Unfortunately, there are no medications that help with the poor judgment and inappropriate behaviors that are so common in FTD.  Behavioral strategies are an important aspect of managing these symptoms and are essential as a general alternative and /or supplement to medications.  Caregiver education is key. Caregivers should be referred to AFTD (www.theaftd.org [1]) for advice on available resources in their area.

KEY REFERENCES

Link to full article [2]
Boxer AL and Boeve BF. Frontotemporal dementia treatment: Current symptomatic therapies and implications of recent genetic, biochemical, and neuroimaging studies. Alzheimer Dis Assoc Disord. 2007 Oct-Dec. 21 (4) S79-S87.

Link to full article [3]
Boxer AL, Knopman DS, Kaufer DI, Grossman M, Onyike C, Graf-Radford N, Mendez M, Kerwin D, Lerner A, Wu CK, Koestler M, Shapira J, Sullivan K, Klepac K, Lipowski K, Ullah J, Fields S, Kramer JH, Merrilees J, Neuhaus J, Mesulam MM, Miller BL. Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2013 Feb; 12(2):149-56.

Link to full article [4]
Huey ED, Putnam KT and Grafman J. A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia. Neurology. 2006; 66:17-22.

Link to full article [5]
Jicha GA and Nelson PT. Management of frontotemporal dementia: targeting symptom management in such a heterogeneous disease requires a wide range of therapeutic options. Neurodegener Dis Manag. 2011 April; 1(2): 141–156.

UCSF Memory and Aging Center, Treatments and Trials http://www.memory.ucsf.edu/ftd/medical/treatment [6]

Also:

Dolder CR, Davis LN, McKinsey. Use of psychostimulants in patients with dementia. J.Ann Pharmacother. 2010 Oct;44 (10):1624-32.

Reed DA, Johnson NA, Thompson C, Weintraub S, Mesulam M, A clinical trial of bromocriptine for treatment of primary progressive aphasia. Annals of Neurology. 2004 Nov. 56 (5) 750.

van Swieten JC, Rosso SM, Heutink P. in: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2000 Nov 07 [updated 2010 Oct 26].)