Fluoxetine in Alzheimer's Disease with Severe Obsessive Compulsive Symptoms and a Low Density of Serotonin Transporter Sites

Introduction

Behavioral disturbances are important problems in the management of Alzheimer's disease (AD) and are major determinants of nursing home placement. A common behavioral disturbance associated with AD is agitation, which affects nearly three-fourths of patients and typically increases in severity as the disease progresses. Agitation often co-occurs with anxiety, delusions, and irritability [7]. Severe obsessive-compulsive symptoms are less frequently observed in AD patients. The obsessive behavior in Alzheimer disease patients may differ from classical obsessive-compulsive disorder insofar as the subjects are unaware of it while at the same time resisting change [6].

The pathophysiology underlying behavioral disturbances is not well understood. Recent advances in neuroimaging provide a means to investigate an involvement of serotoninergic neurons in the behavioral features of aging [8]. [I-123]-2 beta-carbomethoxy-3 beta-(4-iodophenyl) tropane (123I-beta-CIT) single photon emission computed tomography (SPECT) scanning is a method to detect changes in the serotonin transporter sites [4] [14] [15]. To our knowledge there are no data available demonstrating changes with beta-CIT SPECT at the serotonin transporter sites of AD patients with obsessive-compulsive symptoms.

In the present case report, we investigated whether changes in the serotoninergic system could be responsible for the severe compulsive symptoms in a patient with Alzheimer's disease. An involvement of the serotoninergic system was studied first with beta-CIT SPECT following fluoxetine treatment, and then a reassessment with beta-CIT SPECT was done to examine possible changes in transporter sites induced by fluoxetine treatment.

Abstract

The treatment of behavioral disturbances is particularly challenging in patients suffering from dementia. In an 80-year-old female patient with probable AD and severe obsessive and compulsive symptoms, we demonstrated a significant reduction in the density of serotonin transporter sites using 123I-beta-CIT SPECT. Treatment with fluoxetine for 6 months resulted in significant symptom relief and an increasing density of serotonin transporter sites when compared to the beginning of treatment. Therefore, this report provides evidence that fluoxetine is a treatment option for patients with AD and severe obsessive-compulsive symptoms and highlights the importance of the serotoninergic system.

Case

The patient, an 82-year-old woman, had a history of AD for 2 years according to DSM-IV criteria. With the increase of memory loss secondary to AD, she became increasingly obsessive and compulsive. The obsession consisted of remembering names of saints and the compulsion comprised excessive crying of her husband's name. Crying was present over the day. Four weeks before admittance, her symptoms worsened, resulting in an irresistible crying of names of other family members. It was very frightening and embarrassing for the patient. Even while taking her meal, the crying did not stop. Different benzodiazepines caused only short-term relief for 1 or 2 hours. She was treated unsuccessfully with various antipsychotics before her admittance to our hospital. An 8-week therapy with trazodone also did not improve the patient's symptoms.

After a 1-week washout period, she was treated with fluoxetine that was carefully titrated up to a therapeutic concentration of 60 mg within 9 weeks. Fluoxetine medication was continued for 4 months. An interruption of fluoxetine medication for 2 weeks resulted in a significant worsening of the compulsive symptoms, which improved after restarting with fluoxetine medication. Seven months after the beginning of fluoxetine treatment, our patient was free of obsessive and compulsive symptoms except for very short periods when a stressful situation appeared. Her score from the Yale-Brown Obsessive-Compulsive Scale dropped from 29 to 11. The Hamilton depression score was 9 prior to fluoxetine treatment and 7 six months after beginning fluoxetine treatment. Fluoxetine plasma levels were at a range of 96 ± 28.9 ng/ml. Fluoxetine was well tolerated by the patient. Gastrointestinal disturbances occurred at the beginning but disappeared thereafter and were not observed even at a dosage of 60 mg. Her Folstein Mini-Mental State Examination score increased from 17 to 19. Most of the cognitive domains assessed in an extensive neuropsychological examination either did not change during fluoxetine treatment or slightly improved, e. g., the delayed recall. Laboratory tests and electrocardiograms were normal. Electroencephalographic recordings did not change under fluoxetine treatment. Before and after 6 months of fluoxetine treatment, magnetic resonance imaging revealed cerebral atrophy that was most pronounced in the temporal lobe.

The availability of presynaptic serotonin transporters in the thalamus/hypothalamus and the midbrain/pons was measured using SPECT and 123I-beta-CIT, a long-acting ligand for serotonin and dopamine transporters [1]. The serotonin transporters were measured before we started fluoxetine treatment and again 6 months later. In order to obtain improved accuracy in the diagnosis of dementia, dopamine transporter binding in the striatum and the regional cerebral blood flow using [99mTc]-ECD as perfusion tracer were also investigated (Fig. [1]).

For the measurement of serotonin transporter binding, the values of circular, hand-drawn midline regions of interest with the highest count rates were added up. The average counts per pixel were calculated. Cerebellar activity was assumed to represent nonspecific binding of the tracer. Values of the cerebellar regions of interest in consecutive transverse slices were added up, and average cerebellar counts were calculated. The control group consisted of 5 healthy, non-demented, subjects matched for age (mean age in years 75.5 ± 4.3 SD).

The specific-to-nondisplaceable I123I-beta-CIT binding (V3″) in the thalamus/hypothalamus and in the midbrain/pons area was calculated in analogy to previously published beta-CIT SPECT studies [17].

Prior to the onset of fluoxetine treatment, the measurement of the serotonin transporter in the thalamus/hypothalamus revealed a significant lower ratio in the patient than in controls (2.74 vs. 3.24 ± 0.25, respectively). Serotonin transporter binding was reduced to 19 % of control values. Reassessment after 6 months treatment with fluoxetine treatment revealed a ratio that was not different from controls. In the midbrain/pons area, however, the patient's V3″ did not differ significantly from controls prior to fluoxetine treatment (2.56 vs. 2.63 ± 0.22; Fig. [1] B, C).

Image inspection of 123I-beta-CIT SPECT revealed a normal scintigraphic pattern of striatal tracer uptake in the patient (Fig. [1] D, E), which was confirmed by the data analysis.

Fig. 1 Transverse slices at the level of midbrain/pons [MP], thalamus/hypothalamus [TH], and striatum [S]. Decreased regional cerebral blood flow (rCBF) is shown in the temporal cortex bilaterally (A). A decrease in serotonin transporter [5-HTT] binding was seen at onset of symptoms (B) compared to controls (not shown). At follow-up, 6 months later, a relative increase of [5-HTT] binding is demonstrated (C). Normal dopamine transporter binding was found initially (D) and during follow-up (E).

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