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<p class="ltrs-br-ltr-br-title">Donepezil and Concurrent Sertraline Treatment Is Associated With Increased Hippocampal Volume in a Patient With Depression</p>
<p class="ltrs-br-ltr-br-body-text"><span class="bold">To the Editor:</span> Donepezil is a widely used acetylcholinesterase inhibitor that has been shown to slow the progress of cognitive impairment in patients with mild-to-moderate Alzheimer’s disease. We observed a case of refractory depression with a hippocampal volume reduction identical to that commonly observed in early-onset Alzheimer’s disease. Addition of donepezil in our case led to complete remission of depression that concurred with a robust increase in hippocampal volume. Herein, we report this intriguing case.</p>
<p class="ltrs-br-ltr-br-body-text">&nbsp;</p>
<p class="ltrs-br-ltr-br-body-text"><span class="bold-italic">Case report.</span> Ms A, a 44-year-old woman with a 4-year history of depression, was admitted for the second time to the University Hospital of the Hamamatsu University School of Medicine, Hamamatsu, Japan, in May 2007. Over the refractory course of the disorder, she had responded poorly to various treatments, including recommended maximum doses of paroxetine, clomipramine, lithium carbonate, and a combination therapy of paroxetine and olanzapine, as well as cognitive-behavioral therapy that was administered during her previous first hospitalization. At the current admission, she reported depressive mood with prominent anxiety, diminished interest/pleasure, slowness of thought, forgetfulness, loss of energy, inability to concentrate, and insomnia. She had no history of head trauma, seizure, or loss of consciousness. Results of her neurologic and medical examinations, laboratory tests, and electroencephalogram were all normal. She met the <span class="italic">DSM-IV-TR</span> criteria for major depressive disorder and scored 20 on the Hamilton Depression Rating Scale (HDRS).<span class="superscript">1</span> </p>
<p class="ltrs-br-ltr-br-body-text">At routine cognitive assessment, she was found to have deficits in global cognitive function, with an IQ of 67 based on the Wechsler Adult Intelligence Scale-Third Edition.<span class="superscript">2</span> An impairment of verbal episodic memory was also evident; on the Wechsler Memory Scale-Revised (WMS-R),<span class="superscript">3</span> immediate recall of logical memory was 13 (normal range, 17–31) and delayed recall of logical memory was 5 (normal range, 11–29). Since her IQ as assessed during her first hospitalization was 111, cognitive decline was apparent (a 40% decline in IQ).</p>
<p class="ltrs-br-ltr-br-body-text">Scanning with a GE Signa1 5-T magnetic resonance imaging (MRI) scanner (General Electric, Milwaukee, Wisconsin) revealed noticeable morphological changes, particularly in the hippocampal area, although no abnormality (ie, no atrophy in the hippocampus) had been noted on a routine MRI scan at Ms A’s first admission. On the basis of this finding, we performed volumetric analyses as described elsewhere.<span class="superscript">4</span> A marked hippocampal volume reduction was observed bilaterally, especially on the left (hippocampal volume [mL] adjusted for total intracranial volume [L]; left: 1.64 mL/L, right: 1.84 mL/L) (<span class="callout"><a href="#" onclick="createFigure('f1'); return false;">Figure 1A</a></span>, <span class="callout"><a href="#" onclick="createFigure('t1'); return false;">Table 1</a></span>). Although she did not meet standard criteria for Alzheimer’s disease (ie, National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association [NINCDS-ADRDA] criteria) owing to the presence of depression, her total hippocampal volume loss was identical to that of the early stage of Alzheimer’s disease.<span class="superscript">5</span> On the basis of Ms A’s salient cognitive deterioration, in particular impairment of verbal episodic memory, along with corresponding brain structure abnormalities, potential conversion to early-onset Alzheimer’s disease was suspected.<span class="superscript">6,7</span> Donepezil administration was thus initiated.</p>
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  <a href="#" onclick="createFigure('t1'); return false;"><img src="v71n0619t1.gif" alt="Table 1" id="t1" border="0" /></a>
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<p class="ltrs-br-ltr-br-body-text">In September 2007, treatment was started with donepezil at a dose of 10 mg/d. For Ms A’s depressive symptoms, sertraline was started in March 2007, titrated up to 150 mg/d during the current admission, and maintained throughout the donepezil challenge. Surprisingly, during the 2-month period of treatment with donepezil, her deficits in cognition were drastically alleviated (IQ<span class="thinspace"> </span>=<span class="thinspace"> </span>90; WMS-R immediate recall of logical memory<span class="thinspace"> </span>=<span class="thinspace"> </span>21, delayed recall of logical memory<span class="thinspace"> </span>=<span class="thinspace"> </span>14), in parallel with a clinically significant improvement in depression (HDRS score<span class="thinspace"> </span>=<span class="thinspace"> </span>10). Simultaneously, she achieved robust volume recovery in the bilateral hippocampus relative to the previous scan (left: 1.93 mL/L [+17.7%], right: 2.05 mL/L [+11.7%]) (<span class="callout"><a href="#" onclick="createFigure('t1'); return false;">Table 1</a></span>). She was discharged from the hospital.</p>
<p class="ltrs-br-ltr-br-body-text">In February 2008, the patient’s depressive symptoms were fully ameliorated (HDRS score<span class="thinspace"> </span>=<span class="thinspace"> </span>3), and further hippocampal volume recovery was noted on the follow-up MRI (left: 2.07 mL/L, right: 2.17 mL/L, corresponding to increases of 26.5% and 18.1%, respectively, relative to the first scan; <span class="callout"><a href="#" onclick="createFigure('f1'); return false;">Figure 1B</a></span>, <span class="callout"><a href="#" onclick="createFigure('t1'); return false;">Table 1</a></span>). No recurrence of depression was observed over the subsequent 16-week period.</p>
<p class="ltrs-br-ltr-br-body-text">&nbsp;</p>
<p class="ltrs-br-ltr-br-body-text">In the present case, the patient developed severe cognitive impairment and had a significant volume reduction of the hippocampus (&gt;<span class="thinspace"> </span>25% for the left); hence, she was suspected of having early-onset Alzheimer’s disease. However, after successful treatment with donepezil, which has previously been shown to merely slow the progress of cognitive impairment in Alzheimer’s disease, she achieved complete remission of cognitive impairment, hippocampal volume loss, and depressive symptoms. From such a recovery, it is concluded that all of the phenomena (the hippocampal volume loss and cognitive impairment) can be ascribed to depression (ie, pseudodementia<span class="superscript">8</span>). It is of note, however, that the depression-associated loss in hippocampal volume has previously been reported to be less than 19%,<span class="superscript">9</span> which the present case exceeded (ie, &gt;<span class="thinspace"> </span>25%). </p>
<p class="ltrs-br-ltr-br-body-text">A previous study reported that donepezil combined with antidepressant treatment temporarily, in the first few months of treatment, improves verbal episodic memory in <span class="italic">elderly</span> patients with depression plus cognitive impairment.<span class="superscript">10</span> Another study has demonstrated that donepezil monotherapy improves affective symptoms of patients with mild Alzheimer’s disease, whereas it shows no beneficial effect on cognitive dysfunction.<span class="superscript">11</span> To the best of our knowledge, there has, thus far, been no clinical report showing the ability of donepezil plus a selective serotonin reuptake inhibitor to reverse both hippocampal atrophy and considerable cognitive deficits. In the present case, such a combination treatment was found effective in treating depression with a volume loss in the hippocampus larger than previously reported and a substantial level of cognitive impairment identical to that in early-onset Alzheimer’s disease. </p>
<p class="ltrs-br-ltr-br-body-text">Our experience with the present case suggests that although further studies are needed to evaluate the effectiveness of donepezil per se in the treatment of depression, donepezil may have a beneficial effect in relatively young adults who have a severe and refractory course of depression along with salient cognitive impairment and a hippocampal volume reduction.</p>
<p class="ltrs-br-ltr-br-references-head"><span class="smallcaps">References</span></p>
<p class="references-references-text-1-9"> 1. Hamilton M. A rating scale for depression. <span class="italic">J Neurol Neurosurg Psychiatry</span>. 1960;23:56–62.<span class="bold"> </span></p>
<p class="references-references-text-1-9"> 2. Wechsler D. <span class="italic">Wechsler Adult Intelligence Scale-III</span>. San Antonio, TX: The Psychological Corporation; 1997.<span class="bold"> </span></p>
<p class="references-references-text-1-9"> 3. Wechsler D. <span class="italic">Wechsler Memory Scale-Revised</span>. New York, NY: Psychological Corporation; 1987.</p>
<p class="references-references-text-1-9"> 4. Sheline YI, Wang PW, Gado MH, et al. Hippocampal atrophy in recurrent major depression. <span class="italic">Proc Natl Acad Sci U S A</span>. 1996;93(9):3908–3913. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8632988&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1073/pnas.93.9.3908">doi:10.1073/pnas.93.9.3908</a></span></p>
<p class="references-references-text-1-9"> 5. Krasuski JS, Alexander GE, Horwitz B, et al. Volumes of medial temporal lobe structures in patients with Alzheimer’s disease and mild cognitive impairment (and in healthy controls). <span class="italic">Biol Psychiatry</span>. 1998;43(1):60–68. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9442345&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1016/S0006-3223(97)00013-9">doi:10.1016/S0006-3223(97)00013-9</a></span></p>
<p class="references-references-text-1-9"> 6. Barnes J, Whitwell JL, Frost C, et al. Measurements of the amygdala and hippocampus in pathologically confirmed Alzheimer disease and frontotemporal lobar degeneration. <span class="italic">Arch Neurol</span>. 2006;63(10):1434–1439. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17030660&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1001/archneur.63.10.1434">doi:10.1001/archneur.63.10.1434</a></span></p>
<p class="references-references-text-1-9"> 7. Rémy F, Mirrashed F, Campbell B, et al. Verbal episodic memory impairment in Alzheimer’s disease: a combined structural and functional MRI study. <span class="italic">Neuroimage</span>. 2005;25(1):253–266. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15734360&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1016/j.neuroimage.2004.10.045">doi:10.1016/j.neuroimage.2004.10.045</a></span></p>
<p class="references-references-text-1-9"> 8. Wells CE. Pseudodementia. <span class="italic">Am J Psychiatry</span>. 1979;136(7):895–900. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=453349&dopt=Abstract">PubMed</a></span></p>
<p class="references-references-text-1-9"> 9. Sheline YI. 3D MRI studies of neuroanatomic changes in unipolar major depression: the role of stress and medical comorbidity. <span class="italic">Biol Psychiatry</span>. 2000;48(8):791–800. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11063975&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1016/S0006-3223(00)00994-X">doi:10.1016/S0006-3223(00)00994-X</a></span></p>
<p class="references-references-text-10-99"> 10. Pelton GH, Harper OL, Tabert MH, et al. Randomized double-blind placebo-controlled donepezil augmentation in antidepressant-treated elderly patients with depression and cognitive impairment: a pilot study. <span class="italic">Int J Geriatr Psychiatry</span>. 2008;23(7):670–676. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=18088076&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1002/gps.1958">doi:10.1002/gps.1958</a></span></p>
<p class="references-references-text-10-99"> 11. Requena C, López Ibor MI, Maestú F, et al. Effects of cholinergic drugs and cognitive training on dementia. <span class="italic">Dement Geriatr Cogn Disord</span>. 2004;18(1):50–54. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15084794&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1159/000077735">doi:10.1159/000077735</a></span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Shiro Suda, MD, PhD</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Genichi Sugihara, MD, PhD</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Rie Suyama, MD</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Norio Mori, MD, PhD</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Nori Takei, MD, PhD, MSc</span></p>
<p class="ltrs-br-ltr-br-author"><a href="mailto:ntakei@hama-med.ac.jp" target="_blank">ntakei@hama-med.ac.jp</a></p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="bold-italic">Author affiliations:</span> Department of Psychiatry and Neurology (Drs Suda, Suyama, and Mori) and Research Center for Child Mental Development (Drs Suda, Sugihara, and Takei), Hamamatsu University School of Medicine, Hamamatsu, Japan; and Division of Psychological Medicine, Institute of Psychiatry, King’s College London, London, United Kingdom (Drs Sugihara and Takei). <span class="bold-italic">Potential conflicts of interest: </span>None reported. <span class="bold-italic">Funding/support:</span> None reported.</p>
<p class="ltrs-br-ltr-br-copyright-doi"><span class="doi">doi:10.4088/JCP.09l05101gry</span></p>
<p class="ltrs-br-ltr-br-copyright-doi"><span class="italic">© Copyright 2010 Physicians Postgraduate Press, Inc.</span></p>
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