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Therapeutic effects of the selective serotonin noradrenaline reuptake inhibitor milnacipran on depressive symptoms in patients with Alzheimer's disease
Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 349–352
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p n p b p
Therapeutic effects of the selective serotonin noradrenaline reuptake inhibitor milnacipran on depressive symptoms in patients with Alzheimer's disease Katsuyoshi Mizukami a,⁎, Kimitaka Hatanaka b, Yoshiro Tanaka b, Shinji Sato c, Takashi Asada a a b c
Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, Tsukuba City, Japan Department of Psychiatry, Ishizaki Hospital, Ibaraki machi, Japan Department of Psychiatry, Tsukuba Memorial Hospital, Tsukuba City, Japan
a r t i c l e
i n f o
Article history: Received 26 September 2008 Received in revised form 26 December 2008 Accepted 26 December 2008 Available online 6 January 2009 Keywords: Alzheimer's disease Depression Milnacipran SNRI
a b s t r a c t To clarify the profile of depressive symptoms in major depressive episodes in patients with Alzheimer's disease (AD-MD), we compared AD-MD with major depressive disorder in non-demented elderly patients (MDD) matched for age, using the 17-item Hamilton Rating Scale for Depression (HAM-D17). In addition, to clarify which depressive symptoms of AD patients respond to treatment with the selective serotonin and noradrenaline reuptake inhibitor (SNRI) milnacipran, we compared the HAM-D17 average score and the score of each HAM-D item, the mini-mental state examination (MMSE) score, and GAF score according to the DSM-IV evaluation of ADMD patients at baseline and at the endpoint (12 weeks). Depressive mood, loss of interest in hobbies and social activities and anxiety (psychic) scored the highest in both AD-MD and MDD groups, while psychomotor retardation scored significantly higher in AD-MD, and insomnia and anxiety (somatic) significantly did so in MDD. We also found that depressive mood, suicidal tendency, loss of interest, psychomotor retardation, anxiety (psychic), gastrointestinal symptoms, general somatic symptoms, and hypochondriasis remarkably improved in patients of AD-MD treated with milnacipran. Our results suggest that in general the profiles of depression in AD-MD and MDD are similar, despite some different clinical features between both conditions. Our study also suggests that milnacipran is promising to treat a broad range of depressive symptoms in AD-MD patients. © 2008 Published by Elsevier Inc.
1. Introduction One of the peculiar clinical features of depressive state in elderly people is the association with dementia, such as Alzheimer's disease (AD). It is documented that around one fourth of patients with AD experience major depressive episodes (Burns et al., 1990; Migliorelli et al., 1994), which have an immense impact on the quality of life of AD patients (Gonzales-Salvdor et al., 2000). However, thus far, there have been very few studies focusing on the clinical features of major depressive symptoms in patients with AD (AD-MD), and clinical features of AD-MD are still unclear. Abbreviations: AD, Alzheimer's disease; AD-MD, Major depressive episodes in patients with Alzheimer's disease; BRSD, Behavior rating scale for dementia; CDR, Clinical dementia rating; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders; FAST, Functional assessment staging; HAM-D17, The 17-item Hamilton Rating Scale for Depression; MDD, Major depressive disorder; MMSE, Mini-mental state examination; NINCDS/ADRDA, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association; SNRI, Selective serotonin and noradrenaline reuptake inhibitor; SSRI, Selective serotonin reuptake inhibitors. ⁎ Corresponding author. Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba City, Ibaraki 305-0006, Japan. Tel./fax: +81 29 853 3182. E-mail address: [email protected] (K. Mizukami). 0278-5846/$ – see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.pnpbp.2008.12.019
In the treatment for AD-MD, it is well known that the anticholinergic effect of antidepressants on cognitive function is critical (Teri et al., 1991), thus selective serotonin reuptake inhibitors (SSRIs) may be effective (Katz, 1998). However, there have been few studies on the effectiveness of SSRIs (Burke et al., 1997; Taragano et al., 1997; Magai et al., 2000; Petracca et al., 2001; Lyketsos et al., 2003), and their results are inconsistent. In addition, despite a relative low prevalence of side effects associated with SSRIs, these drugs are sometimes intolerable for older people since they experience nausea, vomiting, dizziness and drowsiness (Wilson and Mottram, 2004). In addition, SSRIs are metabolized via the cytochrome P450 system and inhibit isoenzymes, which involve the risk of adverse effects due to drug interactions. Thus, it is important to develop other effective and safe drugs for AD-MD. Milnacipran is a selective serotonin and noradrenaline reuptake inhibitor (SNRI) (Puech et al., 1997) that is devoid of any postsynaptic activity (Moret et al., 1985). Furthermore, milnacipran has metabolic advantages over SSRIs, because it does not inhibit any cytochrome P450 isoenzymes (Puozzo and Leonard, 1996), reducing thereby the risk of adverse effects due to drug interactions, compared to SSRIs. Accordingly, SNRI should be an important antidepressant for patients with AD-MD, although thus far we have carried out the only study that showed effectiveness of milnacipran in such patients (Mizukami et al.,
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K. Mizukami et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 349–352
Table 1 Demographic data of 14 patients with AD and major depressive episodes (AD-MD) and 22 non-AD elderly patients with major depressive disorder (MDD)
No. of subjects Sex Female Male Mean age ~ 60's 70's 80's HAM-D score 10–19 20–29 30– GAF score
AD
Non-AD
14
22
10 4 74.3 ± 10.1 4 6 4 18.0 ± 3.6 9 5 0 34.1 ± 12.3
14 8 71.9 ± 5.8 9 11 2 20.8 ± 5.7 9 12 1 49.6 ± 7.6
p = 0.9038 (χ2 test) p = 0.3742 (t test) p = 0.3010 (χ2 test)
p = 0.1083 (t test) p = 0.3306 (χ2 test)
p b 0.0001 (t test) Fig. 1. HAM-D17 scores of AD-MD and MDD patients.
2006). Nevertheless, the effectiveness and safety of SNRI remain to be clarified. Thus, the first objective of this study is to clarify the profile of the depressive state in AD-MD and compare the clinical features between AD-MD and major depressive disorder (MDD) in elderly patients matched for age. The second objective of this paper is to clarify which depressive symptoms of AD patients respond to treatment with milnacipran. 2. Materials and methods 2.1. Patients Fourteen consecutive patients (75.2 ± 9.4 years old) were enrolled in this study; all of them were recruited from the outpatient clinic of Ishizaki Hospital, and patients themselves or their care providers gave their written informed consent to participate in the study. This study protocol was approved by the Internal Review Board of Ishizaki Hospital, and was carried out in accordance with the ethics and principles embodied in the 1975 Declaration of Helsinki. AD was clinically diagnosed based on DSM-IV (American Psychiatric Association, 1994) and NINCDS/ADRDA (McKhann et al., 1984) criteria. In addition, all 14 patients fulfilled the DSM-IV criteria for major depressive episode, and their HAM-D17 (Hamilton, 1960) scores were greater than 12. The subjects for the clinical dementia rating (CDR) (Hughes et al., 1982) 1 and CDR 2 were 8 and 6, respectively, and those for functional assessment staging (FAST) (Reisberg, 1988) 4, 5, and 6 stages were 10, 3, and 1, respectively. One of the 14 patients (Case 3) had a past history of major depressive episodes. We compared the HAM-D17 data of the 14 AD-MD patients with those from 22 MDD
patients. Demographic data of the 14 AD-MD and 22 MDD patients are given in Tables 1 and 2. The protocol was as previously described (Mizukami et al., 2006). AD-MD patients were started on milnacipran at 15 mg or 30 mg daily. If a patient showed no improvement within 2 weeks, the dose was increased every 2 weeks by 15 mg/day increments. Case 3 received antidepressants, such as sulpiride and mianserin, and 10 patients received antidementia drugs. The dose of these concomitant drugs was unchanged during the treatment of milnacipran. The HAM-D17 average score and the score of each HAM-D item, the mini-mental state examination (MMSE) score (Folstein et al., 1975), and GAF score according to the DSM-IV of AD-MD patients at baseline and at the endpoint (at 12 weeks) were compared. If patients discontinued milnacipran before 12 weeks, the week of discontinuation was defined as the endpoint. Statistical analysis was carried out using the χ2 test to examine the differences in sex, age, and HAM-D score between AD-MD and MDD groups. Student's t-test was also used to detect differences in age, HAM-D score, and GAF score between the two groups. Mann– Whitney's U test was used to detect differences in the score of each HAM-D item between the two groups. Wilcoxon method was used to examine differences in the score of each HAM-D item of AD-MD patients between at baseline and at the endpoint. Differences with a p value of b0.05 were regarded as statistically significant. 3. Results The average HAM-D17, MMSE and GAF scores of the 14 AD-MD patients at baseline were 18.0± 3.6 (range 12–24),19.3 ± 4.1 (range 9–25),
Table 2 Summary of clinical data from 14 patients No
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Age
78 84 79 79 71 81 77 79 84 59 56 58 69 86
Sex
F M F F F F F F M F F M M F
CDR
1 2 1 2 2 1 1 2 0.5 1 2 1 1 2
FAST
4 5 4 5 6 4 4 4 4 4 4 4 4 5
No. of depressive episode
Concomitant antidepressants
0 0 1 0 0 0 0 0 0 0 0 0 0 0
None None Sulpiride, mianserin None None None None None None None None None None None
Concomitant antidementia drugs
Nicergoline Donepezil Donepezil Donepezil Amantadine, nicergoline Donepezil
Donepezil Donepezil Donepezil Donepezil
Baseline HAM-D17
MMSE
GAF
22 16 21 24 19 16 12 17 16 16 22 17 13 21
25 15 23 22 9 17 22 22 21 18 19 22 19 16
21 35 25 35 25 45 65 31 35 25 25 35 51 25
K. Mizukami et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 349–352
Fig. 2. Changes in HAM-D17 scores in AD-MD patients.
and 34.1 ± 12.3 (range 21–65), respectively. The overall HAM-D profiles of AD-MD patients and MDD patients were similar (Fig. 1), and both conditions showed the highest scores regarding depressive mood, loss of interest and anxiety (psychic). On the other hand, the score for psychomotor retardation was significantly higher in the AD-MD group than in the MDD group, while the scores for insomnia (initial and delayed) and somatic anxiety were significantly higher in the MDD group than in the AD-MD group. In the AD-MD group, the maximum average dose of milnacipran was 40.4 ± 18.5 mg (range 15–75 mg). The average HAM-D17 and GAF scores at the endpoint were 5.7 ± 5.8 (range 0–22) and 54.1 ± 14.3 (range 21–75), both of which were significantly better (p = 0.0001 and p = 0.0001, respectively). Eleven of the 14 patients (78.6%) showed a HAM-D score below 7 at the endpoint. In contrast, there was no significant difference between the baseline average MMSE score and that at the endpoint. Among the HAM-D items, depressive mood, suicidal tendency, loss of interest, psychomotor retardation, anxiety (psychic), gastrointestinal symptoms, general somatic symptoms, hypochondriasis, and insight, were remarkably improved by treatment with milnacipran (Fig. 2). Adverse reactions were observed in four patients (daytime somnolence in two, and mild hypomanic state in two other) (28.6%), but quickly resolved after decreasing the dose or discontinuing the medication. 4. Discussion Our results suggest that the profiles of depressive state are similar in AD-MD and MDD, and that in both conditions, depressive mood, loss of interest, and anxiety (psychic) are remarkable. Chemerinski et al. (2001) compared the HAM-D17 scores of 92 AD-MD and 47 MDD matched for age, and found that AD-MD patients had a profile of depressive symptoms similar to that of MDD patients; furthermore, they reported that the above-mentioned three items had the highest scores in both conditions. Thus, our results are consistent with those obtained by Chemerinski et al. In addition, Jacobs et al. (1998) using the behavior rating scale for dementia (BRSD), found that depression in AD was characterized by depressive symptoms (e.g., patients were tearful, pessimistic, and had a sad face) and anxiety symptoms (e.g., they were nervous, tense, and easily startled). Taken together, it is plausible that patients with AD-MD and those with MDD have similar depressive symptoms. On the other hand, we also found some different clinical features between the two conditions. In AD-MD, psychomotor retardation was significantly severe, while in MDD, insomnia (initial and delayed) and anxiety (somatic) were significantly severe. Chemerinski et al. (2001) also reported that the score of psychomotor retardation was significantly higher in AD-MD, while that for anxiety (somatic) was significantly higher in MDD. However, they reported
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that the score of suicidal tendency was significantly higher in the MDD group than in the AD-MD group, while our results showed the score of suicidal tendency was relatively higher in AD-MD. Although the suicide rate in AD patients has been inconsistently reported, recent studies have shown an increase of the rate of suicidal tendency and suicide among patients with AD (Erlangsen et al., 2008; Lim et al., 2005). These studies together with our results suggest that we should carefully monitor AD patients. In addition, the fact that the GAF score was significantly lower in the AD-MD group than in the MDD group implies that an AD-MD patient is more severely disturbed regarding social functioning. Our study supports the idea that depression is a critical symptom in AD patients and requires appropriate treatment. This study demonstrated that milnacipran is promising in AD patients suffering major depressive episodes and it is well-tolerated, as reported in our previous study (Mizukami et al., 2006). The present study showed that milnacipran remarkably improved various symptoms in AD-MD patients, including depressive mood, suicidal tendency, loss of interest, psychomotor retardation, anxiety (psychic), gastrointestinal symptoms, general somatic symptoms, hypochondriasis, and insight. That the dose of concomitant drugs was unchanged during the treatment of milnacipran suggests that these drugs are not likely contributing to improvements of the symptoms. Milnacipran also has been reported to be effective in MDD in elderly patients. Tignol et al. (1998) examined the efficacy and safety of milnacipran in comparison with imipramine, and demonstrated that milnacipran improved various depressive symptoms of MDD and was more effective against anxiety (psychic), hypochondriasis and insight in elderly patients with MDD than imipramine. In their study, up to 100 mg daily of milnacipran was used and the remission rate (less than 7 of HAM-D17 score) was 32% (36% for imipramine group), while in our study the remission rate was 78.6%. In the study by Tignol et al., the HAM-D scores of the participants at baseline were greater than 17, and around 30% of the participants were hospitalized. Thus, it is possible that the depressive state in their participants was much more severe. In addition, it is also possible that the AD pathology alters the pharmacological response, and AD patients are more sensitive to treatment with milnacipran. Tokuyama et al. (2004) demonstrated that a mean daily dose of 60.7 mg (25– 150 mg) of milnacipran was effective against a broad spectrum of depressive symptoms of MDD in elderly patients, especially loss of interest, hypochondriasis, anxiety and agitation. Taken together, the results of these studies suggest that milnacipran improves various symptoms of major depressive episodes in patients with AD as well as of MDD in the elderly. In comparing treatment with imipramine, milnacipran was reported to display a better safety profile (Tignol et al., 1998). In this study, only 4 of 14 patients developed adverse reactions, and somnolence and hypomanic state were observed in two patients each, but no serious adverse reaction was observed. In the study by Tokuyama et al. (2004), 12 of 30 participants developed adverse reactions and 6 of 12 patients showed somnolence. Taking these findings together, we need to pay attention on somnolence in elderly patients even if they are under treatment with a low dose of milnacipran. In addition, it has been reported that dysuria is observed significantly more frequently, especially in male patients, with milnacipran than with tricyclic antidepressants and SSRIs (Puech et al. 1997; Tignol et al., 1998), although no patients suffered from dysuria in the study by Tokuyama et al. or our studies. Since elderly patients often suffer from prostatomegaly, it is also important to pay attention to manifestations of dysuria during treatment. In conclusion, our study suggests that in general the profiles of depression in AD-MD and MDD are similar, despite some different clinical features between both conditions. Our study also suggests that milnacipran is promising for depressive symptoms in AD-MD as well as MDD.
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References American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th edn. Washington, DC: American Psychietric Association; 1994. Burke WJ, Dewan V, Wengel SP, Roccaforte WH, Nadolny GC, Folks DG. The use of selective serotonin reuptake inhibitors for depression and psychosis complicating dementia. Int J Geriatr Psychiatry 1997;12:519–25. Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer's disease, III: disorders of mood. Br J Psychiatry 1990;157:81–6. Chemerinski E, Petracca G, Sabe L, Kremer J, Starkstein SE. The specificity of depressive symptoms in patients with Alzheimer's disease. Am J Psychiatry 2001;158:68–72. Erlangsen A, Zarit SH, Conwell Y. Hospital-diagnosed dementia and suicide: a longitudinal study using prospective, nationwide register data. Am J Geriatr Psychiatry 2008;16:220–8. Folstein MF, Folstein S, McHugh PR. “Mini-mental state”: a practical method for grading the mental state of patients for the clinician. J Psychiatr Res 1975;12:189–96. Gonzales-Salvdor T, Lyketsos CG, Baker AS, Roques C, Hovanek L, Steele CD, et al. Quality of life of patients with dementia in long-term care. Int J Geriatr Psychiatry 2000;15:181–9. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatry 1982;140:566–72. Jacobs MR, Strauss ME, Patterson MB, Mack JL. Characterization of depression in Alzheimer's disease by the CERAD behavior rating scale for dementia (BRSD). Am J Geriatr Psychiatry 1998;6:53–8. Katz IR. Diagnosis and treatment of depression in patients with Alzheimer's disease and other dementia. J Clin Psychiatry 1998;59(suppl 9):38–44. Lim WS, Rubin EH, Coats M, Morris JC. Early-stage Alzheimer disease represents increased suicidal risk in relation to later stages. Alzheimer Dis Assoc Disord 2005;19:214–9. Lyketsos CG, DelCampo L, Steinberg M, Miles Q, Steele CD, Munro C, et al. Treating depression in Alzheimer disease: efficacy and safety of sertraline therapy, and the benefits of depression reduction: the DIADS. Arch Gen Psychiatry 2003;60:737–46. Magai C, Kennedy G, Cohen CI, Gomberg D. A controlled clinical trial of sertraline in the treatment of depression in nursing home patients with late-stage Alzheimer's disease. Am J Geriatr Psychiatry 2000;8:66–74. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of Health and Human Services Task Force on Alzheimer's disease. Neurology 1984;34:939–44.
Migliorelli R, Teson A, Sabe L, Petracchi M, Leiguarda R, Starkstein SE. Prevalence and correlates of dysthymia and major depression in Alzheimer's disease. Am J Psychiatry 1994;152:37–44. Mizukami K, Tanaka Y, Asada T. Efficacy of milnacipran of depressive state in the patients with in Alzheimer's disease. Prog Neuro-psychopharmacol Biol Psychiatry 2006;30:1342–6. Moret C, Charveron J, Finberg JPM, Couzinier JP, Briley M. Biochemical profile of midalcipran (F2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug. Neuropharmacology 1985;24:1211–9. Petracca GM, Chemerinski E, Starkstein SE. A double-blind, placebo-controlled study of fluoxetine in depressed patients with Alzheimer's disease. Int Psychogeriatr 2001;13:233–40. Puech A, Montgomery SA, Prost JF, Solles A, Briley M. Milnacipran, a new serotonin and noradrenaline reuptake inhibitor: an overview of its antidepressant activity and clinical tolerability. Int Clin Psychopharmacol 1997;12:99-108. Puozzo C, Leonard BE. Pharmacokinetics of milnacipran in comparison with other antidepressants. Int Clin Psychopharmacol 1996;11(Suppl.4):15–27. Reisberg B. Functional assessment staging (FAST). Psychopharmacol Bull 1988;24:653–9. Taragano FE, Lyketsos CG, Mangone CA, Allegri RF, Comesaña-Diaz E. A double-blind, randomized, fixed-dose trial of fluoxetine vs. amitriptyline in the treatment of major depression complicating Alzheimer's disease. Psychosomatics 1997;38:246–52. Teri L, Reifler BV, Veith RC, Barnes R, White E, Mclean P, et al. Imipramine in the treatment of depressed Alzheimer's patients: impact on cognition. J Gerontol 1991;46:372–7. Tignol J, Pujol-Domenech L, Chartres JP, Léger JM, Plétan Y, Tonelli I, et al. Double-blind study of the efficacy and safety of milnacipran and imipramine in elderly patients with major depressive episode. Arch Psychiatr Scand 1998;97:157–65. Tokuyama A, Nakamura Y, Morikawa M, Hirayama T, Kou M, Inoue Y, et al. Efficacy of eight weeks treatment with milnacipran in senile depressive disorder. Rinsho Seishin Yakuri 2004;7:363–70 (in Japanese). Wilson K, Mottram A. Comparison of side effects of selective serotonin reuptake inhibitors and tricyclic antidepressants in older depressed patients: a meta-analysis. Int J Geriatr Psychiatry 2004;19:754–62.
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p n p b p
Therapeutic effects of the selective serotonin noradrenaline reuptake inhibitor milnacipran on depressive symptoms in patients with Alzheimer's disease Katsuyoshi Mizukami a,⁎, Kimitaka Hatanaka b, Yoshiro Tanaka b, Shinji Sato c, Takashi Asada a a b c
Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, Tsukuba City, Japan Department of Psychiatry, Ishizaki Hospital, Ibaraki machi, Japan Department of Psychiatry, Tsukuba Memorial Hospital, Tsukuba City, Japan
a r t i c l e
i n f o
Article history: Received 26 September 2008 Received in revised form 26 December 2008 Accepted 26 December 2008 Available online 6 January 2009 Keywords: Alzheimer's disease Depression Milnacipran SNRI
a b s t r a c t To clarify the profile of depressive symptoms in major depressive episodes in patients with Alzheimer's disease (AD-MD), we compared AD-MD with major depressive disorder in non-demented elderly patients (MDD) matched for age, using the 17-item Hamilton Rating Scale for Depression (HAM-D17). In addition, to clarify which depressive symptoms of AD patients respond to treatment with the selective serotonin and noradrenaline reuptake inhibitor (SNRI) milnacipran, we compared the HAM-D17 average score and the score of each HAM-D item, the mini-mental state examination (MMSE) score, and GAF score according to the DSM-IV evaluation of ADMD patients at baseline and at the endpoint (12 weeks). Depressive mood, loss of interest in hobbies and social activities and anxiety (psychic) scored the highest in both AD-MD and MDD groups, while psychomotor retardation scored significantly higher in AD-MD, and insomnia and anxiety (somatic) significantly did so in MDD. We also found that depressive mood, suicidal tendency, loss of interest, psychomotor retardation, anxiety (psychic), gastrointestinal symptoms, general somatic symptoms, and hypochondriasis remarkably improved in patients of AD-MD treated with milnacipran. Our results suggest that in general the profiles of depression in AD-MD and MDD are similar, despite some different clinical features between both conditions. Our study also suggests that milnacipran is promising to treat a broad range of depressive symptoms in AD-MD patients. © 2008 Published by Elsevier Inc.
1. Introduction One of the peculiar clinical features of depressive state in elderly people is the association with dementia, such as Alzheimer's disease (AD). It is documented that around one fourth of patients with AD experience major depressive episodes (Burns et al., 1990; Migliorelli et al., 1994), which have an immense impact on the quality of life of AD patients (Gonzales-Salvdor et al., 2000). However, thus far, there have been very few studies focusing on the clinical features of major depressive symptoms in patients with AD (AD-MD), and clinical features of AD-MD are still unclear. Abbreviations: AD, Alzheimer's disease; AD-MD, Major depressive episodes in patients with Alzheimer's disease; BRSD, Behavior rating scale for dementia; CDR, Clinical dementia rating; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders; FAST, Functional assessment staging; HAM-D17, The 17-item Hamilton Rating Scale for Depression; MDD, Major depressive disorder; MMSE, Mini-mental state examination; NINCDS/ADRDA, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association; SNRI, Selective serotonin and noradrenaline reuptake inhibitor; SSRI, Selective serotonin reuptake inhibitors. ⁎ Corresponding author. Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba City, Ibaraki 305-0006, Japan. Tel./fax: +81 29 853 3182. E-mail address: [email protected] (K. Mizukami). 0278-5846/$ – see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.pnpbp.2008.12.019
In the treatment for AD-MD, it is well known that the anticholinergic effect of antidepressants on cognitive function is critical (Teri et al., 1991), thus selective serotonin reuptake inhibitors (SSRIs) may be effective (Katz, 1998). However, there have been few studies on the effectiveness of SSRIs (Burke et al., 1997; Taragano et al., 1997; Magai et al., 2000; Petracca et al., 2001; Lyketsos et al., 2003), and their results are inconsistent. In addition, despite a relative low prevalence of side effects associated with SSRIs, these drugs are sometimes intolerable for older people since they experience nausea, vomiting, dizziness and drowsiness (Wilson and Mottram, 2004). In addition, SSRIs are metabolized via the cytochrome P450 system and inhibit isoenzymes, which involve the risk of adverse effects due to drug interactions. Thus, it is important to develop other effective and safe drugs for AD-MD. Milnacipran is a selective serotonin and noradrenaline reuptake inhibitor (SNRI) (Puech et al., 1997) that is devoid of any postsynaptic activity (Moret et al., 1985). Furthermore, milnacipran has metabolic advantages over SSRIs, because it does not inhibit any cytochrome P450 isoenzymes (Puozzo and Leonard, 1996), reducing thereby the risk of adverse effects due to drug interactions, compared to SSRIs. Accordingly, SNRI should be an important antidepressant for patients with AD-MD, although thus far we have carried out the only study that showed effectiveness of milnacipran in such patients (Mizukami et al.,
350
K. Mizukami et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 349–352
Table 1 Demographic data of 14 patients with AD and major depressive episodes (AD-MD) and 22 non-AD elderly patients with major depressive disorder (MDD)
No. of subjects Sex Female Male Mean age ~ 60's 70's 80's HAM-D score 10–19 20–29 30– GAF score
AD
Non-AD
14
22
10 4 74.3 ± 10.1 4 6 4 18.0 ± 3.6 9 5 0 34.1 ± 12.3
14 8 71.9 ± 5.8 9 11 2 20.8 ± 5.7 9 12 1 49.6 ± 7.6
p = 0.9038 (χ2 test) p = 0.3742 (t test) p = 0.3010 (χ2 test)
p = 0.1083 (t test) p = 0.3306 (χ2 test)
p b 0.0001 (t test) Fig. 1. HAM-D17 scores of AD-MD and MDD patients.
2006). Nevertheless, the effectiveness and safety of SNRI remain to be clarified. Thus, the first objective of this study is to clarify the profile of the depressive state in AD-MD and compare the clinical features between AD-MD and major depressive disorder (MDD) in elderly patients matched for age. The second objective of this paper is to clarify which depressive symptoms of AD patients respond to treatment with milnacipran. 2. Materials and methods 2.1. Patients Fourteen consecutive patients (75.2 ± 9.4 years old) were enrolled in this study; all of them were recruited from the outpatient clinic of Ishizaki Hospital, and patients themselves or their care providers gave their written informed consent to participate in the study. This study protocol was approved by the Internal Review Board of Ishizaki Hospital, and was carried out in accordance with the ethics and principles embodied in the 1975 Declaration of Helsinki. AD was clinically diagnosed based on DSM-IV (American Psychiatric Association, 1994) and NINCDS/ADRDA (McKhann et al., 1984) criteria. In addition, all 14 patients fulfilled the DSM-IV criteria for major depressive episode, and their HAM-D17 (Hamilton, 1960) scores were greater than 12. The subjects for the clinical dementia rating (CDR) (Hughes et al., 1982) 1 and CDR 2 were 8 and 6, respectively, and those for functional assessment staging (FAST) (Reisberg, 1988) 4, 5, and 6 stages were 10, 3, and 1, respectively. One of the 14 patients (Case 3) had a past history of major depressive episodes. We compared the HAM-D17 data of the 14 AD-MD patients with those from 22 MDD
patients. Demographic data of the 14 AD-MD and 22 MDD patients are given in Tables 1 and 2. The protocol was as previously described (Mizukami et al., 2006). AD-MD patients were started on milnacipran at 15 mg or 30 mg daily. If a patient showed no improvement within 2 weeks, the dose was increased every 2 weeks by 15 mg/day increments. Case 3 received antidepressants, such as sulpiride and mianserin, and 10 patients received antidementia drugs. The dose of these concomitant drugs was unchanged during the treatment of milnacipran. The HAM-D17 average score and the score of each HAM-D item, the mini-mental state examination (MMSE) score (Folstein et al., 1975), and GAF score according to the DSM-IV of AD-MD patients at baseline and at the endpoint (at 12 weeks) were compared. If patients discontinued milnacipran before 12 weeks, the week of discontinuation was defined as the endpoint. Statistical analysis was carried out using the χ2 test to examine the differences in sex, age, and HAM-D score between AD-MD and MDD groups. Student's t-test was also used to detect differences in age, HAM-D score, and GAF score between the two groups. Mann– Whitney's U test was used to detect differences in the score of each HAM-D item between the two groups. Wilcoxon method was used to examine differences in the score of each HAM-D item of AD-MD patients between at baseline and at the endpoint. Differences with a p value of b0.05 were regarded as statistically significant. 3. Results The average HAM-D17, MMSE and GAF scores of the 14 AD-MD patients at baseline were 18.0± 3.6 (range 12–24),19.3 ± 4.1 (range 9–25),
Table 2 Summary of clinical data from 14 patients No
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Age
78 84 79 79 71 81 77 79 84 59 56 58 69 86
Sex
F M F F F F F F M F F M M F
CDR
1 2 1 2 2 1 1 2 0.5 1 2 1 1 2
FAST
4 5 4 5 6 4 4 4 4 4 4 4 4 5
No. of depressive episode
Concomitant antidepressants
0 0 1 0 0 0 0 0 0 0 0 0 0 0
None None Sulpiride, mianserin None None None None None None None None None None None
Concomitant antidementia drugs
Nicergoline Donepezil Donepezil Donepezil Amantadine, nicergoline Donepezil
Donepezil Donepezil Donepezil Donepezil
Baseline HAM-D17
MMSE
GAF
22 16 21 24 19 16 12 17 16 16 22 17 13 21
25 15 23 22 9 17 22 22 21 18 19 22 19 16
21 35 25 35 25 45 65 31 35 25 25 35 51 25
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Fig. 2. Changes in HAM-D17 scores in AD-MD patients.
and 34.1 ± 12.3 (range 21–65), respectively. The overall HAM-D profiles of AD-MD patients and MDD patients were similar (Fig. 1), and both conditions showed the highest scores regarding depressive mood, loss of interest and anxiety (psychic). On the other hand, the score for psychomotor retardation was significantly higher in the AD-MD group than in the MDD group, while the scores for insomnia (initial and delayed) and somatic anxiety were significantly higher in the MDD group than in the AD-MD group. In the AD-MD group, the maximum average dose of milnacipran was 40.4 ± 18.5 mg (range 15–75 mg). The average HAM-D17 and GAF scores at the endpoint were 5.7 ± 5.8 (range 0–22) and 54.1 ± 14.3 (range 21–75), both of which were significantly better (p = 0.0001 and p = 0.0001, respectively). Eleven of the 14 patients (78.6%) showed a HAM-D score below 7 at the endpoint. In contrast, there was no significant difference between the baseline average MMSE score and that at the endpoint. Among the HAM-D items, depressive mood, suicidal tendency, loss of interest, psychomotor retardation, anxiety (psychic), gastrointestinal symptoms, general somatic symptoms, hypochondriasis, and insight, were remarkably improved by treatment with milnacipran (Fig. 2). Adverse reactions were observed in four patients (daytime somnolence in two, and mild hypomanic state in two other) (28.6%), but quickly resolved after decreasing the dose or discontinuing the medication. 4. Discussion Our results suggest that the profiles of depressive state are similar in AD-MD and MDD, and that in both conditions, depressive mood, loss of interest, and anxiety (psychic) are remarkable. Chemerinski et al. (2001) compared the HAM-D17 scores of 92 AD-MD and 47 MDD matched for age, and found that AD-MD patients had a profile of depressive symptoms similar to that of MDD patients; furthermore, they reported that the above-mentioned three items had the highest scores in both conditions. Thus, our results are consistent with those obtained by Chemerinski et al. In addition, Jacobs et al. (1998) using the behavior rating scale for dementia (BRSD), found that depression in AD was characterized by depressive symptoms (e.g., patients were tearful, pessimistic, and had a sad face) and anxiety symptoms (e.g., they were nervous, tense, and easily startled). Taken together, it is plausible that patients with AD-MD and those with MDD have similar depressive symptoms. On the other hand, we also found some different clinical features between the two conditions. In AD-MD, psychomotor retardation was significantly severe, while in MDD, insomnia (initial and delayed) and anxiety (somatic) were significantly severe. Chemerinski et al. (2001) also reported that the score of psychomotor retardation was significantly higher in AD-MD, while that for anxiety (somatic) was significantly higher in MDD. However, they reported
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that the score of suicidal tendency was significantly higher in the MDD group than in the AD-MD group, while our results showed the score of suicidal tendency was relatively higher in AD-MD. Although the suicide rate in AD patients has been inconsistently reported, recent studies have shown an increase of the rate of suicidal tendency and suicide among patients with AD (Erlangsen et al., 2008; Lim et al., 2005). These studies together with our results suggest that we should carefully monitor AD patients. In addition, the fact that the GAF score was significantly lower in the AD-MD group than in the MDD group implies that an AD-MD patient is more severely disturbed regarding social functioning. Our study supports the idea that depression is a critical symptom in AD patients and requires appropriate treatment. This study demonstrated that milnacipran is promising in AD patients suffering major depressive episodes and it is well-tolerated, as reported in our previous study (Mizukami et al., 2006). The present study showed that milnacipran remarkably improved various symptoms in AD-MD patients, including depressive mood, suicidal tendency, loss of interest, psychomotor retardation, anxiety (psychic), gastrointestinal symptoms, general somatic symptoms, hypochondriasis, and insight. That the dose of concomitant drugs was unchanged during the treatment of milnacipran suggests that these drugs are not likely contributing to improvements of the symptoms. Milnacipran also has been reported to be effective in MDD in elderly patients. Tignol et al. (1998) examined the efficacy and safety of milnacipran in comparison with imipramine, and demonstrated that milnacipran improved various depressive symptoms of MDD and was more effective against anxiety (psychic), hypochondriasis and insight in elderly patients with MDD than imipramine. In their study, up to 100 mg daily of milnacipran was used and the remission rate (less than 7 of HAM-D17 score) was 32% (36% for imipramine group), while in our study the remission rate was 78.6%. In the study by Tignol et al., the HAM-D scores of the participants at baseline were greater than 17, and around 30% of the participants were hospitalized. Thus, it is possible that the depressive state in their participants was much more severe. In addition, it is also possible that the AD pathology alters the pharmacological response, and AD patients are more sensitive to treatment with milnacipran. Tokuyama et al. (2004) demonstrated that a mean daily dose of 60.7 mg (25– 150 mg) of milnacipran was effective against a broad spectrum of depressive symptoms of MDD in elderly patients, especially loss of interest, hypochondriasis, anxiety and agitation. Taken together, the results of these studies suggest that milnacipran improves various symptoms of major depressive episodes in patients with AD as well as of MDD in the elderly. In comparing treatment with imipramine, milnacipran was reported to display a better safety profile (Tignol et al., 1998). In this study, only 4 of 14 patients developed adverse reactions, and somnolence and hypomanic state were observed in two patients each, but no serious adverse reaction was observed. In the study by Tokuyama et al. (2004), 12 of 30 participants developed adverse reactions and 6 of 12 patients showed somnolence. Taking these findings together, we need to pay attention on somnolence in elderly patients even if they are under treatment with a low dose of milnacipran. In addition, it has been reported that dysuria is observed significantly more frequently, especially in male patients, with milnacipran than with tricyclic antidepressants and SSRIs (Puech et al. 1997; Tignol et al., 1998), although no patients suffered from dysuria in the study by Tokuyama et al. or our studies. Since elderly patients often suffer from prostatomegaly, it is also important to pay attention to manifestations of dysuria during treatment. In conclusion, our study suggests that in general the profiles of depression in AD-MD and MDD are similar, despite some different clinical features between both conditions. Our study also suggests that milnacipran is promising for depressive symptoms in AD-MD as well as MDD.
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