Abstract
To prevent recurrent depression, patients should ideally continue treatment for >6 months with the antidepressant dose that effectively suppressed acute depressive symptoms. However, there are inter-individual differences in the antidepressant doses required to achieve response and maintenance. Therefore, this study was conducted to examine the role of clinical features, including genetic polymorphisms, on the antidepressant dose required for maintenance therapy in 82 Japanese patients with depression. We calculated the antidepressant dose using the imipramine equivalent scale and the dose of concomitant anxiolytics and hypnotics using the diazepam equivalent scale. The 82 participants were classified into two groups based on the median imipramine equivalent dose, and we examined the influence of patient characteristics and the presence of genetic polymorphisms of brain-derived neurotropic factor (BDNF; rs6265) and cyclic adenosine monophosphate responsive element-binding protein 1 (CREB1; rs2253306, rs4675690, rs769963) on the antidepressant maintenance dose. Using a multivariate logistic regression analysis, we found that the concomitant diazepam equivalent dose and presence of the CREB1 rs4675690 polymorphism were significantly associated with the antidepressant maintenance dose. We concluded that these factors influenced the antidepressant dose in maintenance therapy among Japanese patients with depression. However, further research is required in large cohorts.
Depressive disorder is a common psychiatric disorder, with approximately 350 million people being affected worldwide.1) Moreover, it is associated with a high rate of recurrence and chronicity, with 12–35% of all cases becoming chronic and 13.2% experiencing recurrence within 5 years.2–5) When starting antidepressant therapy, the dose of antidepressant is low and is slowly increased, and careful attention is paid to the development of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania, the so-called “activation syndrome.” The target dose is the lowest dose that adequately suppresses depressive symptoms with tolerable side effects. After achieving remission, the therapeutic dose acutely required is continued as maintenance therapy for >6 months to prevent recurrence.6,7)
Several reports suggest that when an antidepressant is ineffective in suppressing depressive symptoms, combination therapy with another antidepressant or anxiolytic or hypnotic drugs is more effective than increasing the dose of the pre-existing antidepressant.8–10)
In studies on Japanese patients with depression, 23.4–35.9% of cases were treated with antidepressant combination therapy and 60.3–73.0% were treated with concomitant anxiolytic or hypnotic drugs. In addition, it is known that inter-individual differences exist in the daily dosing requirements for antidepressants.11–13)
Regarding these differences in therapeutic needs, many investigators have considered the association between the daily dose and synergism among antidepressants and patient characteristics, including genetic polymorphisms. However, many of these studies on genetic polymorphisms have focused on the effects on antidepressant pharmacokinetics. To the best of our knowledge, there are no reports regarding the association between antidepressant maintenance dose and the presence of genetic polymorphisms. Furthermore, no such studies have considered the roles of combination therapy with antidepressants or concomitant therapy with anxiolytic and hypnotic drugs.
Among the polymorphisms that have gained attention, brain-derived neurotropic factor (BDNF) and cyclic adenosine monophosphate responsive element-binding protein 1 (CREB1), which is transcriptional factor of BDNF, are known to be crucial mediators of neuroplasticity.14–16) In fact, the 2- to 6-week lag to obtain antidepressant efficacy from the start of treatment has been attributed to BDNF and CREB1.17) Several genetic polymorphisms in BDNF and CREB1 affect depressive symptoms and antidepressant response. The BDNF rs6265 polymorphism is the most common single-nucleotide mutation, affecting activity-dependent secretion of BDNF and hippocampal function.18) Regarding the CREB1 polymorphism, Serretti et al. have reported that the CREB1 rs2253206, rs4675690, and rs7569963 polymorphisms are associated with resistance to antidepressant treatment.19)
We aimed to examine the influence of patient characteristics (age, gender, anxiolytic and hypnotic drug doses), including genetic polymorphisms (BDNF rs6265, CREB1 rs2253206, rs4675690, rs7569963), on the antidepressant maintenance dose among Japanese patients with depression. To facilitate analysis, we calculated the concomitant antidepressant dose using the imipramine equivalent dose and calculated the concomitant anxiolytic and hypnotic dose using the diazepam equivalent dose.
PARTICIPANTS AND METHODS
ParticipantsThis retrospective study was conducted in accordance with the requirements of the Declaration of Helsinki and Good Clinical Practice guidelines and was approved by the ethics committees of Shizuoka General Hospital (approved number 11-05-07). Written informed consent was obtained from each patient after a detailed briefing of the study purposes and protocols. The study was conducted in the outpatient department of Shizuoka General Hospital between June 2012 and December 2014.
We included Japanese patients with a diagnosis of a depressive disorder, according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision, who had been treated with selective serotonin transporter reuptake inhibitors or serotonin and noradrenaline reuptake inhibitors. In this study, there was no potential subject who showed noncompliance with therapy, who was treated with antipsychotic drugs or mood stabilizers, who had severe hepatic or renal dysfunction (aspartate aminotransferase or alanine aminotransferase >500 U/L and/or serum creatinine >3 mg/dL), who was using St. John’s wort, and who was pregnant.
Maintenance DoseWe interviewed each patient and retrospectively reviewed their electronic medical records for characteristics such as age, gender, liver and renal function, and medication usage (e.g., antidepressant, antianxiety, hypnotic, and supplement usage, including St. John’s wort). We calculated the antidepressant and anxiolytic/hypnotic drug doses as the imipramine equivalent and diazepam equivalent doses, respectively, using the most recent doses20) (Tables 1, 2). If the patient was treated with >1 antidepressant or anxiolytic and hypnotic drugs, the respective imipramine equivalent or diazepam equivalent doses were totaled.
Table 1. Dose Equivalence of Antidepressants
| Antidepressant | Dose equivalent (mg) | Antidepressant | Dose equivalent (mg) |
|---|
| Imipramine | 150 | Paroxetine | 40 |
| Duloxetine | 30 | Paroxetine CR | 50 |
| Fluvoxamine | 150 | Sertraline | 100 |
| Mianserin | 60 | Sulpiride | 300 |
| Milnacipran | 100 | Trazodone | 300 |
| Mirtazapine | 30 | | |
CR; controlled release. The data was quoted from antidepressant dose equivalent scale20) and showed imipramine and antidepressants used in this study.
Table 2. Dose Equivalence of Anxiolytic and Hypnotic Drugs
| Anxiolytic and hypnotic drug | Dose equivalent (mg) | Anxiolytic and hypnotic drug | Dose equivalent (mg) |
|---|
| Diazepam | 5 | Fludiazepam | 0.5 |
| Alprazolam | 0.8 | Nitrazepam | 5 |
| Brotizolam | 0.25 | Quazepam | 15 |
| Clotiazepam | 10 | Zolpidem | 10 |
| Etizolam | 1.5 | Zopiclone | 7.5 |
| Flunitrazepam | 1 | | |
The data was quoted from anxiolytic and hypnotic drug dose equivalent scale20) and showed anxiolytic and hypnotic drugs used in this study.
Oral mucous cells were taken from patients using a cotton-tipped stick, which was allowed to dry at room temperature for 2 h before being immersed in phosphate-buffered saline (PBS). Genomic DNA was extracted from the PBS solution containing oral mucous cells using a QIAamp DNA Blood Mini Kit (Qiagen, Tokyo, Japan), according to the manufacturer’s instructions. We determined the presence of BDNF rs6265, CREB1 rs2253206, and CREB1 rs7569963 polymorphisms using PCR-restriction fragment length polymorphism (RFLP) (Table 3). In brief, genomic DNA (100 ng) was amplified in a PCR buffer containing deoxyribonucleotide triphosphate (dNTP) (200 µM), forward primer (1 µM), reverse primer (1 µM), 1.5 mM MgCl2, and HotStar Taq plus DNA polymerase (1.25 units; Qiagen). Amplification was performed using an i-Cycler thermal cycler (Bio-Rad, Tokyo, Japan). PCR comprised an initial denaturation/enzyme activation step at 95°C for 5 min, amplification for 35 or 40 cycles at 94°C for 30 s, an appropriate annealing temperature for 30 s, treatment at 72°C for 30 s, and a final extension step at 72°C for 10 min. PCR products were digested with each restriction enzyme (New England BioLab., Beverly, MA, U.S.A.), according to the manufacturer’s instructions. The digested products were separated by electrophoresis on a 4% agarose gel and genotyped based on the digestion patterns. The accuracy of this PCR-RFLP-based method was confirmed by direct sequencing of the amplified PCR product.
Table 3. Brain-Derived Neurotropic Factor and Cyclic Adenosine Monophosphate Responsive Element-Binding Protein 1 Genetic Polymorphisms and Primers of PCRs, Annealing Temperature, Cycles, Corresponding Restriction Enzymes and Digest Fragments
| Polymorphisms | Primers | Annealing temperature (°C) | Cycles | Restriction enzymes | Digest fragments (bp) |
|---|
| BDNF rs6265 | F; 5ʹ-ACTCTGGAGAGCGTGAAT-3ʹ | 56 | 35 | NlaIII | G: 243+65 A: 168+75+65 |
| R; 5ʹ-ATACTGTCACACACGCTC-3ʹ |
| CREB1 rs2253206 | F; 5ʹ-TACCTGCACAATTACATGGAC-3ʹ | 60 | 40 | MseI | A: 74+69 G: 143 |
| R; 5ʹ-CTTCAGGGCATTTACACATGC-3ʹ |
| CREB1 rs7569963 | F; 5ʹ-CTGTGCTTCTAATTTGTAGGCC-3ʹ | 52 | 40 | StyI | A: 150 G: 129+21 |
| R; 5ʹ-GTTAGAGGTGGGGAGCTTCA-3ʹ |
| CREB1 rs4675690 | F; 5ʹ-CTCAACCTCCTGAGTAGCTAG-3ʹ | 59 | 33 | None | 291 |
| C allele specific R; 5ʹ-TGTCTGATCTGTTCTGTTTCG-3ʹ |
| T allele specific R; 5ʹ-TGTCTGATCTGTTCTGTTTCA-3ʹ |
F; forward primer, R; reverse primer.
The presence of the CREB1 rs4675690 polymorphism was determined by allele-specific PCR as previously reported21) (Table 3). In brief, genomic DNA (100 ng) was amplified in a PCR buffer containing dNTP mixture (200 µM), forward primer (1 µM), allele-specific reverse primer (1 µM), 1.5 mM MgCl2, and HotStar Taq plus DNA polymerase (1.25 units). Amplification was then performed using an i-Cycler thermal cycler, and PCR comprised an initial denaturation/enzyme activation step at 95°C for 5 min, amplification for 33 cycles at 94°C for 30 s and 59°C for 30 s, treatment at 72°C for 30 s, and a final extension step at 72°C for 5 min. The PCR products were electrophoresed on 3% agarose gel and genotyped based on the appearance of an amplified band (291 base pairs) either with the wild-type A allele reverse primer or with the mutant G allele reverse primer. The accuracy of this allele-specific PCR method was confirmed by direct sequencing of the PCR products amplified with primer sets (forward, 5′-TGG TGC GAT CTC AGC TCA CT-3′; reverse, 5′-ATG TGA CTT ACT GCC TCT CAG-3′).
Statistical AnalysisDeviation of genotyping data based on the Hardy–Weinberg equilibrium was analyzed using the chi-square test for goodness of fit. We established two study groups (low and high) based on the median imipramine equivalent dose. The Shapiro–Wilk test was used to determine the normality of the distributions, and we used two-tailed student t-tests for normally distributed data and two-tailed Mann–Whitney U-tests for non-normally distributed data. Two-tailed chi-square tests were used to compare quantitative variables (age, gender, anxiolytic and hypnotic drug doses, and the presence of polymorphisms) between the two groups established by the median imipramine equivalent dose in the cohort. Variables that showed a moderate relationship (p<0.15) with the antidepressant dose in the univariate analysis were included in the multivariate logistic regression analysis, using the stepwise method (p<0.05). All statistical analyses were performed using SPSS Version 18.0 (IBM, Tokyo, Japan). Statistical differences were considered significant at p<0.05 unless otherwise stated.
RESULTS
Patient CharacteristicsThe characteristics of the 82 participants (age, 32–87 years) are presented in Table 4. The median imipramine equivalent dose was 75 mg, and the cohort was divided into high-dose antidepressant treatment (n=39, >75 mg) and low-dose antidepressant treatment (n=43, ≤75 mg).
Table 4. Variables for Imipramine Equivalent Dose in Univariate Analysis
| Number of patients (% of total), mean±S.D., or median (range) | p |
|---|
| Low imipramine equivalent value group (n=43) | High imipramine equivalent value group (n=39) |
|---|
| Age (years) | 66.65±13.24 | 60.82±13.59 | 0.053a,d) |
| Gender (Male/Female) | 10 (23.3)/33 (76.7) | 11 (28.2)/28 (71.8) | 0.608b) |
| Imipramine equivalent dose (mg) | 62.5 (18.75–75.00) | 175.00 (87.50–337.50) | <0.001c) |
| Number of prescribed antidepressants | 1 (1–2) | 2 (1–3) | <0.001c) |
| 1 | 41 (95.3) | 13 (33.3) | |
| 2, 3 | 2 (4.7) | 26 (66.7) | |
| Treated concomitantly with anxiolytic or hypnotic drugs | 30 (69.8) | 31 (79.5) | |
| Concomitant diazepam equivalent dose (mg) | 3.75 (0–13.33) | 5.00 (0–17.50) | 0.016c,d) |
| Antidepressants | | |
| Paroxetine, Paroxetine CR | 37 (45.1) | |
| Sertraline | 21 (25.6) | |
| Milnacipran | 17 (20.7) | |
| Duloxetine | 13 (15.9) | |
| Trazodone | 10 (12.2) | |
| Mirtazapine | 7 (8.5) | |
| Sulpiride | 6 (7.3) | |
| Fluvoxamine | 2 (2.4) | |
| Mianserin | 1 (1.2) | |
| Anxiolytic or hypnotic drugs | | |
| Zolpidem | 30 (36.6) | |
| Alprazolam | 17 (20.7) | |
| Zopiclone | 13 (15.9) | |
| Brotizolam | 11 (13.4) | |
| Etizolam | 11 (13.4) | |
| Flunitrazepam | 5 (6.1) | |
| Nitrazepam | 3 (3.7) | |
| Clotiazepam | 2 (2.4) | |
| Diazepam | 2 (2.4) | |
| Quazepam | 2 (2.4) | |
| Fludiazepam | 1 (1.2) | |
| Polymorphisms | | |
| BDNF rs6265 | GG: 12 (27.9), GA: 18 (41.9), AA: 13 (30.2) (having G allele: 30, not having G allele: 13) | GG: 10 (25.6), GA: 17 (43.6), AA: 12 (30.8) (having G allele: 27, not having G allele: 12) | 0.973b) 0.958b) |
| CREB1 rs2253206 | AA: 4 (9.3), AG: 23 (53.5), GG: 16 (37.2) (having A allele: 27, not having A allele: 16) | AA: 2 (5.1), AG: 19 (48.7), GG: 18 (46.2) (having A allele: 21, not having A allele: 18) | 0.615b) 0.412b) |
| CREB1 rs4675690 | CC: 5 (11.6), CT: 25 (58.1), TT: 13 (30.2) (having C allele: 30, not having C allele: 13) | CC: 2 (5.1), CT: 16 (41.0), TT: 21 (53.8) (having C allele: 18, not having C allele: 21) | 0.084b) 0.030b,d) |
| CREB1 rs7569963 | AA: 2 (4.7), AG: 15 (34.9), GG: 26 (60.5) (having A allele: 17, not having A allele: 26) | AA: 0 (0), AG: 7 (17.9), GG: 32 (82.0) (having A allele: 7, not having A allele: 32) | 0.069b) 0.032b,d) |
CR; controlled release. a) Two-tailed student t-test. b) Two-tailed chi-square test. c) Two-tailed Mann–Whitney U-test. d) Four variables showed a moderate relationship (p<0.15) were included in multivariate logistic regression analysis.
The imipramine equivalent doses, concomitant diazepam equivalent doses, and number of prescribed antidepressants were not normally distributed (Shapiro–Wilk test, p<0.001). Therefore, the median values and ranges are shown for these data in Table 4. In contrast, the data for age was normally distributed (Shapiro–Wilk test, p>0.05), and the mean and standard deviations are shown in Table 4.
The distributions of the BDNF rs6265 and the CREB1 rs2253206, rs4675690, and rs7569963 polymorphisms did not significantly deviate from the Hardy–Weinberg equilibrium.
Association between Patient Variables and Amount of AntidepressantWe evaluated each variable by the imipramine equivalent dose using univariate analysis (Table 4). These analyses revealed that age, concomitant diazepam equivalent dose, and the CREB1 rs4675690 and rs7569963 polymorphisms had p-values of <0.15. Furthermore, the CREB1 rs4675690 polymorphism did not show multicollinearity with the CREB1 rs7569963 polymorphism by Spearman’s analysis (r=0.378). Therefore, we subjected these four variables to a stepwise multivariate logistic regression analysis (Table 5). This analysis revealed that the diazepam equivalent dose (p=0.017) and the absence of the C allele of the CREB1 rs4675690 polymorphism (p=0.029) were influencing factors for higher imipramine equivalent doses. The odds ratios for an increased concomitant diazepam equivalent dose and the absence of the C allele of the CREB1 rs4675690 polymorphism were 1.144 (95% confidence interval, 1.024–1.279) and 2.881 (95% confidence interval, 1.115–7.449), respectively. Age and the CREB1 rs7569963 polymorphism were not included in the stepwise multivariate logistic regression analysis.
Table 5. Influence Factors on Imipramine Equivalent Dose in Multivariate Logistic Regression Analysis
| Variable | OR (95% CI) | p |
|---|
| Concomitant diazepam equivalent dose (per mg) | 1.144 (1.024–1.279) | 0.017* |
| CREB1 rs4675690 (not having C allele) | 2.881 (1.115–7.449) | 0.029* |
The 4 variable factors (age, concomitant diazepam equivalent dose, CREB1 rs4675690 polymorphism, and CREB1 rs7569963 polymorphism) that showed a moderate relationship (p<0.15) with imipramine equivalent dose in univariate analysis were included in multivariate logistic regression analysis. Age and CREB1 rs7569963 polymorphism were not included in the stepwise multivariate logistic regression analysis. Odds ratio (OR) and 95% confidence interval (95% CI) show the elevating imipramine equivalent dose of per mg concomitant diazepam equivalent dose or absence of C allele (TT genotype) compared with having C allele (CC and CT genotypes) in CREB1 rs4675690 C>T polymorphism. * p<0.05.
DISCUSSION
We examined the factors influencing the antidepressant maintenance dose among Japanese patients with depression, for which we used the dose equivalent scales proposed by Inagaki and Inada.20) Although there are several other dose equivalent scales,22–24) those would not have covered all antidepressants used in this study. In contrast, Inagaki and Inada’s dose equivalent scale for antidepressant, anxiolytic, and hypnotic drugs covers the full spectrum of medication we encountered and used in several reports.25–27) Furthermore, the dose equivalencies were determined by comparison with the therapeutic effects in clinical double-blind trials in Japan, making them more specific to the Japanese population in this cohort.
In this study, the median imipramine equivalent dose was 75 mg, the percentage of patients treated with a combination of antidepressants was 31.7%, and the percentage of patients treated concomitantly with anxiolytic or hypnotic drugs was 74.4%. In a previous report on the prescribing patterns for Japanese patients with depression, which also used the Inagaki and Inada scales, the mean imipramine equivalent doses were 78.2 and 79.4 mg in 2005 and 2009, respectively.11)
In addition, the ratios of patients treated with antidepressant combinations and concomitant anxiolytic/hypnotic drugs were 23.4–35.9 and 60.3–73.0%, respectively,11–13) showing that our results were comparable. Given that there are several other equivalency scales, further investigation is required to compare them with this existing data to see if there are any differences.
The two key findings of this study are that the concomitant diazepam equivalent dose and presence of the CREB1 rs4675690 polymorphism were significantly associated with the antidepressant maintenance dose. The odds ratio for the CREB1 rs4675690 polymorphism was also higher than that for the concomitant diazepam equivalent dose. These are discussed in further detail below.
Concomitant anxiolytic and hypnotic drug usage offers greater benefit in terms of symptomatic recovery or side effects when compared with the use of antidepressants alone10) and is often used to treat anxiety, agitation, or insomnia in patients with moderate or severe depression. Research shows that comorbid sleep disturbance is usually associated with a more severe major depressive episode.28) Therefore, the ratio of patients treated with concomitant anxiolytic and hypnotic drugs was higher in the high-dose imipramine equivalent group compared with the low-dose imipramine equivalent group, probably because of the high number of patients with severe depression. This suggests that the concomitant anxiolytic and hypnotic drug dose is associated with the antidepressant maintenance dose.
Unfortunately, we were unable to examine the influence of the number of recurrences of depression on the antidepressant maintenance dose. This was because we did not include this data in either the electronic medical records or patient interview. Indeed, the association between the number of depression recurrences and the doses of antidepressant or concomitant anxiolytic/hypnotic drugs during maintenance therapy remains unknown. Furthermore, it is known that the activity of the mechanism of action of antidepressants (e.g., pathways in the serotonergic and noradrenergic systems) or the drug-metabolizing enzymes and transporters of antidepressants (e.g., cytochrome P450s and ATP-binding cassette transporters) vary among different individuals and influence the response of antidepressants.29–31) However, the relationship of these factors with the maintenance dose for antidepressant therapy is unknown. Further studies are required to determine if there is any such association; however, such research should include a larger number of participants because our sample size may have been too small, even if data were available.
Regarding the role of CREB1, Serretti et al. reported that among three known CREB1 polymorphisms (rs2253206, rs4675690, rs7569963), the rs7569963 polymorphism was the most associated with remission on antidepressant therapy.19) In contrast, CREB1 rs4675690 was more highly correlated with the antidepressant dose than CREB1 rs7569963 during maintenance therapy in the present study. Genotype distributions of the CREB1 rs4675690 and rs7569963 polymorphisms in Caucasian populations19) differ from those in Japanese populations and may justify this difference. For example, the frequency of the rs4675690 T allele is higher in Japanese populations than in Caucasian populations. We suggest that it is more important to analyze the genotype of CREB1 rs4675690 polymorphism in the Japanese population than in the Caucasian population for setting the maintenance dose for antidepressant therapy. Perlis et al. have also reported that the presence of the rs4675690 T allele of CREB1 is associated with a greater internal effort at anger control and a greater risk of treatment-emergent suicidal ideation in patients with major depressive disorders.32,33) Depressed patients can also have significantly greater levels of anger compared with normal controls,34) and bouts of anger can be improved by antidepressant treatment.35) This effect on anger might partially overlap with the effects on depression.36,37) We consider that CREB1 rs4675690 polymorphism is associated with CREB1 activity, and the patients without the C allele in CREB1 rs4657690 polymorphism requires setting for a higher maintenance dose than those with the C allele for antidepressant therapy. However, the amount of antidepressant dose for maintenance therapy is unclear from these results.
In contrast to the findings for CREB1, we did not observe any association between the BDNF rs6265 polymorphism and the antidepressant maintenance dose. This is consistent with several other reports in Japanese patients with depression in which the BDNF rs6265 polymorphism was not associated with antidepressant response.38–40) The effect of BDNF genetic variation on antidepressant treatment is modified by variations in the gene of CREB1.41) Furthermore, Serretti et al. examined the association between the haplotype of three CREB1 polymorphisms (rs2253206, rs4675690, rs7569963) and remission on antidepressant therapy in 190 Caucasian patients having major depression.19) However, because of our small sample size, we could not examine the association between antidepressant maintenance dose with the combination of BDNF rs6265 and the three CREB1 polymorphisms or the haplotype of three CREB1 polymorphisms. Further investigation is necessary to examine this association in a larger study.
In conclusion, we found that the concomitant diazepam equivalent dose and the presence of the CREB1 rs4675690 polymorphism were associated with antidepressant maintenance doses. These factors could be used to identify the dosing strategies.
Acknowledgments
This study was partly supported by a Grant-in-Aid for Young Scientists (Grant No. 23790191) and Scientific Research (Grant No. 25460191) from Japan Society for the Promotion of Science (JSPS).
Conflict of Interest
The authors declare no conflict of interest.
REFERENCES
- 1) World Health Organization (WHO). “Fact sheets N°369, depression.”: 〈http://www.who.int/mediacentre/factsheets/fs369/en/〉, October 2015.
- 2) Keller MB, Shapiro RW, Lavori PW, Wolfe N. Relapse in major depressive disorder: analysis with the life table. Arch. Gen. Psychiatry, 39, 911–915 (1982).
- 3) Kennedy N, Abbott R, Paykel ES. Remission and recurrence of depression in the maintenance era: long-term outcome in a Cambridge cohort. Psychol. Med., 33, 827–838 (2003).
- 4) Richards D. Prevalence and clinical course of depression: a review. Clin. Psychol. Rev., 31, 1117–1125 (2011).
- 5) Hardeveld F, Spijker J, De Graaf R, Nolen WA, Beekman AT. Recurrence of major depressive disorder and its predictors in the general population: results from the Netherlands Mental Health Survey and Incidence Study (NEMESIS). Psychol. Med., 43, 39–48 (2013).
- 6) American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder, third edition. American Psychiatric Association (2011).
- 7) Lam RW, Kennedy SH, Grigoriadis S, McIntyre RS, Milev R, Ramasubbu R, Parikh SV, Patten SB, Ravindran AV, Canadian Network for Mood and Anxiety Treatments (CANMAT). Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy. J. Affect. Disord., 117 (Suppl. 1), S26–S43 (2009).
- 8) Licht RW, Qvitzau S. Treatment strategies in patients with major depression not responding to first-line sertraline treatment. A randomised study of extended duration of treatment, dose increase or mianserin augmentation. Psychopharmacology (Berl.), 161, 143–151 (2002).
- 9) Blier P, Ward HE, Tremblay P, Laberge L, Hébert C, Bergeron R. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. Am. J. Psychiatry, 167, 281–288 (2010).
- 10) Furukawa TA, Streiner DL, Young LT. Antidepressant and benzodiazepine for major depression. Cochrane Database Syst. Rev., 1, CD001026 (2002).
- 11) Nakagawa A. Report of Ministry of Health, Labour Science Research Grant Special Research, International Comparison of Psychotropic Medication Prescription Patterns (2011).
- 12) Uchida H, Suzuki T, Mamo DC, Mulsant BH, Tsunoda K, Takeuchi H, Kikuchi T, Nakajima S, Nomura K, Tomita M, Watanabe K, Kashima H. Survey of benzodiazepine and antidepressant use in outpatients with mood disorders in Japan. Psychiatry Clin. Neurosci., 63, 244–246 (2009).
- 13) Uchida H, Suzuki T, Mamo DC, Mulsant BH, Kikuchi T, Takeuchi H, Tomita M, Watanabe K, Yagi G, Kashima H. Benzodiazepine and antidepressant use in elderly patients with anxiety disorders: a survey of 796 outpatients in Japan. J. Anxiety Disord., 23, 477–481 (2009).
- 14) Thoenen H. Neurotrophins and neuronal plasticity. Science, 270, 593–598 (1995).
- 15) Lonze BE, Ginty DD. Function and regulation of CREB family transcription factors in the nervous system. Neuron, 35, 605–623 (2002).
- 16) Finkbeiner S. Calcium regulation of the brain-derived neurotrophic factor gene. Cell. Mol. Life Sci., 57, 394–401 (2000).
- 17) Malberg JE, Blendy JA. Antidepressant action: to the nucleus and beyond. Trends Pharmacol. Sci., 26, 631–638 (2005).
- 18) Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112, 257–269 (2003).
- 19) Serretti A, Chiesa A, Calati R, Massat I, Linotte S, Kasper S, Lecrubier Y, Antonijevic I, Forray C, Snyder L, Bollen J, Zohar J, De Ronchi D, Souery D, Mendlewicz J. A preliminary investigation of the influence of CREB1 gene on treatment resistance in major depression. J. Affect. Disord., 128, 56–63 (2011).
- 20) Inada T, Inagaki A. Psychotropic dose equivalence in Japan. Psychiatry Clin. Neurosci., 69, 440–447 (2015).
- 21) Inoue K, Ando N, Suzuki E, Hayashi H, Tsuji D, Itoh K. Genotype distributions and allele frequencies of possible major depressive disorder-associated single nucleotide polymorphisms, cyclic adenosine monophosphate response element binding protein 1 rs4675690 and Piccolo rs2522833, in a Japanese population. Biol. Pharm. Bull., 35, 265–268 (2012).
- 22) Hayasaka Y, Purgato M, Magni LR, Ogawa Y, Takeshima N, Cipriani A, Barbui C, Leucht S, Furukawa TA. Dose equivalents of antidepressants: Evidence-based recommendations from randomized controlled trials. J. Affect. Disord., 180, 179–184 (2015).
- 23) Salzman C. Clinical Geriatric Psychopharmacology. 4. Lippincott Williams and Wilkins, Philadelphia (2005).
- 24) Tansella M, Micciolo R. Trends in the prescription of antidepressants in urban and rural general practices. J. Affect. Disord., 24, 117–125 (1992).
- 25) Hashimoto E, Tayama M, Ishikawa H, Yamamoto M, Saito T. Influence of comorbid alcohol use disorder on treatment response of depressive patients. J. Neural Transm. (Vienna), 122, 301–306 (2015).
- 26) Kato T, Kasahara T, Kubota-Sakashita M, Kato TM, Nakajima K. Animal models of recurrent or bipolar depression. Neuroscience, 321, 189–196 (2016).
- 27) Takeshima N, Ogawa Y, Hayasaka Y, Furukawa TA. Continuation and discontinuation of benzodiazepine prescriptions: A cohort study based on A large claims database in Japan. Psychiatry Res., 237, 201–207 (2016).
- 28) Soehner AM, Kaplan KA, Harvey AG. Prevalence and clinical correlates of co-occurring insomnia and hypersomnia symptoms in depression. J. Affect. Disord., 167, 93–97 (2014).
- 29) Bondy B. Pharmacogenomics in depression and antidepressants. Dialogues Clin. Neurosci., 7, 223–230 (2005).
- 30) Zhou SF, Di YM, Chan E, Du YM, Chow VD, Xue CC, Lai X, Wang JC, Li CG, Tian M, Duan W. Clinical pharmacogenetics and potential application in personalized medicine. Curr. Drug Metab., 9, 738–784 (2008).
- 31) Lloret-Linares C, Bellivier F, Haffen E, Aubry JM, Daali Y, Heron K, Berney P, Desmeules J, Besson M. Markers of individual drug metabolism: towards the development of a personalized antidepressant prescription. Curr. Drug Metab., 16, 17–45 (2015).
- 32) Perlis RH, Purcell S, Fagerness J, Cusin C, Yamaki L, Fava M, Smoller JW. Clinical and genetic dissection of anger expression and CREB1 polymorphisms in major depressive disorder. Biol. Psychiatry, 62, 536–540 (2007).
- 33) Perlis RH, Purcell S, Fava M, Fagerness J, Rush AJ, Trivedi MH, Smoller JW. Association between treatment-emergent suicidal ideation with citalopram and polymorphisms near cyclic adenosine monophosphate response element binding protein in the STAR*D study. Arch. Gen. Psychiatry, 64, 689–697 (2007).
- 34) Riley WT, Treiber FA, Woods MG. Anger and hostility in depression. J. Nerv. Ment. Dis., 177, 668–674 (1989).
- 35) Fava GA, Kellner R, Lisansky J, Park S, Perini GI, Zielezny M. Hostility and recovery from melancholia. J. Nerv. Ment. Dis., 174, 414–417 (1986).
- 36) Choi-Kwon S, Han SW, Kwon SU, Kang DW, Choi JM, Kim JS. Fluoxetine treatment in poststroke depression, emotional incontinence, and anger proneness: a double-blind, placebo-controlled study. Stroke, 37, 156–161 (2006).
- 37) Davidson JR, Landerman LR, Farfel GM, Clary CM. Characterizing the effects of sertraline in post-traumatic stress disorder. Psychol. Med., 32, 661–670 (2002).
- 38) Yoshimura R, Kishi T, Hori H, Ikenouchi-Sugita A, Umene-Nakano W, Katsuki A, Hayashi K, Iwata N, Nakamura J. No association between the response to the addition of an atypical antipsychotic drug to an SSRI or SNRI and the BDNF (Val66Met) polymorphism in refractory major depressive disorder in Japanese patients. Clin. Psychopharmacol. Neurosci., 10, 49–53 (2012).
- 39) Katsuki A, Yoshimura R, Kishi T, Hori H, Umene-Nakano W, Ikenouchi-Sugita A, Hayashi K, Atake K, Iwata N, Nakamura J. Serum levels of brain-derived neurotrophic factor (BDNF), BDNF gene Val66Met polymorphism, or plasma catecholamine metabolites, and response to mirtazapine in Japanese patients with major depressive disorder (MDD). CNS Spectr., 17, 155–163 (2012).
- 40) Yoshimura R, Kishi T, Suzuki A, Umene-Nakano W, Ikenouchi-Sugita A, Hori H, Otani K, Iwata N, Nakamura J. The brain-derived neurotrophic factor (BDNF) polymorphism Val66Met is associated with neither serum BDNF level nor response to selective serotonin reuptake inhibitors in depressed Japanese patients. Prog. Neuropsychopharmacol. Biol. Psychiatry, 35, 1022–1025 (2011).
- 41) Murphy GM Jr, Sarginson JE, Ryan HS, O’Hara R, Schatzberg AF, Lazzeroni LC. BDNF and CREB1 genetic variants interact to affect antidepressant treatment outcomes in geriatric depression. Pharmacogenet. Genomics, 23, 301–313 (2013).
