Minocycline as adjunctive therapy for patients with unipolar psychotic depression: An open-label study

Progress in Neuro-Psychopharmacology & Biological Psychiatry 37 (2012) 222–226

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Minocycline as adjunctive therapy for patients with unipolar psychotic depression: An open-label study Tsuyoshi Miyaoka ⁎, Rei Wake, Motohide Furuya, Kristian Liaury, Masa Ieda, Kazunori Kawakami, Keiko Tsuchie, Michiyo Taki, Kotomi Ishihara, Tomoko Araki, Jun Horiguchi Department of Psychiatry, Shimane University School of Medicine, Izumo, Japan

a r t i c l e

i n f o

Article history: Received 11 November 2011 Received in revised form 30 January 2012 Accepted 5 February 2012 Available online 10 February 2012 Keywords: Psychotic depression Minocycline Adjunctive therapy Open-label study

a b s t r a c t Background: Approximately 25% of patients admitted to a hospital as a result of depression are actually suffering from psychotic depression. Psychotic symptoms can be present in patients with either unipolar depression or bipolar depression and can be difficult to treat. It was reported the second-generation tetracycline may exert potential antidepressant effects through its robust neuroprotective activities, which include neurogenesis, antioxidation, and anti-glutamate excitotoxicity, and may direct regulation of pro-inflammatory agents. Methods: This was a 6-week, open-label study to evaluate the efficacy and safety of minocycline in combination with antidepressants in adult inpatients (n = 25) diagnosed with major depression with psychotic features (psychotic depression) according to DSM-IV-TR. The primary endpoint was the change from baseline in the Hamilton Depression Rating Scale (HAM-D-21) score from baseline to week 6. Secondary endpoints were changes in the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) Scale scores from baseline to week 6. Spontaneously reported adverse events were recorded. Results: The patients' average age was 46.9± 10.2 years. Minocyline (150 mg/day) in combination with antidepressants (fulvoxamine, paroxetine, and sertraline) provided significant improvement in depression. Mean (± SD) HAM-D-21 was reduced to 6.7 ± 1.9 at week 6 from a baseline value of 40.4± 2.5. Significant improvement of psychotic symptoms (mean ± SD) was indicated by the decrease in BPRS scores from baseline (63.3 ± 8.7) to week 6 (4.6± 2.4). No serious adverse events occurred. Conclusions: These preliminary data suggest that minocycline in combination with antidepressants is effective and well tolerated in the treatment of unipolar psychotic depression. Further studies using larger, doubleblind, parallel-group design are warranted to confirm these findings. © 2012 Elsevier Inc. All rights reserved.

1. Introduction Approximately 25% of patients admitted to the hospital as a result of depression are actually suffering from psychotic depression (Coryell et al., 1987). Psychotic symptoms can be present in patients with either unipolar depression or bipolar depression and can be difficult to treat. Patients with psychotic depression are likely to have poorer outcomes than patients with non-psychotic depression both with pharmacotherapy alone and in combination with psychotherapy (Coryell, 1996; Gaudiano et al., 2005). For example, mortality rates (measured as death within 15 years of first hospitalization) are significantly higher Abbreviations: DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision; HAM-D-21, 21-item Hamilton Rating Scale for Depression; SSRI, selective-serotonin reuptake inhibitor; BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impression; ITT, intent-to-treat; LOCF, last observation carried forward; ECT, electroconvulsive therapy. ⁎ Corresponding author at: Department of Psychiatry, Shimane University School of Medicine, 89-1 Enyacho, Izumo 693-8501, Japan. Tel.: + 81 853 20 2262; fax: + 81 853 20 2260. E-mail address: [email protected] (T. Miyaoka). 0278-5846/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2012.02.002

among patients with psychotic depression than those with nonpsychotic depression (41% versus 20%) (Vythilingam et al., 2003). Based on 10 randomized, controlled trials, Wijkstra et al. (2005, 2006) quantified that the combination of an antidepressants and an antipsychotic was more effective than an antipsychotic alone, while the benefit of their combination over an antidepressant alone did not reach significance. An earlier meta-analysis of lager sample of clinical studies, however, indicate that a combination was significantly more effective than both antipsychotic and antidepressant medication alone (Parker et al., 1992). Electroconvulsive therapy has been shown to be at least as effective as pharmacological treatment (Keller et al., 2007). Compared with non-psychotic depressed patients, those with psychotic depression appear to show a poor response to antidepressant medications alone as well as to combined antidepressant medication and psychotherapy treatment (Gaudiano et al., 2005). The latter findings, however, have been viewed as based only on limited data (Gaudiano et al., 2007). Recently, it was reported that combination atypical antipsychotics and antidepressants (Matthews et al., 2009; Meyers et al., 2009; Wijkstra et al., 2010). However, due to the occurrence of many adverse events (including extrapyramidal symptoms

T. Miyaoka et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 37 (2012) 222–226

and tardive dyskinesia), it is difficult to treat psychotic depression with antipsychotics. The second-generation tetracycline antibiotic drug minocycline has powerfully anti-inflammatory and neuroprotective effects (Maes et al., 2009; Ponzini, 2012). Although the precise mechanism of minocycline is currently unclear, the action of minocycline have been reported as follows: the inhibition of mitochondrial permeabilitytransition mediated cytochrome c release from the mitochondria, the inhibition of caspase-1 and -3 expressions, and the suppression of microglial activation, involvement in some signal pathways, and metalloprotease activity inhibition (Kim and Suh, 2009). In the forced-swim test, minocycline reduced immobility by increasing climbing (MolinaHernandez et al., 2008a). Co-administration of minocycline synergized the antidepressant-like action of sub-threshold doses of desipramine (but not fluoxetine), mGluR1 antagonist EMQMGM, mGluR5 antagonist MTEP, and NMDA receptor antagonist dizocilpine (Molina-Hernandez et al., 2008b). Thus, minocycline alone produced antidepressant-like actions in the forced-swim test, and the combination of sub-threshold dose of minocycline plus a sub-threshold dose of desipramine and several glutamate receptor antagonists produced antidepressant-like actions as well. These findings also suggest that minocycline may be use for the augmentation of noradrenergic antidepressant drugs (MolinaHernandez et al., 2008a; Pae et al., 2008). Furthermore, it was reported that minocycline attenuated lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines, and that this drug prevented LPSinduced development of depressive-like behaviors in mice (O'Gonnor et al., 2009). Interestingly, a case report documents the antidepressant effects of minocycline in a patient with bipolar disorder (Levine et al., 1996). Additionally, minocycline is reportedly efficacious in patients with schizophrenia (Ahuja and Carroll, 2007; Hashimoto, 2008; Levkovitz et al., 2010; Miyaoka, 2008; Miyaoka et al., 2007, 2008) as well as in animal models of schizophrenia (Fujita et al., 2008) and drug abuse (Hashimoto, 2009; Hashimoto et al., 2007; Zhang et al., 2006). Considering the role of immune-mediated alterations of glutamate in the neurobiology of psychotic depression, it may be of great interest to study whether or not minocycline displays antidepressant actions in patient with psychotic depression. And these reports suggested the need for clinical studies to elucidate whether minocycline has clinical efficacy as an antidepressant, and such studies will hopefully link antidepressant efficacy with biological markers of minocycline's neuroprotective and anti-inflammatory effects. This study investigated the efficacy and safety of minocycline in combination with antidepressants in patients with unipolar psychotic depression.

21-item Hamilton Rating Scale for Depression (HAM-D-21) (Hamilton, 1960) in order to confirm the severity of depression (Table 1). Exclusion criteria were known or suspected intolerance to minocycline, presence of another axis I psychiatric disorder, a history of medication non-adherence, substance dependence, or participation in another drug trial or compassionate use program within 4 weeks of the baseline visit, pregnancy or lactation (a pregnancy test was carried out at baseline and at week 4 and had to be negative in both instances), significant clinical or laboratory findings that may have interfered with the efficacy evaluation, or a medical history that included convulsive disorders, organic brain disorders, head trauma, severe allergic reactions, suicidal ideation, or any reason to indicate the patient may not be able to complete the study.

2.3. Study treatments All patients had been taking a stable dose of antidepressant medication for at least one month before baseline screening and entry into the open-label minocycline treatment phase of the study. Patients continued to take the same dose of antidepressant medication for the duration of their involvement in the protocol. All patients were taking selective-serotonin reuptake inhibitor (SSRI) medications, including fluvoxamine, paroxetine, and sertraline. After baseline assessment with the aforementioned instruments, minocycline treatment was initiated according to the following titration schedule: 50 mg orally twice daily for the first week, and 50 mg orally three times daily from weeks 2 through 6.

2.4. Efficacy endpoints The primary efficacy endpoint was the change from baseline to week 6 on the HAM-D-21. Response rates, the number of patients who achieved >50% reduction in the HAM-D score from baseline to endpoint, was also calculated. Secondary efficacy variables were changes from the baseline in Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962) and Clinical Global Impression (CGI) (Guy, 1976) scores at week 6.

Table 1 Baseline demographics and disease characteristics; intent-to-treat (ITT).

2. Methods

Demographic/disease characteristic

2.1. Study design

Sex, n (%) Male Female Mean age, years (SD) DSM-IV-TR diagnosis, n (%) Severe depressive episode with psychotic symptoms Recurrent depressive disorder, current episode severe with psychotic symptoms Medications Antidepressants, n (%) Flralvoxamine, n (%) Paroxetine, n (%) Sertraline, n (%) Axiolytics, n (%) Hypnotics, n (%) Antipsychotics, n (%) Mean disease duration, months (SD) Mean baseline HAMD-D (SD) Mean baseline BPRS (SD) Mean baseline CGI-S (SD)

This study was a 6-week, multicenter, open-label evaluation of minocycline (150 mg/day) in patients with unipolar psychotic depression. This study was approved by the Helsinki Committee (institutional review board) of the Department of Psychiatry of the Shimane University School of Medicine. Prior to participation, all subjects gave written informed consent according to institutional guidelines and the recommendations of the Declaration of Helsinki. 2.2. Patient selection Twenty-five patients experiencing symptoms of unipolar psychotic depression were enrolled in this study. All patients were adults, aged 20 to 60 years, with depression with psychotic features according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) (American Psychiatry Association, 2000). Inclusion criteria also required a baseline score of >25 points on the

223

Standard deviation = SD.

Minocycline in combination with antidepressants (n = 25) 13 (52) 12 (48) 46.9(10.2) 6 (24.0) 19 (76.0)

25 (100) 10 (40) 12 (48%) 3 (12%) 15 (60%) 15 (60%) 2 (8%) 58.6 (46.8) 40.4 (2.6) 63.3 (8.7) 5.8 (2.4)

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70

2.5. Safety endpoints The incidence of adverse events was recorded and a physical examination including vital signs, electroencephalogram, electrocardiogram and clinical laboratory tests was carried out. Adverse effects were systematically reviewed at each clinic visit by the investigators. In addition, the Side Effects Review Form, a listing of potential adverse effects common to minocycline, was completed. Assessments were carried out biweekly over the 6-week treatment period (four total assessments).

BPRS sum of scores

224

63.3

60 50 40

30.9

30 20 10 0

6.4

Baseline

2 weeks

4.6

4 weeks

6 weeks

Treatment week

2.6. Statistical analysis Analysis of the change from the baseline HAM-D-21 and BPRS scores were performed on the intent-to-treat (ITT) population with the last observation carried forward (LOCF) method. All data analyses were performed using Statistical Package for the Social Science Windows, Version 15.0 (SPSS, Chicago IL, USA). Descriptive statistics considered of the mean ± standard deviation (SD). Wilcoxon signed ranking test was conducted on the groups to determine statistical significance. We completed analysis for multiple comparisons using Bonferroni's adjustment with correction for correlation between observations. Significance for adjusted differences was set at P b 0.008. 3. Results

P<0.008 versus baseline (Wilcoxon and Wilcox) Fig. 2. BPRS total score at each assessment from baseline to week 6 (ITT, LOCF).

decrease in the mean (±SD) BPRS total score (P b 0.001) from baseline (63.28 ± 8.74), and at week 6 (4.56 ± 2.4) (Fig. 2). Improvements were observed across all items of the BPRS during the study and were statistically significant on the 12 subscale items of somatic concern (P b 0.001), anxiety (P b 0.001), emotional withdrawal (P b0.001), conceptual disorganization (P b 0.001), guilt feelings (P b 0.001), tension (P b 0.001), depressive mood (P b 0.001), hallucinatory behavior (P b 0.001), excitement (P b 0.001), and suspiciousness (P b 0.001) in 18 of 25 (72%) of patients at the end of the study.

3.1. Patients 3.4. Clinical improvement in symptoms The patients received a mean dose of 150 mg/day minocycline and an antidepressant during the study. The patients received minocycline in the dose ranges of 100 mg orally daily for first week, 150 mg orally daily from weeks 2, and all patients pushed to maximum dose (150 mg/day). The total duration of minocycline administration was 6 weeks. Concomitant medication was carbamazepine use by one patient and lithium use by two patients. 3.2. Improvement in depressive symptoms Patients treated with minocycline in combination with an antidepressant demonstrated a statistically significant reduction in the mean HAMD-21 score compared with the baseline from the first assessment (week 2) to the endpoint (week 6) (Fig. 1). A response (>50% reduction in HAMD-D score from baseline to endpoint) was achieved in 20 patients (80%). 3.3. Improvement in psychotic symptoms

HAM -D-21 sum of scores

Combined treatment with minocycline plus antidepressant significantly improved psychotic symptoms, as indicated by the 45 40

At baseline, all patients in the ITT population (n = 25) had a severity of illness score between 5 and 7, i.e. ‘marked’, ‘severe’, or ‘extreme’. Severity of illness was ameliorated over the 6-week period of treatment with minocycline plus antidepressants, and by week 6, only three patients had a disease rating score indicative of ‘moderate’ severity of illness. Table 2 illustrates the increasing number of patients with a disease severity classified as ‘mild’ following treatment with minocycline plus antidepressants (baseline: 0; week 2: 2; week 4: 4; week 6; 13). Similar increases in the number of patients classified as ‘borderline’ were noted over the 6-week treatment period (baseline: 0; week 2: 0; week 4:4; week 6: 7). 3.4.1. Safety and tolerability No serious adverse events were noted in any patient during this study. Laboratory parameters were within the normal range at baseline and remained in the reference range for the whole sample throughout the 6-week trial. There were no reports of serious adverse effects attributable to the study drug. The adverse effects were mild and transient (headache) in two cases. Minocycline was well tolerated overall, with no severe or serious adverse effects recorded during the study. None of the adverse effects was treatment limiting. No subjects exited the study due to drug-related adverse events.

40.4

3.4.2. Vital signs At baseline, mean systolic and diastolic blood pressures were 130.13 mm Hg and 82.38 mm Hg, respectively, and the mean pulse rate was 79.74 bpm. There were small fluctuations during treatment, and after 6 weeks of treatment, mean systolic and diastolic blood

35 30 25 21

20 15 10

6.4

5

4.7

0 Baseline

2 weeks

4 weeks

Table 2 Clinical Global Impression (CGI) severity of illness across treatment duration.

6 weeks

Treatment week P<0.008 versus baseline (Wilcoxon and Wilcox) Fig. 1. HAM-D total score at each assessment from baseline to week 6 (ITT, LOCF).

Timepoint

Not III

Borderline

Mild

Moderate

Marked

Severe

Extreme

Week Week Week Week

0 0 0 2

0 0 4 7

0 2 4 13

0 7 12 3

7 11 5 0

15 4 0 0

3 1 0 0

0 2 4 6

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pressures were 126 mm Hg and 79.78 mm Hg, respectively, and the mean pulse rate was 77.06 bpm.

4. Discussion To our knowledge, this is the first study to report the use of minocycline in combination with antidepressants in patients with psychotic depression, although previous case studies had suggested that minocycline alone may provide some efficacy in such patients (Catapano-Friedman, 2001). This study has now provided preliminary evidence that minocycline, in combination with antidepressants, is an effective treatment regimen in treating psychotic depression. Significant improvements were seen across the spectrum of symptoms in psychotic depression, as measured by HAMD-21, BPRS, and CGI rating scales. Minocycline in combination with antidepressants was well tolerated in patients with psychotic depression and was not associated with any unexpected adverse events. The incidence of side effects was low and they were generally mild. One patient experienced a single episode of headache which did not lead to study withdrawal. There were no serious adverse events. The results of this preliminary study support those of the other studies that indicate the efficacy of a combination of a minocycline and antidepressant in patients with psychotic depression (Pae et al., 2008). Given the debilitating nature of psychotic depression, it is imperative to seek new treatments that improve the current mainstays of psychiatric practice. Combination pharmacotherapy (antidepressant + antipsychotic) is often the first-line treatment for this patient population, and electroconvulsive therapy (ECT) is usually reserved for more severe cases. Although these treatment options have some utility in this patient population, they also present very real drawbacks. The newer generation antipsychotics often prescribed for this condition are known to increase a patient's risk of obesity, diabetes, and metabolic syndrome (Baptista et al., 2004) and patients with mental illness already have an approximately two-fold higher all-cause mortality rate relative to the general population. ECT is associated with adverse cognitive effects, financial burden, and is, unfortunately, associated with substantial social stigma. Recently, the concept of the pathogenesis of major depression has been extended to include alterations in brain inflammatory mediators and disruption of neuroprotection in the limbic system. Preclinical and clinical studies have demonstrated that major depression is associated with systemic immune action or inflammatory response (Maes, 1995; Maes et al., 2009). Many subsequent studies have also indicated that increased production of proinflammatory cytokines may play a role in the pathophysiology of major depression. Recent evidence also suggests that impaired neuroprotection is highly involved in the pathogenesis of major depression (Pae et al., 2008). For example, decreased neuronal survival and disordered neurogenesis in the hippocampus have been repeatedly found in patients with major depression and are now considered to be potential pathophysiological factors and therapeutic targets for major depression (Arakawa et al., 2012; Czeh and Lucassen, 2007; Perera et al., 2007). In this regard, the second-generation tetracycline minocycline has powerful anti-inflammatory and neuroprotective effects and is a potential new agent for treatment of major depression (Hashimoto, 2009; Hashimoto and Ishima, 2010; Maes et al., 2009). Hence, we propose that minocycline may exert potential antidepressant effects through its robust neuroprotective activities which include neurogenesis, antioxidation, anti-glutamate excitotoxicity, and direct regulation of pro-inflammatory agents. Based on findings from animal and human studies with minocycline, several lines of evidence support the hypothesis that minocycline may ameliorate major depression

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through anti-inflammatory activity and neuroprotection (neurogenesis, antioxidation, and anti-glutamate excitotoxicity). It is of interest to know the clinical outcome after minocycline discontinuation and the possible difference of outcome when used as augmentation to antidepressants with different mechanism of action. The study of this subject is going now in our laboratories. This study had several limitations. First, the open-label design, small patient population, and absence of a control group make it difficult to draw conclusions with substantial clinical confidence. Second, although other antidepressants may provide more effective antidepressant treatment than the antidepressants used (Sanchez et al., 2004), there were none available in Japan at the time this study was carried out. Third, because patients with depression often require long-term treatment to achieve remission, studies longer than 6 weeks in duration are warranted. Fourth, as doses of both minocycline and antidepressants were flexibly prescribed, the specific contribution of each drug to the improvement in symptoms cannot be evaluated. However, the preliminary findings indicate that minocycline in combination with an antidepressant shows promising efficacy and is well tolerated in the treatment of patients with unipolar psychotic depression. 5. Conclusions These results, together with previous evidence supporting the efficacy of minocycline monotherapy in patients with depressive symptoms in schizophrenia and bipolar depression (Miyaoka, 2008), suggest that it may be useful to evaluate the efficacy of this antipsychotic monotherapy in unipolar psychotic depression. Undoubtedly, these findings warrant further investigation in a larger, adequately powered, and well-controlled studies. Acknowledgements Part of this work was supported by Grant-in-Aid for Scientific Research on Priority Areas No. 13770544 and 50284047 from the Ministry of Education, Science, Sports and Culture of Japan. The authors thank Dr. Kenta Murotani, Ph.D., (Translational Research Informatics Center, Foundation for Biomedical Research and Innovation) for precious advice about statistical analysis. References Ahuja N, Carroll BT. Possible anti-catatonic effects of minocycline in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:968–9. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders4th Edition. ; 2000. Text Revision,. Arakawa S, Shirayama Y, Fujita Y, Ishima T, Horio M, Muneoka K, Iyo M, Hashimoto K. Minocycline produced antidepressant-like effects on the learned helplessness rats with alterations in levels of monoamine in the amygdale and no changes in BDNF levels in the hippoicampus at baseline. Prog Neuropsychopharmacol Biol Psychiatry 2012;100:601–6. Baptista T, Zarate J, Joober R, Colasante C, Beaulieu S, Paez X, et al. Drug induced weight gain, an impediment to successful pharmacotherapy: focus or antipsychotics. Curr Drug Targets 2004;5:279–99. Catapano-Friedman L. Effectiveness of quetiapine in the management of psychotic depression in an adolescent boy with bipolar disorder, mixed, with psychosis. J Child Adolesc Psychopharmacol 2001;11:205–6. Coryell W. Psychotic depression. J Clin Psychiatry 1996;57(Suppl. 3):27–31. Coryell W, Lavori P, Endicott J, Keller M, VanEerdewegh M. Outcome in schizoaffective, psychotic, and nonpsychotic depression. Course during a six- to 24-month followup. Arch Gen Psychiatry 1987;41:787–91. Czeh B, Lucassen PJ. What causes the hipocampal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated? Eur Arch Psychiatry Clin Neurosci 2007;257:250–60. Fujita Y, Ishima T, Kunitachi S, Hagiwara H, Zhang L, Iyo M, et al. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antibiotic drug minocycline. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:336–9. Gaudiano BA, Beevers CG, Miller IW. Differential response to combined treatment in patients with psychotic versus nonpsychotic major depression. J Nerv Ment Dis 2005;193:625–8.

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