SEARCH

SEARCH BY CITATION

Keywords:

  • affective disorders;
  • medicine;
  • pharmacopsychiatry;
  • primary care;
  • psychiatry

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The aim of the present 12-week, open-label study was to investigate the effect of olanzapine augmentation in outpatients with depression with melancholic features who demonstrated partial response to standard antidepressants but who were reluctant to change antidepressants. The subjects consisted of 22 outpatients meeting the DSM-IV-TR criteria for major depression. Olanzapine was initially added at 2.5 mg/day and the dose was adjusted according to the clinical condition. Data were analyzed using an intention-to-treat methodology. A paired t-test was used to compare total Montgomery Asberg Depression Rating Scale (MADRS) scores before treatment, at baseline (prior to olanzapine), and 4, 8, and 12 weeks after starting olanzapine. Of 22 enrolled patients, 20 completed the trial. The mean (±SD) MADRS score was 17.1 ± 1.0 at baseline and decreased significantly to 8.1 ± 3.2 at 4 weeks after the administration of olanzapine. This significant reduction continued until 12 weeks, when the mean MADRS score was 4.9 ± 2.9, indicating full remission. These results suggest that olanzapine augmentation may be useful for patients with depression in partial remission. A controlled, double-blind trial, however, is needed to confirm these preliminary findings.

RECENT RESEARCH HAS focused on the importance of achieving complete remission in the treatment of depression. This is because patients who have an insufficient response, even to various antidepressants, are thought to be at risk of relapse. The rate of recurrence of depression is reportedly approximately 15% within 6 months, 30% within 1 year, and at least 70% within 5 years.1 It is therefore important to look for other medication options in order to help patients achieve complete remission from depression. But even experienced clinicians may hesitate to seek an alternative drug treatment that ensures minimal hindrance to social and occupational function for patients who do not achieve complete remission. If there were an effective augmentation without serious side-effects, it would be very useful for clinicians, and important for patients.

Olanzapine, a multi-acting receptor-targeted antipsychotic (MARTA) is known to act on various neurotransmitters in the brain. As a result, olanzapine is useful for depressive symptoms or anxiety in patients with schizophrenia.2,3 Recently, olanzapine has been used in affective disorders, particularly refractory depression,4 and it has been prescribed for these disorders in combination with fluoxetine in the USA.5,6

In the present study we investigated the efficacy of olanzapine augmentation in outpatients with depression with melancholic features who failed to achieve complete remission after authentic antidepressant therapy. These patients had responded to standard antidepressants such as selective serotonin re-uptake inhibitors (SSRI), serotonin noradrenalin re-uptake inhibitors (SNRI), and tricyclic antidepressants (TCA) but had not achieved complete remission, and they were reluctant to change their antidepressant.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Subjects

This study was a non-randomized, 12-week, open-label trial. Subjects were 22 outpatients who met the criteria for DSM-IV-TR major depressive disorder with melancholic features. Their scores on the Montgomery Asberg Depression Rating Scale (MADRS) after standard antidepressant therapy had decreased to ≤20 points, defined as depression in partial remission, but they had not achieved complete remission (MADRS <9). We defined a MADRS score of ≤20 as depression in partial remission following Montgomery and Asberg, who reported that a MADRS score in the range 12–20 is equivalent to mild depression.7 With regard to choice of antidepressant, we used the following algorithm: SSRI were the first-line choice, SNRI were the second, and TCA were the third.8 Subjects were not willing to change to another antidepressant because they had achieved some response and were concerned about side-effects from a new antidepressant. In addition to the existing antidepressant, subjects took olanzapine at a dose of 2.5 mg/day before bedtime after MADRS scores had been stable for >12 weeks. Olanzapine was started at a dose of 2.5 mg/day because Asian subjects have been reported to have decreased tolerance to antipsychotic medications as compared to European subjects.9 The dose of olanzapine was adjusted in 2.5-mg increments according to clinical condition. Subjects were not permitted to use any psychotropic drugs other than benzodiazepines for insomnia. Concomitant medications that had been prescribed before starting olanzapine augmentation were not changed.

Procedure

The MADRS scores were assessed by a psychologist and used for the assessment of depressive symptoms at baseline (a point in time at which MADRS scores had been restored to 20 following treatment with preceding antidepressants, but had not improved further for more than 12 weeks), and at 4, 8, and 12 weeks after starting olanzapine. Serum levels of glucose, triglycerides, and total cholesterol were checked at both baseline and 12 weeks after administration of olanzapine. Prior to study enrollment, all subjects gave written informed consent to participate. The Institutional Review Board of Kyowa Hospital approved this study.

Statistical analysis

An intent-to-treat analysis was completed, including all patients enrolled in the present study. A paired t-test was used to assess changes in MADRS score and laboratory data from baseline to 4, 8, and 12 weeks after administration of olanzapine (P < 0.05). Complete remission was defined as a MADRS score ≤9.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Subject characteristics and clinical efficacy are shown in Table 1. Twenty-two outpatients (mean age, 61.0 ± 16.0 years; M : F, 6:5) participated in the study; two dropped out because of poor response or reluctance to take supplementary olanzapine. Twenty subjects took 20 or 40 mg paroxetine once a day, six took 50–130 mg milnacipran twice a day, two took 60–180 mg imipramine three times a day, and two took 100 mg sertraline or 100 mg fluvoxamine, respectively, once a day before starting augmentation with olanzapine.

Table 1.  Subject characteristics and total MADRS scores
Age (years)/sexNo. past depressive episodesAntidepressants (mg/day)Concomitant medications (mg/day)Olanzapine dosage (mg/day)Maintenance period at baseline (weeks)Total MADRS score
Before medicationBaseline4 weeks8 weeks12 weeks
  1. MADRS, Montgomery Asberg Depression Rating Scale.

47 M0Paroxetine (40)Alprazolam (0.2), lormetazepam (1.0)2.5163017432
49 F0Paroxetine (40)Lormetazepam (1.0), brotizolam (0.25)2.5203117422
57 M0Paroxetine (40)2.5123718322
32 M0Paroxetine (40)Lormetazepam (1.0)51232161236
61 M0Paroxetine (40)2.5242717742
74 M1Paroxetine (40)2.5202416622
80 M0Milnacipran (100)Lormetazepam (1.0), brotizolam (0.25)2.5243716622
60 M0Imipramine (180)Lormetazepam (1.0), triazolam (0.25)51248191243
74 F1Imipramine (60)Lormetazepam (1.0)52424161144
25 M0Paroxetine (40)Zopiclone (7.5), flurazepam (15)2.5133217522
57 F0Milnacipran (130)2.5162716665
61 F0Sertraline (100)Zolpidem (10), flunitrazepam (1.0)2.5184016411
66 F0Paroxetine (20)Zolpidem (5.0), lormetazepam (1.0)51443161176
80 M0Milnacipran (50)Brotizolam (0.25), triazolam (0.25)51634181296
77 F1Fluvoxamine (100)Brotizolam (0.25)2.5143516433
75 F1Milnacipran (50)Triazolam (0.25), flurazepam (15)2.5124019964
77 F1Milnacipran (80)Clotiazepam (10)51227181183
34 M1Paroxetine (40)51232171264
51 F1Paroxetine (40)Brotizolam (0.25)2.5143118854
77 F2Milnacipran (50)Triazolam (0.25), flurazepam (15)2.5143419864
75 M2Paroxetine (40)2.51629171010 
54 M0Paroxetine (40)2.5163417   

The mean (±SD) total MADRS score before treatment with antidepressants was 33.1 ± 5.9. The dosage of antidepressants in patients 9 and 13 was suboptimal because further increase in dose induced troublesome side-effects such as drowsiness and sedation.

Concerning biochemical data, triglyceride level increased to 249 mg/dL (reference range: 30–150 mg/dL) in patient 22 but rapidly fell to 132 mg/dL after olanzapine was stopped. We examined neurological findings at each stage and confirmed that there were no extrapyramidal side-effects. The mean MADRS score decreased significantly from 17.1 ± 1.0 at baseline to 8.1 ± 3.2 at 4 weeks, 5.0 ± 2.5 at 8 weeks, and 4.1 ± 2.9 at 12 weeks (P < 0.001). All patients achieved complete remission except for the two who dropped out of the study. The mean MADRS score at the end of the study was 4.1 ± 2.9, equivalent to that in healthy volunteers.10

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In the present study the mean (±SD) MADRS score before medication was 33.1 ± 5.9 compared with 17.1 ± 1.0 at baseline after standard therapy with SSRI, SNRI, or TCA. This represents a decrease of 51.7% in MADRS score, indicating that the present subjects were responders to standard antidepressant medications. Other reports investigating the effect of olanzapine augmentation in major depressive disorder have found mean MADRS scores at baseline of 30.0 ± 6.8 and 33.6 ± 3.5.4,6 These relatively high baseline MADRS scores probably relate to the fact that the previous studies investigated the efficacy of augmentation with olanzapine in refractory depression. Therefore, to our knowledge, the present study is the first to assess the effect of olanzapine in patients who had partial response to conventional therapy and who could be considered to be in quasi-complete remission.

It is also worth noting that the definition of complete remission on the basis of MADRS score varies from <1211 to 10.9 Zimmerman et al. also reported that total MADRS score in healthy volunteers was ≤4 points.10 In the present study the mean total MADRS score at the end of the study was 4.1 ± 2.9, indicating that subjects achieved complete remission, and that augmentation with olanzapine was very useful.

Many studies have suggested that the efficacy of antidepressants should be evaluated after 8–10 weeks of treatment. In the present study, subjects took olanzapine after more than 12 weeks of treatment with preceding antidepressants. Because MADRS scores did not show further improvement during this period, we considered that the effect of the previous treatment did not continue during the augmentation phase in the present subjects. Generally, clinicians often attempt to avoid prescribing excessive antidepressants to elderly patients due to the possibility of side-effects. Consequently, elderly patients may not be able to achieve complete remission. In the present study, many of the subjects were elderly (mean age 61 years). Interestingly, however, augmentation with olanzapine did not result in serious side-effects, and many of the subjects were able to achieve complete remission in MADRS score following low-dose augmentation with olanzapine.

The pharmacological mechanism of augmentation with olanzapine is not clear, but several authors have suggested worthwhile hypotheses.3,12 We speculate that olanzapine, having multiple actions on important neurotransmitters such as dopamine, serotonin, and noradrenalin, may act synergistically with various antidepressants to increase treatment efficacy. We believe that olanzapine augmentation in depression in partial remission with melancholic features is a unique strategy for the following reasons: (i) the combination is well tolerated without any serious side-effects; and (ii) the effect is seen as soon as 4 weeks after adding olanzapine.

The present results should be interpreted in light of one key limitation: because the sample size was only 22 and there was no control group, the findings are considered to be preliminary. Further studies with a controlled, double-blind design are needed to confirm the observations.

Complete remission should be established as a goal of treatment in order to prevent future relapse. The present study suggests that olanzapine augmentation is effective in bringing about complete remission in patients with major depressive disorder with melancholic features who responded only partially to treatment with other antidepressants. There are some reports examining the effect of augmentation with olanzapine for major depressive disorder with melancholic features.4,13,14 Because the present results suggest that augmentation with olanzapine may be useful particularly in cases of major depressive disorder with melancholic features, this is the recommended choice despite its sedative effect.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Angst J. Major depression in 1998: Are we providing optimal therapy? J. Clin. Psychiatry 1999; 60: 59.
  • 2
    Tollefson GD, Sanger TM, Beasley CM, Tran PV. A double-blind, controlled comparison of the novel antipsychotic olanzapine versus haloperidol or placebo on anxious and depressive symptoms accompanying schizophrenia. Biol. Psychiatry 1998; 43: 803810.
  • 3
    Tran PV, Hamilton SH, Kuntz AJ et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J. Clin. Psychopharmacol. 1997; 17: 407418.
  • 4
    Takahashi H, Kamata M, Yoshida K, Higuchi H, Ishigooka J. Augmentation with olanzapine in TCA-refractory depression with melancholic features: A consecutive case series. Hum. Psychopharmacol. 2008; 23: 217220.
  • 5
    Shelton RC, Williamson DJ, Corya SA et al. Olanzapine/fluoxetine combination for treatment-resistant depression: A controlled study of SSRI and nortriptyline resistance. J. Clin. Psychiatry 2005; 66: 12891297.
  • 6
    Corya SA, Williamson D, Sanger TM, Briggs SD, Case M, Tollefson G. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Depress. Anxiety 2006; 23: 364372.
  • 7
    Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br. J. Psychiatry 1979; 134: 382389.
  • 8
    Shioe K, Hirano M, Kanba S. The treatment algorithm of major depressive disorders. In: OhhashiN (ed.). Pharmacological Treatment Algorithm of Mood Disorder. Jihou, Tokyo, 2003; 1946.
  • 9
    Binder RL, Levy R. Extrapyramidal reactions in Asians. Am. J. Psychiatry 1981; 138: 12431244.
  • 10
    Zimmerman M, Posternak MA, Cheminski I. Derivation of a definition of remission on the Montgomery-Asberg depression rating scale corresponding to the definition of remission on the Hamilton rating scale for depression. J. Psychiatr. Res. 2004; 38: 577582.
  • 11
    Montgomery SA, Andersen HF. Escitalopram versus venlafaxine XR in the treatment of depression. Int. Clin. Psychopharmacol. 2006; 21: 297309.
  • 12
    Li XM, Perry KW, Wong DT, Bymaster FP. Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum. Psychopharmacology 1998; 136: 153161.
  • 13
    Huang CC, Shiah IS, Chen HK, Mao WC, Yeh YW. Adjunctive use of methylphenidate in the treatment of psychotic unipolar depression. Clin. Neuropharmacol. 2002; 31: 2457.
  • 14
    Matthews JD, Bottonari KA, Polania LM et al. An open study of olanzapine and fluoxetine for psychotic major depressive disorder: Interim analyses. J. Clin. Psychiatry 2002; 63: 11641170.