Author's Accepted Manuscript
Depression treatment by withdrawal of shortterm low-dose antipsychotic, a proof-ofconcept randomized double-blind study Sidney H. Kennedy, Franca Placenza, Craig J. Hudson, Philip Seeman, Mary V. Seeman
www.elsevier.com/locate/jad
PII: DOI: Reference:
S0165-0327(14)00198-0 http://dx.doi.org/10.1016/j.jad.2014.04.014 JAD6681
To appear in:
Journal of Affective Disorders
Received date: 14 March 2014 Accepted date: 11 April 2014 Cite this article as: Sidney H. Kennedy, Franca Placenza, Craig J. Hudson, Philip Seeman, Mary V. Seeman, Depression treatment by withdrawal of short-term low-dose antipsychotic, a proof-of-concept randomized double-blind study, Journal of Affective Disorders, http://dx.doi.org/10.1016/j.jad.2014.04.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Mar. 1, 2014 Journal of Affective Disorders Abstract words: 246 Text Words: 2,123
Depression treatment by withdrawal of short-term low-dose antipsychotic, a proof-of-concept randomized double-blind study Sidney H. Kennedy*1, Franca Placenza1, Craig J. Hudson2, Philip Seeman3, and Mary V. Seeman3 1
Department of Psychiatry, Toronto General Hospital, University Health Network, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. 2
Department of Psychiatry, Alexandra Marine and General Hospital, 120 Napier Street, Goderich, Ontario, Canada N7A 1W5. 3
Clera Inc., 260 Heath Street West, Unit 605, Toronto, Ontario, Canada M5P 3L6.
*Corresponding author: E-mail address: [email protected] Keywords: Depression, Antidepressant, Antipsychotic, Dopamine D2High receptor Dopamine supersensitivity
1
ABSTRACT Background and Objective: Because increased dopamine neurotransmission occurs with most antidepressants, and because antipsychotics cause behavioural supersensitivity to dopamine, short-term low-dose antipsychotic treatment was tested on depressed patients with an expectation of clinical improvement in the supersensitive phase following drug withdrawal.
Method:
This was a randomized, double-blind, placebo-controlled study of 48
patients who met criteria for DSM-IV® Major Depressive Disorder, were in a Major Depressive Episode, and had a Hamilton Depression Rating Scale (HAMD) rating of 14. Half the participants received 0.25 mg oral haloperidol each day for 7 days, after which they received placebo daily for 4 weeks. The other half received placebo throughout the trial.
Results:
One week after stopping the medication, the HAMD ratings of the drug-
treated patients fell by 9.96 points, as compared to a reduction of 8.73 points in the placebo-treated patients, when comparing visits 1 and 4. There was no such difference when comparing visits 2 and 4. The differences were not significant, but indicated a trend. One week after the medication was stopped, the Clinical Global Index fell 1.64 ± 0.18 units for the medication-treated patients, compared to 1.12 ± 0.26 units for the placebo group (P = 0.05). The regimen was well tolerated.
Conclusions: Seven days of an ultra-low dose of 0.25 mg haloperidol, followed by withdrawal of haloperidol, resulted in clinical depression improvement greater than placebo and significantly decreased psychomotor retardation, consistent with haloperidolinduced behavioural supersensitivity to dopamine.
Limitations: The sample was small. More patients are needed in a future study.
2
1. Introduction Major Depressive Disorder (MDD) is one of the most prevalent mental health problems worldwide and brings with it considerable social and economic burdens. One person in five fulfills the Diagnostic and Statistical Manual of Mental Disorders (DSM IVTR) criteria for MDD over the course of a lifetime (Üstün et al., 2000). Although there is a considerable difference in the range of symptoms (persistent sadness, loss of self esteem, difficulty concentrating, guilt, hopelessness, avoiding other people, loss of appetite, loss of interest or pleasure, and suicidal thoughts) and in their severity, role functioning is usually affected adversely and the toll of disability is high. In 2000, MDD was the fourth leading cause of global disease burden, accounting for 4.4% of total disability-adjusted life-years (DALYs), causing the largest amount of non-fatal burden, and represents 12% of all total years lived with disability (Üstün et al., 2000). By 2020, it is predicted that MDD will be second among all diseases in the International Burden of Disease (Reddy, 2010)
The present study examines whether enhanced dopamine supersensitivity can quickly, if transiently, alleviate depressive symptoms. Most antidepressants take time to have therapeutic efficacy and need to be taken for at least one year and up to lifetime, depending upon risk factors for recurrence and patient preference (Suehs et al., 2008) . They include compounds that inhibit the neural uptake of norepinephrine, serotonin, and dopamine, or stimulate the receptors for these neurotransmitters, but there are currently no strategies for enhancing the sensitivity of these receptors so that patients can respond more quickly and at lower doses.
The purpose of this study, therefore, was to enhance dopamine supersensitivity in patients by means of an ultra-low antipsychotic dose for a brief period (7 days) and then withdraw the drug in the expectation of a clinical improvement after drug withdrawal, when dopamine supersensitivity is known to occur (Seeman, 2011). The molecular mechanism underlying this type of post-antipsychotic supersensitivity is the induction of dopamine D2High receptors by the antipsychotic (Seeman, 2011). The dopamine D2 receptor is the major target of antipsychotic drugs. The D2 receptor can exist in either a
3
state of high-affinity for dopamine, known as D2High, or in a state of low affinity for dopamine, known as D2Low. The D2High state is known to be the functional state of the D2 receptor (George et al., 1985).
It has been shown that treatment with antidepressant drugs (at normal antidepressant doses) produces a sensitization of behavioural responses to agonists acting at dopamine D2 receptors (so-called dopamine supersensitivity; Willner, 1997; Healy and McKeon, 2000; Spyraki and Fibiger, 1981; Kapur and Mann, 1992). Such a sensitizing action presumably assists in eliciting the clinical antidepressant effect. However, in contrast to the strategy of the present study, the antidepressant doses used in these earlier studies were maintained for relatively long periods of time.
Although the use of antipsychotics for depression has been controversial (Robertson and Trimble, 1982), the antidepressants amoxapine and trazodone appear to exert both antidepressant and antipsychotic effects (Apiquian et al., 2003). In addition, Robertson and Trimble (1982) have summarized studies showing that thioridazine, chlorpromazine, perphenazine, fluphenazine, thiothixene, flupenthixol, and chlorprothixene are as effective as imipramine, amitriptyline, or doxepin in treating depression, especially within the context of psychosis or schizophrenia. The doses of these antipsychotics for treating depression are generally lower than for psychosis. More recently, there have been reviews of low doses of the atypical antipsychotic amisulpride (50-100 mg/day) or levo-sulpiride (50-150 mg/day) used for dysthymia, a mild chronic form of depression (Pani and Gessa, 2002; Mucci et al., 1995). Blier (2013) has recently addressed the wider issue of using low dose atypical antipsychotics for depression.
However, the brief use of drugs that sensitize dopamine D2 receptors in order to effect a rapid, if transient, reversal of depression has not been previously described. The present study employed a short-term ultra-low-dose antipsychotic and sought to determine whether the subsequent rebound dopamine supersensitivity would be clinically beneficial in alleviating depressive symptoms.
4
2. Method The study was approved by Health Canada as “A pilot placebo-controlled, double-blind, randomized parallel group study to evaluate the efficacy of treatment with CLR3001 in depression”. Haloperidol (CLR3001) was given at a dose of 0.25 mg once per day orally in capsule form. The placebo, prepared commercially, was identical in shape and colour to the drug-containing pill. The protocol was approved by the Research Ethics Board of the University Health Network (Toronto, Ontario) where the study was conducted. At the beginning of the study, subjects were informed of the possibility of receiving a placebo at the start of the study. A series of 70 subjects (a sample size calculated to allow for drop-outs and to have sufficient power to reliably distinguish between 1 and 2 weeks after drug discontinuation in the two groups – 80% at the p=0.05 level) was recruited by advertisement in newspapers and posters in Toronto, Ontario, Canada, as well as by physician referral. Participants were randomized after providing written consent. Inclusion criteria were: male or female outpatients aged 18 to 65 years meeting criteria for Major Depressive Disorder with a current Major Depressive Episode as per DSM-IV® and no more than 5 prior episodes. Patients had to be antidepressantfree for at least one week (28 days for prior fluoxetine and 14 days for prior irreversible monoamine oxidase inhibitors), not currently receiving psychotherapy, and able to provide written informed consent. The HAMD-17 score had to be 14 at both screening and at randomization visits. Patients had to be able to understand and complete questionnaires, and communicate with the study coordinator. Female participants of childbearing potential or those who were not at least 2 years postmenopausal or surgically sterile or totally abstinent or whose partner had a vasectomy needed to be using a reliable, medically acceptable form of contraception and agreeable to continuing such use throughout the duration of the study. Exclusion criteria were the following: investigators and immediate family members, treatment within the last 90 days with a drug that had not received regulatory approval at the time of study entry, lifetime diagnosis of bipolar disorder or any form of psychotic disorder, a primary diagnosis of Panic Disorder, Generalized Anxiety Disorder, Post-Traumatic Stress Disorder, Social Anxiety Disorder, Obsessive-Compulsive Disorder within the past year, the presence of
5
an Axis II disorder, which, in the opinion of the investigator, would interfere with compliance in the study. At screening, a medical history was recorded and laboratory tests (electrocardiogram, clinical chemistry, hematology and urinalysis) were completed. The Mini Neuropsychiatric Interview (MINI) was used to confirm MDD diagnosis and current MDE. At each visit, the patient was evaluated by a psychiatrist. The HAMD-17 rating scale was used to assess the severity of depression symptoms and the Clinical Global Impressions (CGI) scale was used to provide the clinician’s general impression of the severity of the patient’s condition. Because of the known ability of antipsychotics to induce behavioural dopamine supersensitivity and dopamine D2High receptors (Seeman et al., 2005), the psychomotor retardation item on HAMD-17 was identified a priori for individual item analysis. In addition, the Simpson Angus Scale (Simpson and Angus, 1970) was used to screen for extrapyramidal side effects at each study visit. The protocol called for a total of 7 visits, where visit 1 was considered the screening visit and visit 2 served as the baseline visit, but both visits were used for a final analysis. The medication or the placebo was taken daily after the second visit until the third visit. Forty-eight subjects completed the protocol to at least Visit 4, the week following discontinuation of the treatment, resulting in 26 control and 22 treated evaluable subjects. Reasons given for early drop out are shown in Figure 1.
3. Results
HAMD-17 ratings: The placebo-treated patients (N = 26) had an average HAMD-17 score of 21.69 ± 0.74 (mean ± s.e.) at visit 1, and 21.96 ± 0.75 at visit 2, before starting the placebo. At visit 4, the average HAMD-17 score was 12.96 ± 1.16, a reduction of 8.73 points from visit 1 and a reduction of 9.00 points from visit 2 (Table 1).
6
The drug-treated patients (N = 22) had an average HAMD-17 score of 22.36 ± 0.8 (mean ± s.e.) at visit 1, and a rating of 21.35 ± 0.95 at visit 2, before starting the medication. At visit 4, which was one week after stopping the medication, the average HAMD-17 score was 12.4 ± 1.1 (mean ± s.e.), a reduction of 9.96 points, as compared to a reduction of 8.73 points in the placebo group at visit 1 (Table 1, Fig. 2). However, the reduction was 8.95 points from visit 2 when compared to a 9.00 point reduction in the placebo group (Table 1). CGI-I: The difference in the CGI-I score (between visit 1 and visit 4) averaged 1.12 ± 0.26 (mean ± s.e.) points for the placebo-treated patients (N = 26), and 1.64 ± 0.18 points for the drug-treated patients (N = 22) (P = 0.05, using a 1-tailed t-test with unequal variance) (Fig. 3). Psychomotor rating: For Question #8 on the HAMD-17, the value for the control subjects (N = 27) was 0.87 points (maximum was 4 points), while that for the drug-treated subjects (N = 22) was 1.25 points (values compare visit 2 with visit 4) (Fig.4). The difference between visit 1 and visit 4 averaged 0.35 ± 0.13 (mean ± s.e.) points for the placebo-treated patients, and 0.84 ± 0.15 points for the drug-treated patients (P = 0.0098, using a 1-tailed t-test with unequal variance) (Fig. 3). Safety: Side effects in this study were few. Transient headache was reported in 11 placebo-treated subjects and in 9 drug-treated subjects. Slight muscle stiffness was reported in 6 drug-treated participants, but disappeared within a week. One drug-treated participant who dropped out had a generalized rash, which faded after drug withdrawal. One placebo-treated subject reported itchy skin. No clinically significant extrapyramidal side-effects occurred. The Simpson Angus scores were essentially nil throughout.
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4. Discussion The results indicate that one week after the withdrawal of haloperidol 0.25 mg, the reduction in depressive symptoms exceeded that found with placebo treatment, when comparing visits 4 and 1, but not when comparing visits 4 and 2 (Table 1). Although the drug lowered the HAMD-17 score by 9.96 points (as compared to visit 1), which was 1.22 points or 14% more than the reduction in the placebo group, this effect was not statistically significant. However, both the CGI-I and the psychomotor subscale showed statistically significant improvements over placebo. Interestingly, although the difference of 1.22 points between the drug and the placebo on the HAMD-17 was less than the ideal of 3 points, the data fit the general observation that the difference between marketed antidepressants and placebo on the HAMD-17 scale is generally less than 2 points (Kirsch et al., 2002; Kirsch and Sapirstein, 1998; Salamone, 2000). The significant improvement in psychomotor retardation was hypothesized on the basis of dopamine supersensitivity and dopamine D2High receptors (Seeman et al., 2005). Because the high-affinity state of the D2 receptors is considered to be the functional state of the D2 receptor (Seeman, 2013), an increase in such D2High receptors appears to be the basis of psychomotor activation, namely, behavioural dopamine supersensitivity. While an antidepressant effect in the present study is supported by the lower HAMD-17 score, the improved Clinical Global Index and the improved psychomotor rating, further research is needed to determine the optimum drug dosage for this effect and the optimum time on drug to produce upregulation of D2High receptors, dopamine supersensitivity, and antidepressant efficacy.
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5. Limitations The present study recruited 70 patients of whom 48 could be evaluated. Considering that depression arises in the context of various conditions (see Introduction), a more extensive study needs to be done with many more participants and with a variety of origins and intensities of depression. The study primarily focussed on the effect of the medication at visit 4, which was one week after stopping the medication. This time-point was the expected time for a maximum increase in the number of D2High receptors, as predicted from animal data (Seeman et al., 2005). Different regimens will be needed to extend the pharmacological effect. While the use of haloperidol may be considered a limitation because it is an antagonist at dopamine D2 receptors and may cause parkinsonism, it is, nevertheless, known that low doses of haloperidol can act as an indirect agonist (Dias et al., 2012), which has been a basis of the present study.
6. Conclusion
Inducing postsynaptic supersensitivity to dopamine is a potentially novel method of treating depression. On the basis of the HAMD-17 scores, there was no statistically significant difference between the drug and placebo groups. However, the HAMD-17 scale is far from being a perfect instrument (Bagby et al., 2004) and the Clinical Global Index did show differences between drug and placebo (week 2 to week 4), indicating that this strategy is worth pursuing. A study with a larger number of patients is required.
9
Role of funding source Funding for this study was provided by Clera Inc., which has patent applications for this method of treating depression.
Conflict of Interest M.V. Seeman, and P. Seeman are employed by Clera Inc. Contributors S.H. Kennedy, P. Seeman, M.V. Seeman and C.J. Hudson designed the study. F. Placenza and S.H. Kennedy carried out the trial including all clinical ratings. M.V. Seeman and C.J. Hudson analyzed the data. P. Seeman prepared the Figs and drafted the manuscript with all authors.
Acknowledgements We thank Sakina Rizvi for her input into protocol design.
10
Fig. legends: Fig. 1. CONSORT (Consolidated Standards of Reporting Trials) flow chart.
Fig. 2. The drug-treated patients (N = 22) had an average Hamilton rating of 22.36 ± 0.8 (mean ± s.e.) at visit 1. At visit 4 (one week after stopping the medication), the average Hamilton rating was 12.4 ± 1.1 (mean ± s.e.), a reduction of 9.96 units. This drug-assisted reduction of 9.96 units was 1.22 units or 14% more than the placebo reduction of 8.73 units.
Fig. 3. The improvement or difference in the Clinical Global Index (between the initial visit and the fourth visit) averaged 1.12 ± 0.26 (mean ± s.e.) units for the placebo patients (N = 26), and 1.64 ± 0.18 units for the drug-treated patients (N = 22) (P = 0.05, using a 1tailed t-test with unequal variance).
Fig. 4. The psychomotor rating in the Hamilton rating scale was 0.87 units for control subjects (N = 26), and was 1.25 units for the drug-treated subjects (N = 22). The difference between the initial visit and the fourth visit averaged 0.35 ± 0.13 (mean ± s.e.) units for the placebo patients, and 0.84 ± 0.15 units for the drug-treated patients (P = 0.0098, using a 1-tailed t-test with unequal variance).
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References
Apiquian, R., Ulloa, E., Fresan, A., Loyzaga, C., Nicolini, H., Kapur, S., 2003. Amoxapine shows atypical antipsychotic effects in patients with schizophrenia: results from a prospective open-label study. Schizophr. Res. 59(1), 35-39. Bagboy, R.M., 2004. The Hamilton depression rating scale: Has the gold standard become a lead weight? Amer. J. Psychiatry 161, 2163-2177. Blier, P., 2013. Rational site-directed pharmacotherapy for major depressive disorder. Int. J. Neuropsychopharmacol. June 10, 1-12. [Epub ahead of print] Dias, F.R., de Matos, L.W., Sampaio, M. de F., Carey, R.J., Carrera, M.P., 2012. Opposite effects of low versus high dose haloperidol treatments on spontaneous and apomorphine induced motor behavior: evidence that at a very low dose haloperidol acts as an indirect dopamine agonist. Behav. Brain Res. 229, 153-159. George, S.R., Watanabe, M., Di Paolo, T., Falardeau, P., Labrie, F., Seeman, P., 1985. The functional state of the dopamine receptor in the anterior pituitary is in the high-affinity form. Endocrinology 117, 690-697. Healy, E., McKeon, P., 2000. Dopaminergic sensitivity and prediction of antidepressant response. J. Psychopharmacol. 14(2), 152-156. Kapur, S., Mann, J.J., 1992. Role of the dopaminergic system in depression. Biol. Psychiatry 32(1), 1-17. Kirsch, I., Sapirstein, G., 1998. Listening to Prozac but hearing placebo: a meta-analysis of antidepressant medication. Prevent. Treat. 1, 1-17. Kirsch, I., Moore, T.J., Ciboria., A., et al., 2002. The emperor’s new drugs: an analysis of antidepressant medication data submitted to the US Food and Drug Administration. Prevention and Treatment [Internet]Cited 30 Nov. 2006. www.content.apa.org/journals/pre/5/1/23. Cited by Moncrieff, J., 2007. Are antidepressants as effective as claimed? No, they are not effective at all. Can. J. Psychiatry 52, 96-97. Mucci, A., Rolfe, G., Maj, M., 1995. Levosulpiride: a review of its clinical use in psychiatry. Pharmacol. Res. 31(2), 95-101. Pae, C.U., Patkar, A.A., 2013. Clinical issues in use of atypical antipsychotics for depressed patients. CNS Drugs 27 Suppl. 1, S39-S45. Pani, L., Gessa, G.L., 2002. The substituted benzamides and their clinical potential on
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dysthymia and on the negative symptoms of schizophrenia. Mol. Psychiatry 7(3), 247-253. Reddy, M.S., 2010. Depression: The Disorder and the Burden. Indian J. Psychol. Med. (1), 32, 1–2. Robertson, M.M., Trimble, M.R., 1982. Major tranquillisers used as antidepressants. A review. J Affect Disord. 4(3), 173-193. Salamone, J.D., 2000. A critique of recent studies on placebo effects of antidepressants: importance of research on active placebos. Psychopharmacology 152, 1-6. Seeman, P., 2011. All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2High receptors. CNS Neuroscience and Therapeutics. 17(2), 118-132. Seeman, P., 2013. Schizophrenia and dopamine receptors. Eur. Neuropsychopharmacol. Epub July 13, 2013. doi:pii: S0924-977X(13)00180-6. Seeman, P., Weinshenker, D., Quirion, R., Srivastava, L.K., Bhardwaj, S.K., Grandy, D.K., Premont, R.T., Sotnikova, T.D., Boksa, P., El-Ghundi, M., O'dowd, B.F., George, S.R., Perreault, M.L., Männistö, P.T., Robinson, S., Palmiter, R.D., Tallerico, T., 2005. Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc. Natl. Acad. Sci. U.S.A. 102(9), 3513-3518. Simpson, G.M., Angus, J.W.S., 1970. A rating scale for extrapyramidal side effects. Acta Psychiatrica Scand. 212, 11-19. Suehs, B.T., Argo, T.R., Beudele, S.D., et al. Texas Medication Algorithm Project Procedure Manual. Major Depressive Disorder Algorithms. Austin Tx. Texas Department of State Health Services: 2008. Spyraki, C., Fibiger, H.C., 1981. Behavioural evidence for supersensitivity of postsynaptic dopamine receptors in the mesolimbic system after chronic administration of desipramine. Eur. J. Pharmacol. 74(2-3), 195-206. Üstün, T.B., Ayuso-Mateos, J.L., Chatterji, S., Mathers, C., Murray, C.J.L., 2004. Global burden of depressive disorders in the year 2000. Br J Psychiatry 184, 386-392. Willner, P., 1997. The mesolimbic dopamine system as a target for rapid antidepressant action. Int. Clin. Psychopharmacol. 12 Suppl 3, S7-S14.
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Table 1. HAMD Depression Ratings ± s.e.
Visit
Patients on placebo
Patients on test drug
Visit 1
21.69 ± 0.74
22.36 ± 0.80
Visit 2
21.96 ± 0.75
21.35 ± 0.95
Visit 4
12.96 ± 1.16
12.40 ± 1.13
Visit 7
12.75 ± 1.44
12.22 ± 1.39
Visit 1 minus visit 4
8.73 ± 1.00
*9.96 ± 1.14
Visit 2 minus visit 4
9.00 ± 0.99
8.95 ± 1.07
Visit 2 minus visit 7
9.20 ± 1.36
9.13 ± 1.33
*Improvement trend over placebo, but not statistically significant.
14
Role of funding source Funding for this study was provided by Clera Inc., which has patent applications for this method of treating depression.
15
Contributors S.H. Kennedy, P. Seeman, M.V. Seeman and C.J. Hudson designed the study. F. Placenza and S.H. Kennedy carried out the trial including all clinical ratings. M.V. Seeman and C.J. Hudson analyzed the data. P. Seeman prepared the Figs and drafted the manuscript with all authors.
16
Conflict of Interest S. Kennedy has received Grant/Research Support from: Lundbeck, Ontario Brain Institute, Canadian Institutes for Health Research, St. Jude Medical, Bristol-Myers Squibb and Clera Inc. He has also received speaking fees from and is a member of advisory boards for Eli Lilly, Lundbeck, Lundbeck Institute, Pfizer, Servier and Forest. M.V. Seeman, and P. Seeman are employed by Clera Inc.
17
Acknowledgements We thank Sakina Rizvi for her input into protocol design.
18
Figure 1
Figure 2
Figure 3
Figure 4
Depression treatment by withdrawal of shortterm low-dose antipsychotic, a proof-ofconcept randomized double-blind study Sidney H. Kennedy, Franca Placenza, Craig J. Hudson, Philip Seeman, Mary V. Seeman
www.elsevier.com/locate/jad
PII: DOI: Reference:
S0165-0327(14)00198-0 http://dx.doi.org/10.1016/j.jad.2014.04.014 JAD6681
To appear in:
Journal of Affective Disorders
Received date: 14 March 2014 Accepted date: 11 April 2014 Cite this article as: Sidney H. Kennedy, Franca Placenza, Craig J. Hudson, Philip Seeman, Mary V. Seeman, Depression treatment by withdrawal of short-term low-dose antipsychotic, a proof-of-concept randomized double-blind study, Journal of Affective Disorders, http://dx.doi.org/10.1016/j.jad.2014.04.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Mar. 1, 2014 Journal of Affective Disorders Abstract words: 246 Text Words: 2,123
Depression treatment by withdrawal of short-term low-dose antipsychotic, a proof-of-concept randomized double-blind study Sidney H. Kennedy*1, Franca Placenza1, Craig J. Hudson2, Philip Seeman3, and Mary V. Seeman3 1
Department of Psychiatry, Toronto General Hospital, University Health Network, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. 2
Department of Psychiatry, Alexandra Marine and General Hospital, 120 Napier Street, Goderich, Ontario, Canada N7A 1W5. 3
Clera Inc., 260 Heath Street West, Unit 605, Toronto, Ontario, Canada M5P 3L6.
*Corresponding author: E-mail address: [email protected] Keywords: Depression, Antidepressant, Antipsychotic, Dopamine D2High receptor Dopamine supersensitivity
1
ABSTRACT Background and Objective: Because increased dopamine neurotransmission occurs with most antidepressants, and because antipsychotics cause behavioural supersensitivity to dopamine, short-term low-dose antipsychotic treatment was tested on depressed patients with an expectation of clinical improvement in the supersensitive phase following drug withdrawal.
Method:
This was a randomized, double-blind, placebo-controlled study of 48
patients who met criteria for DSM-IV® Major Depressive Disorder, were in a Major Depressive Episode, and had a Hamilton Depression Rating Scale (HAMD) rating of 14. Half the participants received 0.25 mg oral haloperidol each day for 7 days, after which they received placebo daily for 4 weeks. The other half received placebo throughout the trial.
Results:
One week after stopping the medication, the HAMD ratings of the drug-
treated patients fell by 9.96 points, as compared to a reduction of 8.73 points in the placebo-treated patients, when comparing visits 1 and 4. There was no such difference when comparing visits 2 and 4. The differences were not significant, but indicated a trend. One week after the medication was stopped, the Clinical Global Index fell 1.64 ± 0.18 units for the medication-treated patients, compared to 1.12 ± 0.26 units for the placebo group (P = 0.05). The regimen was well tolerated.
Conclusions: Seven days of an ultra-low dose of 0.25 mg haloperidol, followed by withdrawal of haloperidol, resulted in clinical depression improvement greater than placebo and significantly decreased psychomotor retardation, consistent with haloperidolinduced behavioural supersensitivity to dopamine.
Limitations: The sample was small. More patients are needed in a future study.
2
1. Introduction Major Depressive Disorder (MDD) is one of the most prevalent mental health problems worldwide and brings with it considerable social and economic burdens. One person in five fulfills the Diagnostic and Statistical Manual of Mental Disorders (DSM IVTR) criteria for MDD over the course of a lifetime (Üstün et al., 2000). Although there is a considerable difference in the range of symptoms (persistent sadness, loss of self esteem, difficulty concentrating, guilt, hopelessness, avoiding other people, loss of appetite, loss of interest or pleasure, and suicidal thoughts) and in their severity, role functioning is usually affected adversely and the toll of disability is high. In 2000, MDD was the fourth leading cause of global disease burden, accounting for 4.4% of total disability-adjusted life-years (DALYs), causing the largest amount of non-fatal burden, and represents 12% of all total years lived with disability (Üstün et al., 2000). By 2020, it is predicted that MDD will be second among all diseases in the International Burden of Disease (Reddy, 2010)
The present study examines whether enhanced dopamine supersensitivity can quickly, if transiently, alleviate depressive symptoms. Most antidepressants take time to have therapeutic efficacy and need to be taken for at least one year and up to lifetime, depending upon risk factors for recurrence and patient preference (Suehs et al., 2008) . They include compounds that inhibit the neural uptake of norepinephrine, serotonin, and dopamine, or stimulate the receptors for these neurotransmitters, but there are currently no strategies for enhancing the sensitivity of these receptors so that patients can respond more quickly and at lower doses.
The purpose of this study, therefore, was to enhance dopamine supersensitivity in patients by means of an ultra-low antipsychotic dose for a brief period (7 days) and then withdraw the drug in the expectation of a clinical improvement after drug withdrawal, when dopamine supersensitivity is known to occur (Seeman, 2011). The molecular mechanism underlying this type of post-antipsychotic supersensitivity is the induction of dopamine D2High receptors by the antipsychotic (Seeman, 2011). The dopamine D2 receptor is the major target of antipsychotic drugs. The D2 receptor can exist in either a
3
state of high-affinity for dopamine, known as D2High, or in a state of low affinity for dopamine, known as D2Low. The D2High state is known to be the functional state of the D2 receptor (George et al., 1985).
It has been shown that treatment with antidepressant drugs (at normal antidepressant doses) produces a sensitization of behavioural responses to agonists acting at dopamine D2 receptors (so-called dopamine supersensitivity; Willner, 1997; Healy and McKeon, 2000; Spyraki and Fibiger, 1981; Kapur and Mann, 1992). Such a sensitizing action presumably assists in eliciting the clinical antidepressant effect. However, in contrast to the strategy of the present study, the antidepressant doses used in these earlier studies were maintained for relatively long periods of time.
Although the use of antipsychotics for depression has been controversial (Robertson and Trimble, 1982), the antidepressants amoxapine and trazodone appear to exert both antidepressant and antipsychotic effects (Apiquian et al., 2003). In addition, Robertson and Trimble (1982) have summarized studies showing that thioridazine, chlorpromazine, perphenazine, fluphenazine, thiothixene, flupenthixol, and chlorprothixene are as effective as imipramine, amitriptyline, or doxepin in treating depression, especially within the context of psychosis or schizophrenia. The doses of these antipsychotics for treating depression are generally lower than for psychosis. More recently, there have been reviews of low doses of the atypical antipsychotic amisulpride (50-100 mg/day) or levo-sulpiride (50-150 mg/day) used for dysthymia, a mild chronic form of depression (Pani and Gessa, 2002; Mucci et al., 1995). Blier (2013) has recently addressed the wider issue of using low dose atypical antipsychotics for depression.
However, the brief use of drugs that sensitize dopamine D2 receptors in order to effect a rapid, if transient, reversal of depression has not been previously described. The present study employed a short-term ultra-low-dose antipsychotic and sought to determine whether the subsequent rebound dopamine supersensitivity would be clinically beneficial in alleviating depressive symptoms.
4
2. Method The study was approved by Health Canada as “A pilot placebo-controlled, double-blind, randomized parallel group study to evaluate the efficacy of treatment with CLR3001 in depression”. Haloperidol (CLR3001) was given at a dose of 0.25 mg once per day orally in capsule form. The placebo, prepared commercially, was identical in shape and colour to the drug-containing pill. The protocol was approved by the Research Ethics Board of the University Health Network (Toronto, Ontario) where the study was conducted. At the beginning of the study, subjects were informed of the possibility of receiving a placebo at the start of the study. A series of 70 subjects (a sample size calculated to allow for drop-outs and to have sufficient power to reliably distinguish between 1 and 2 weeks after drug discontinuation in the two groups – 80% at the p=0.05 level) was recruited by advertisement in newspapers and posters in Toronto, Ontario, Canada, as well as by physician referral. Participants were randomized after providing written consent. Inclusion criteria were: male or female outpatients aged 18 to 65 years meeting criteria for Major Depressive Disorder with a current Major Depressive Episode as per DSM-IV® and no more than 5 prior episodes. Patients had to be antidepressantfree for at least one week (28 days for prior fluoxetine and 14 days for prior irreversible monoamine oxidase inhibitors), not currently receiving psychotherapy, and able to provide written informed consent. The HAMD-17 score had to be 14 at both screening and at randomization visits. Patients had to be able to understand and complete questionnaires, and communicate with the study coordinator. Female participants of childbearing potential or those who were not at least 2 years postmenopausal or surgically sterile or totally abstinent or whose partner had a vasectomy needed to be using a reliable, medically acceptable form of contraception and agreeable to continuing such use throughout the duration of the study. Exclusion criteria were the following: investigators and immediate family members, treatment within the last 90 days with a drug that had not received regulatory approval at the time of study entry, lifetime diagnosis of bipolar disorder or any form of psychotic disorder, a primary diagnosis of Panic Disorder, Generalized Anxiety Disorder, Post-Traumatic Stress Disorder, Social Anxiety Disorder, Obsessive-Compulsive Disorder within the past year, the presence of
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an Axis II disorder, which, in the opinion of the investigator, would interfere with compliance in the study. At screening, a medical history was recorded and laboratory tests (electrocardiogram, clinical chemistry, hematology and urinalysis) were completed. The Mini Neuropsychiatric Interview (MINI) was used to confirm MDD diagnosis and current MDE. At each visit, the patient was evaluated by a psychiatrist. The HAMD-17 rating scale was used to assess the severity of depression symptoms and the Clinical Global Impressions (CGI) scale was used to provide the clinician’s general impression of the severity of the patient’s condition. Because of the known ability of antipsychotics to induce behavioural dopamine supersensitivity and dopamine D2High receptors (Seeman et al., 2005), the psychomotor retardation item on HAMD-17 was identified a priori for individual item analysis. In addition, the Simpson Angus Scale (Simpson and Angus, 1970) was used to screen for extrapyramidal side effects at each study visit. The protocol called for a total of 7 visits, where visit 1 was considered the screening visit and visit 2 served as the baseline visit, but both visits were used for a final analysis. The medication or the placebo was taken daily after the second visit until the third visit. Forty-eight subjects completed the protocol to at least Visit 4, the week following discontinuation of the treatment, resulting in 26 control and 22 treated evaluable subjects. Reasons given for early drop out are shown in Figure 1.
3. Results
HAMD-17 ratings: The placebo-treated patients (N = 26) had an average HAMD-17 score of 21.69 ± 0.74 (mean ± s.e.) at visit 1, and 21.96 ± 0.75 at visit 2, before starting the placebo. At visit 4, the average HAMD-17 score was 12.96 ± 1.16, a reduction of 8.73 points from visit 1 and a reduction of 9.00 points from visit 2 (Table 1).
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The drug-treated patients (N = 22) had an average HAMD-17 score of 22.36 ± 0.8 (mean ± s.e.) at visit 1, and a rating of 21.35 ± 0.95 at visit 2, before starting the medication. At visit 4, which was one week after stopping the medication, the average HAMD-17 score was 12.4 ± 1.1 (mean ± s.e.), a reduction of 9.96 points, as compared to a reduction of 8.73 points in the placebo group at visit 1 (Table 1, Fig. 2). However, the reduction was 8.95 points from visit 2 when compared to a 9.00 point reduction in the placebo group (Table 1). CGI-I: The difference in the CGI-I score (between visit 1 and visit 4) averaged 1.12 ± 0.26 (mean ± s.e.) points for the placebo-treated patients (N = 26), and 1.64 ± 0.18 points for the drug-treated patients (N = 22) (P = 0.05, using a 1-tailed t-test with unequal variance) (Fig. 3). Psychomotor rating: For Question #8 on the HAMD-17, the value for the control subjects (N = 27) was 0.87 points (maximum was 4 points), while that for the drug-treated subjects (N = 22) was 1.25 points (values compare visit 2 with visit 4) (Fig.4). The difference between visit 1 and visit 4 averaged 0.35 ± 0.13 (mean ± s.e.) points for the placebo-treated patients, and 0.84 ± 0.15 points for the drug-treated patients (P = 0.0098, using a 1-tailed t-test with unequal variance) (Fig. 3). Safety: Side effects in this study were few. Transient headache was reported in 11 placebo-treated subjects and in 9 drug-treated subjects. Slight muscle stiffness was reported in 6 drug-treated participants, but disappeared within a week. One drug-treated participant who dropped out had a generalized rash, which faded after drug withdrawal. One placebo-treated subject reported itchy skin. No clinically significant extrapyramidal side-effects occurred. The Simpson Angus scores were essentially nil throughout.
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4. Discussion The results indicate that one week after the withdrawal of haloperidol 0.25 mg, the reduction in depressive symptoms exceeded that found with placebo treatment, when comparing visits 4 and 1, but not when comparing visits 4 and 2 (Table 1). Although the drug lowered the HAMD-17 score by 9.96 points (as compared to visit 1), which was 1.22 points or 14% more than the reduction in the placebo group, this effect was not statistically significant. However, both the CGI-I and the psychomotor subscale showed statistically significant improvements over placebo. Interestingly, although the difference of 1.22 points between the drug and the placebo on the HAMD-17 was less than the ideal of 3 points, the data fit the general observation that the difference between marketed antidepressants and placebo on the HAMD-17 scale is generally less than 2 points (Kirsch et al., 2002; Kirsch and Sapirstein, 1998; Salamone, 2000). The significant improvement in psychomotor retardation was hypothesized on the basis of dopamine supersensitivity and dopamine D2High receptors (Seeman et al., 2005). Because the high-affinity state of the D2 receptors is considered to be the functional state of the D2 receptor (Seeman, 2013), an increase in such D2High receptors appears to be the basis of psychomotor activation, namely, behavioural dopamine supersensitivity. While an antidepressant effect in the present study is supported by the lower HAMD-17 score, the improved Clinical Global Index and the improved psychomotor rating, further research is needed to determine the optimum drug dosage for this effect and the optimum time on drug to produce upregulation of D2High receptors, dopamine supersensitivity, and antidepressant efficacy.
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5. Limitations The present study recruited 70 patients of whom 48 could be evaluated. Considering that depression arises in the context of various conditions (see Introduction), a more extensive study needs to be done with many more participants and with a variety of origins and intensities of depression. The study primarily focussed on the effect of the medication at visit 4, which was one week after stopping the medication. This time-point was the expected time for a maximum increase in the number of D2High receptors, as predicted from animal data (Seeman et al., 2005). Different regimens will be needed to extend the pharmacological effect. While the use of haloperidol may be considered a limitation because it is an antagonist at dopamine D2 receptors and may cause parkinsonism, it is, nevertheless, known that low doses of haloperidol can act as an indirect agonist (Dias et al., 2012), which has been a basis of the present study.
6. Conclusion
Inducing postsynaptic supersensitivity to dopamine is a potentially novel method of treating depression. On the basis of the HAMD-17 scores, there was no statistically significant difference between the drug and placebo groups. However, the HAMD-17 scale is far from being a perfect instrument (Bagby et al., 2004) and the Clinical Global Index did show differences between drug and placebo (week 2 to week 4), indicating that this strategy is worth pursuing. A study with a larger number of patients is required.
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Role of funding source Funding for this study was provided by Clera Inc., which has patent applications for this method of treating depression.
Conflict of Interest M.V. Seeman, and P. Seeman are employed by Clera Inc. Contributors S.H. Kennedy, P. Seeman, M.V. Seeman and C.J. Hudson designed the study. F. Placenza and S.H. Kennedy carried out the trial including all clinical ratings. M.V. Seeman and C.J. Hudson analyzed the data. P. Seeman prepared the Figs and drafted the manuscript with all authors.
Acknowledgements We thank Sakina Rizvi for her input into protocol design.
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Fig. legends: Fig. 1. CONSORT (Consolidated Standards of Reporting Trials) flow chart.
Fig. 2. The drug-treated patients (N = 22) had an average Hamilton rating of 22.36 ± 0.8 (mean ± s.e.) at visit 1. At visit 4 (one week after stopping the medication), the average Hamilton rating was 12.4 ± 1.1 (mean ± s.e.), a reduction of 9.96 units. This drug-assisted reduction of 9.96 units was 1.22 units or 14% more than the placebo reduction of 8.73 units.
Fig. 3. The improvement or difference in the Clinical Global Index (between the initial visit and the fourth visit) averaged 1.12 ± 0.26 (mean ± s.e.) units for the placebo patients (N = 26), and 1.64 ± 0.18 units for the drug-treated patients (N = 22) (P = 0.05, using a 1tailed t-test with unequal variance).
Fig. 4. The psychomotor rating in the Hamilton rating scale was 0.87 units for control subjects (N = 26), and was 1.25 units for the drug-treated subjects (N = 22). The difference between the initial visit and the fourth visit averaged 0.35 ± 0.13 (mean ± s.e.) units for the placebo patients, and 0.84 ± 0.15 units for the drug-treated patients (P = 0.0098, using a 1-tailed t-test with unequal variance).
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References
Apiquian, R., Ulloa, E., Fresan, A., Loyzaga, C., Nicolini, H., Kapur, S., 2003. Amoxapine shows atypical antipsychotic effects in patients with schizophrenia: results from a prospective open-label study. Schizophr. Res. 59(1), 35-39. Bagboy, R.M., 2004. The Hamilton depression rating scale: Has the gold standard become a lead weight? Amer. J. Psychiatry 161, 2163-2177. Blier, P., 2013. Rational site-directed pharmacotherapy for major depressive disorder. Int. J. Neuropsychopharmacol. June 10, 1-12. [Epub ahead of print] Dias, F.R., de Matos, L.W., Sampaio, M. de F., Carey, R.J., Carrera, M.P., 2012. Opposite effects of low versus high dose haloperidol treatments on spontaneous and apomorphine induced motor behavior: evidence that at a very low dose haloperidol acts as an indirect dopamine agonist. Behav. Brain Res. 229, 153-159. George, S.R., Watanabe, M., Di Paolo, T., Falardeau, P., Labrie, F., Seeman, P., 1985. The functional state of the dopamine receptor in the anterior pituitary is in the high-affinity form. Endocrinology 117, 690-697. Healy, E., McKeon, P., 2000. Dopaminergic sensitivity and prediction of antidepressant response. J. Psychopharmacol. 14(2), 152-156. Kapur, S., Mann, J.J., 1992. Role of the dopaminergic system in depression. Biol. Psychiatry 32(1), 1-17. Kirsch, I., Sapirstein, G., 1998. Listening to Prozac but hearing placebo: a meta-analysis of antidepressant medication. Prevent. Treat. 1, 1-17. Kirsch, I., Moore, T.J., Ciboria., A., et al., 2002. The emperor’s new drugs: an analysis of antidepressant medication data submitted to the US Food and Drug Administration. Prevention and Treatment [Internet]Cited 30 Nov. 2006. www.content.apa.org/journals/pre/5/1/23. Cited by Moncrieff, J., 2007. Are antidepressants as effective as claimed? No, they are not effective at all. Can. J. Psychiatry 52, 96-97. Mucci, A., Rolfe, G., Maj, M., 1995. Levosulpiride: a review of its clinical use in psychiatry. Pharmacol. Res. 31(2), 95-101. Pae, C.U., Patkar, A.A., 2013. Clinical issues in use of atypical antipsychotics for depressed patients. CNS Drugs 27 Suppl. 1, S39-S45. Pani, L., Gessa, G.L., 2002. The substituted benzamides and their clinical potential on
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dysthymia and on the negative symptoms of schizophrenia. Mol. Psychiatry 7(3), 247-253. Reddy, M.S., 2010. Depression: The Disorder and the Burden. Indian J. Psychol. Med. (1), 32, 1–2. Robertson, M.M., Trimble, M.R., 1982. Major tranquillisers used as antidepressants. A review. J Affect Disord. 4(3), 173-193. Salamone, J.D., 2000. A critique of recent studies on placebo effects of antidepressants: importance of research on active placebos. Psychopharmacology 152, 1-6. Seeman, P., 2011. All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2High receptors. CNS Neuroscience and Therapeutics. 17(2), 118-132. Seeman, P., 2013. Schizophrenia and dopamine receptors. Eur. Neuropsychopharmacol. Epub July 13, 2013. doi:pii: S0924-977X(13)00180-6. Seeman, P., Weinshenker, D., Quirion, R., Srivastava, L.K., Bhardwaj, S.K., Grandy, D.K., Premont, R.T., Sotnikova, T.D., Boksa, P., El-Ghundi, M., O'dowd, B.F., George, S.R., Perreault, M.L., Männistö, P.T., Robinson, S., Palmiter, R.D., Tallerico, T., 2005. Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc. Natl. Acad. Sci. U.S.A. 102(9), 3513-3518. Simpson, G.M., Angus, J.W.S., 1970. A rating scale for extrapyramidal side effects. Acta Psychiatrica Scand. 212, 11-19. Suehs, B.T., Argo, T.R., Beudele, S.D., et al. Texas Medication Algorithm Project Procedure Manual. Major Depressive Disorder Algorithms. Austin Tx. Texas Department of State Health Services: 2008. Spyraki, C., Fibiger, H.C., 1981. Behavioural evidence for supersensitivity of postsynaptic dopamine receptors in the mesolimbic system after chronic administration of desipramine. Eur. J. Pharmacol. 74(2-3), 195-206. Üstün, T.B., Ayuso-Mateos, J.L., Chatterji, S., Mathers, C., Murray, C.J.L., 2004. Global burden of depressive disorders in the year 2000. Br J Psychiatry 184, 386-392. Willner, P., 1997. The mesolimbic dopamine system as a target for rapid antidepressant action. Int. Clin. Psychopharmacol. 12 Suppl 3, S7-S14.
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Table 1. HAMD Depression Ratings ± s.e.
Visit
Patients on placebo
Patients on test drug
Visit 1
21.69 ± 0.74
22.36 ± 0.80
Visit 2
21.96 ± 0.75
21.35 ± 0.95
Visit 4
12.96 ± 1.16
12.40 ± 1.13
Visit 7
12.75 ± 1.44
12.22 ± 1.39
Visit 1 minus visit 4
8.73 ± 1.00
*9.96 ± 1.14
Visit 2 minus visit 4
9.00 ± 0.99
8.95 ± 1.07
Visit 2 minus visit 7
9.20 ± 1.36
9.13 ± 1.33
*Improvement trend over placebo, but not statistically significant.
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Role of funding source Funding for this study was provided by Clera Inc., which has patent applications for this method of treating depression.
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Contributors S.H. Kennedy, P. Seeman, M.V. Seeman and C.J. Hudson designed the study. F. Placenza and S.H. Kennedy carried out the trial including all clinical ratings. M.V. Seeman and C.J. Hudson analyzed the data. P. Seeman prepared the Figs and drafted the manuscript with all authors.
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Conflict of Interest S. Kennedy has received Grant/Research Support from: Lundbeck, Ontario Brain Institute, Canadian Institutes for Health Research, St. Jude Medical, Bristol-Myers Squibb and Clera Inc. He has also received speaking fees from and is a member of advisory boards for Eli Lilly, Lundbeck, Lundbeck Institute, Pfizer, Servier and Forest. M.V. Seeman, and P. Seeman are employed by Clera Inc.
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Acknowledgements We thank Sakina Rizvi for her input into protocol design.
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Figure 1
Figure 2
Figure 3
Figure 4
