Gin S. Malhi: A critical analysis of concepts in psychiatry.

Gin S. Malhi, Erica Bell and Richard J. Porter: Serial quelling the typical use of atypical antipsychotic drugs

Aitor Castillo’s comment

         In this very polemic paper, the central question is: “how can one agent  treat so many different psychiatric disorders? The authors try to debate this issue choosing quetiapine as a scapegoat. I wonder why they did this, because the same thing could be applied to olanzapine or many other psychiatric drugs. Let me present a brief series of examples reviewing the indications for some drugs taking into account official and off-label uses in both psychiatric and non-psychiatric conditions (Papadakis, McPhee and Rabow 2019; Golan, Tashjian, Armstrong and Armstrong 2012; Ebert, Leckman and Petrakis 2019):

a) a-Olanzapine (or broadly, the atypical antipsychotics) - schizophrenia, manic episode, bipolar depression, resistant depression, secondary psychosis, anorexia nervosa, insomnia, emesis, acute pain;

b) b-Fluoxetine (or broadly, the Specific Serotonin Reuptake Inhibitors) - major depression, bulimia, panic disorder, obsessive compulsive disorder, generalized anxiety disorder, phobic disorders, premenstrual dysphoric disorder, premature ejaculation, pruritus, chronic pain.

c) c-Lithium: manic episode, bipolar depression, unipolar depression, dyscontrol syndromes, risk of suicide, cluster headache.

d) d-Venlafaxine (or broadly, the dual antidepressants) - major depression, generalized anxiety disorder, fybromialgia, migraine, chronic pain.

e) e-Valproic acid (or broadly, the anticonvulsants) - bipolar disorder, seizures, migraine.

f) f-Carbamazepine: bipolar disorder, manic episode, seizures, trigeminal neuralgia.

g) g-Diazepam (or broadly, the benzodiazepines) - generalized anxiety disorder, insomnia, panic disorder, spasticity, tension headache, seizures, myoclonus, idiopathic torsion dystonia, akathisia.

h) h-Propranolol (or broadly, the beta-adrenergic antagonists) - performance anxiety, akathisia, essential tremor, hypertension, angina, heart failure, pheochromocytoma, galucoma, thyroid storm, migraine.

i) i-Prednisone (or broadly, the glucocorticoids) - cluster headache, multiple sclerosis, essential  tremor, asthma, rheumatoid arthritis, Chron´s disease, temporal arteritis, polyarteritis nodosa, autoinmune diseases.

         Most of these many indications are related to different pharmacodynamics and pharmacokinetics properties, as well as to a wide range of doses. Right now, there is an interesting move to reclassify the psychotropic drugs according to their mechanism of action therefore, for example from a practical clinical point of view, avoiding terms like “antidepressant,” to aid clinicians when prescribing an antidepressant to treat anxiety in patients, without raising patient concerns as they may not understand why he/she receives an “antidepressant” for the treatment of his/her anxiety and also leading to a low treatment adherence (Caraci, Enna, Zohar et al. 2017).

         Now, I want to focus a little bit on the specific case of quetiapine because it is the target in the authors´ paper. They say: “by treating general distress and improving sleep, an ‘antipsychotic’ can appear to be an effective treatment for mood disorders.” Reading  carefully the first pivotal study from Calabrese, Keck, Macfadden et al. (2005) it is useful to refer to their statment discussing their results: “notably, both doses of quetiapine were approximately twice as effective as placebo in reducing suicidal ideation. These findings provide support for the conclusion that quetiapine has specific antidepressant properties.” In a later study, Young, McElroy, Bauer et al. (2010) demonstrated significant efficacy of quetiapine monotherapy “on the majority of the individual MADRS items including the core symptoms of depression (apparent sadness, reported sadness, lassitude, and suicidal thoughts).” So, as far as I know, quetiapine has five positive studies on bipolar depression, including two BOLDER studies (Calabrese, Keck, Macfadden et al. 2005; Thase, Macfadden, Weisler et al. 2006)  two EMBOLDEN (Young, McElroy, Bauer et al. 2010; McElroy, Weisler, Chang et al. 2010) studies and one extended-release formulation study (Suppes, Dato Minkwitz et al. 2010) .  Moreover, the active metabolite  nor-quetiapine has potent  norepinephrine reuptake antagonism and partial R5-HT_1A agonism appearing as the putative mediator of quetiapine´s antidepressant activity (Jensen, Rodriguiz, Caron et al. 2008).

         One more issue raised in the authors´paper is related to their concept that we (clinicians) have a low expectation of pharmacotherapy. As proof of that statment they write, “STAR*D showed that at least two (30.6%), three (13.7%) and sometimes four (13.0%) medications are needed before an adequate response can be achieved.”

         At the very beggining it is necessary to remember that STAR*D deals with the concept of remission and not the concept of response. It is true that the remission rates were lower than expected but it is also true that the first level of citalopram monotherapy reached a remission rate of 27% as measured by HAM-D and 33% as measured by QIDS-SR, and response rate was 47% as measured by QIDS-SR. Then,  patients who did not reach remission were offered either switching strategies or augmentation strategies at level 2, without much difference between both stategies,  although it is important to bear in mind that treatment groups were not equivalent at the point of randomization at the beginning of level 2. For patients who did not remit, a third level with a different pharmacotherapy approach was offered and the final level 4 was implemented for level 3 failures.  Over the four levels of treatment extended for about one year, the theoretical cumulative remission rate was 67%. Remission was more likely to occur during the first two treatment levels (20-30%) than during levels 3 and 4 (10-20%) (Rush, Triverdi, Wisniewski et al. 2006; Gaynes, Warden, Triverdi et al. 2009).

         One more significant point that I think is important for this discussion deals with the field of clinical psychometrics. According to Per Bech (2012), clinical psychometrics has developed into a discipline within clinical psychiatry of similar importance as genetics, epidemiology or pharmacology. Within modern psychometrics the creation of a pharmacopsychometric triangle is of the utmost importance in which angle A covers desired clinical effect, angle B covers side effects and angle C covers patient-reported quality of life. Nowdays, it has been demonstrated that short psychometric scales are useful to measure different clases of drugs. For example, it is possible to use a short HAMD 6-item version instead of using the traditonal 17-item version to focus on core symptoms of depression. In this case we can compare the effect sizes of different antidepressants using both versions. For fluoxetine 20-60 mg/day, for example, effect size is 0.30 using HAMD-17 and 0.38 using HAMD-6; for citalopram 20 mg/day effect size is 0.09 with HAMD-17 and 0.21 with HAMD-6; but for 40 mg/day these numbers are 0.39 and 0.51, respectively. Finally, using HAMD-6 for escitalopram 10 mg/day the effect size is 0.38 and while escitalopram 20 mg/day reaches a much better effect size of 0.61 (Bech 2012). These same perspectives are used for measuring effect sizes of antipsychotic, anti-dementia, anti-anxiety and anti-manic drugs. I think this is the kind of approach we need to use to analyse results of RCTs.

         Last but not least, while industry continues to focus its resources away from innovative research and into evaluation of “me-too” drugs, things are not going to change too much. Thomas Ban devoted many decades of research to develop a pharmacologically valid psychiatric nosology arguing that the field needs clinical end-points to render findings with biological measures clinically interpretable (Ban 1987, 2007).

References:

Ban TA. Prolegomenon to the clinical prerequisite: psychopharmacology and the classification of mental disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry 1987; 1:527-80.

Ban TA. Towards a clinical methodology for neuropsychopharmacology research. Neuropsychopharmacologia Hungarica 2007; 9:81-90.

Bech P. Clinical Psychometrics. Wiley-Blackwell. Oxford, 2012.

Calabrese J, Keck P, Macfadden W, Minkwitz M, Ketter T, Weisler R, Cutler A, McCoy R, Wilson E, Mullen J, The BOLDER Study Group. A Randomized, Double-Blind, Placebo-Controlled Trial of Quetiapine in the Treatment of Bipolar I or II Depression. Am J Psychiatry 2005; 162:1351-60.

Caraci F, Enna S, Zohar J, Racagni G, Zalsman G, van den Brink W, Kasper S, Koob G, Pariante C, Piazza P, Yamada K, Spedding M, Drago F. A new nomenclature for classifying psychotropic drugs. Br J Pharmacol 2017; 83:1614-16.

Gaynes B, Warden D, Triverdi M, Wisniewski S, Fava M, Rush J. What Did STAR*D Teach Us? Results From a Large-Scale, Practical, Clinical Trial for Patients with Depression. Psychiatric Services 2009; 60(11):1439-45.

Golan D, Tashjian A, Armstrong E, Armstrong A, editors. Principles of Pharmacology. The Pathophysiologic Basis of Drug Therapy. Third Edition. Lippincott Williams & Wilkins. Philadelphia, 2012.

Ebert M, Leckman J, Petrakis I, editors. Current Diagnosis & Treatment. Psychiatry. Third Edition. McGraw-Hill Education, New York, 2019.

Jensen N, Rodriguiz R, Caron M, Wetsel W, Rothman R, Roth B. N-Desalkylquetiapine, a Potent Norepinephrine Reuptake Inhibitor and Partial 5-HT_1A Agonist, as a Putative Mediator of Quetiapine´s Antidepressant Activity. Neuropsychopharmacology 2008; 33:2303-12.

Malhi G, Bell E, Porter J. Serial Quelling: the typical use of atypical antipsychotics? Aust N Z  Psychiatry 2019; 53(6):495-8.

McElroy S, Weisler R, Chang W, Olausson B,  Brecher M, Agambaram V, Merideth C,  Nordenhem  A, Young A, EMBOLDEN II (Trial D1447C00134) Investigators. A double-blind, Placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J  Clin Psychiatry 2010; 71:163-74.

Papadakis M, McPhee S, Rabow M, editors. Current Medical Diagnosis & Treatment 2018. Fifty-Eight Edition. McGraw-Hill Education, New York, 2019.

Rush J, Triverdi M, Wisniewski S, Nierenberg A, Stewart J, Warden D, Niederehe G, Thase M, Lavori P, Lebowitz B, McGrath P, Rosenbaum J, Sackeim H, Kupfer D, Luther J, Fava M. Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report. Am J Psychiatry 2006; 163(11):1905-17.

Suppes T, Dato C, Minkwitz M, Nordenhem A, Walker C, Darko D. Effectiveness of the Extended Release Formulation of Quetiapine as Monotherapy for the Treatment of Acute Bipolar Depression.  Journal of Affective Disorders, 2010; 121:106-15.

Thase ME, Macfadden W, Weisler RH, Chang W, Paulsson B, Khan A, Calabrese JR; BOLDER II Study Group. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). J Clin  Psychopharmacol 2006; 26:600-9.

Young A, McElroy S, Bauer M, Philips N, Chang W, Olausson B, Paulsson B, Brecher M, EMBOLDEN I (Trial 001) Investigators. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry 2010; 71(2):150-62.

August 20, 2020