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


Janusz K. Rybakowski comment   


        The Malhi, Bell and Porter paper discusses a justification to call quetiapine an atypical antipsychotic. For me, the common feature of so-called “atypical antipsychotics” is possessing, by most of them, mood-stabilizing properties.

        I suggested an operational definition of mood-stabilizer (MS) as a drug that (1) reduces or ameliorates manic and/or depressive symptoms; (2) acts to prevent recurrent manic and/or depressive episodes when is given as monotherapy for at least one year; and (3) does not induce or worsen manic or depressive episodes. On the basis of the chronology of their being introduced into psychiatric armamentarium, I also proposed a division of mood-stabilizers into first-generation MSs, introduced in the 1960s and 1970s (lithium, valproates, and carbamazepine), and second-generation MSs, introduced since the second half of the 1990s, which include atypical antipsychotics (clozapine, olanzapine, quetiapine, aripiprazole and risperidone) and lamotrigine (Rybakowski, 2007; 2018). The first to suggest a mood-stabilizing effect of an atypical antipsychotic, clozapine, was Zarate, Tohen, Banov et al. (2005)

        In recent years, the concept of predominant polarity (i.e., manic or depressive) as the predominant prophylactic effect of the MSs has been proposed. For example, clozapine, which exerts a predominant antimanic and antipsychotic action, can be placed at the extreme anti-manic end of the polarity continuum. Similarly, atypical antipsychotics like olanzapine, aripiprazole and risperidone may also be placed near the antimanic end of the polarity continuum. First-generation MSs also demonstrate greater antimanic than antidepressant activity. Among them, lithium appears to produce the greatest antidepressant action. Quetiapine exerts a balance of antimanic and antidepressant effectiveness and might best be considered to occupy the mid-position along the polarity continuum. Finally, lamotrigine may best be placed on the antidepressant pole of the polarity continuum along with lithium (Popovic, Reinares, Goikolea et al. 2012).

        Therefore, quetiapine can be defined as a 2x2 mood stabilizer, exerting both therapeutic and prophylactic action for both manic and depressive episodes. Antidepressant activity of quetiapine can result from the fact that norquetiapine, the main active metabolite of quetiapine, is a potent inhibitor of norepinephrine transporter (NET) (Prieto, Meana and Majadas 2010).

        The therapeutic profile of quetiapine in mood disorder may be similar to that of lithium. In the project named the Bipolar CHOICE (The Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder), these two drugs were compared. The 6-month multicenter study in which they were used in typical settings of clinical practice showed similar clinical efficacy of lithium and quetiapine (Nierenberg, McElroy, Friedman et al. 2016). Ketter, Miller, Dell'Osso and Wang (2016)proposed that lithium and quetiapine may have similar efficacy in the treatment of acute episodes of bipolar disorder and its short-term prophylaxis, and the combination of both drugs is significantly more efficacious than either agent alone. However, Altamura, Mundo, Dell'Osso et al. (2008) in a naturalistic study lasting four years showed that the number of patients with euthymia was higher in those receiving lithium 18/39 (46%) than treated with quetiapine 12/49 (29%). Also, after the first episode of mania, quetiapine was inferior to lithium in limiting white matter reduction and regulating neural connection between the ventral striatum and the cerebellum (Berk, Dandash, Daglas et al. 2017; Dandash, Yücel, Daglas et al. 2018).

        Therefore, in my opinion, the better signature for quetiapine than “atypical antipsychotic drug” would be “second-generation mood-stabilizing drug.”



Altamura AC, Mundo E, Dell'Osso B, Tacchini G, Buoli M, Calabrese JR. Quetiapine and classical mood stabilizers in the long-term treatment of Bipolar Disorder: a 4-year follow-up naturalistic study. J Affect Disord 2008; 110:135-41. 

Berk M, Dandash O, Daglas R, Cotton SM, Allott K, Fornito A, Suo C, Klauser P, Liberg B, Henry L, Macneil C, Hasty M, McGorry P, Pantelis C, Yücel M. Neuroprotection after a first episode of mania: a randomized controlled maintenance trial comparing the effects of lithium and quetiapine on grey and white matter volume. Transl Psychiatry 2017; 7:e1011. 

Dandash O, Yücel M, Daglas R, Pantelis C, McGorry P, Berk M, Fornito A. Differential effect of quetiapine and lithium on functional connectivity of the striatum in first episode mania. Transl Psychiatry 2018; 8:59. 

Ketter TA, Miller S, Dell'Osso B, Wang PW. Treatment of bipolar disorder: Review of evidence regarding quetiapine and lithium. J Affect Disord 2016; 191:256-73. 

Nierenberg AA, McElroy SL, Friedman ES, Ketter TA, Shelton RC, Deckersbach T, McInnis MG, Bowden CL, Tohen M, Kocsis JH, Calabrese JR, Kinrys G, Bobo WV, Singh V, Kamali M, Kemp D, Brody B, Reilly-Harrington NA, Sylvia LG, Shesler LW, Bernstein EE, Schoenfeld D, Rabideau DJ, Leon AC, Faraone S, Thase ME. Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness): a pragmatic 6-month trial of lithium versus quetiapine for bipolar disorder. J Clin Psychiatry 2016; 77:90-9.

Popovic D, Reinares M, Goikolea JM, Bonnin CM, Gonzalez-Pinto A, Vieta, E. Polarity index of pharmacological agents used for maintenance treatment of bipolar disorder. Eur Neuropsychopharmacol 2012; 22:339-46. 

Prieto E, Micó JA, Meana JJ, Majadas S. Neurobiological bases of quetiapine antidepresant effect in the bipolar disorder. Actas Esp Psiquiatr, 2010; 38:22-32. 

Rybakowski J.K. Two generations of mood stabilizers. Int J Neuropsychopharmacol 2007; 10:709-11. 

Rybakowski JK. Meaningful aspects of the term 'mood stabilizer'. Bipolar Disord 2018; 20:391-2. 

Zarate CA, Tohen M, Banov MD, Weiss MK, Cole JO. Is clozapine a mood stabilizer? J Clin Psychiatry 1995; 56:108-12.


August 27, 2020