Samuel Gershon: Ketamine, the "new" breakthrough in the trestment of depression


Janusz Rybakowski’s comment


        I would not call ketamine “the breakthrough” in the treatment of depression, however, its introduction challenged some previous pathogenic and therapeutic views on this topic.

        The important point is the observation of a rapid antidepressant (and also anti-suicidal) effect of ketamine which undermined the view about a necessary “delay” in the action of antidepressant drugs. As early as the 1970s, the eminent Polish psychopharmacologist Jerzy Vetulani (1936-2017), working with Fridolin Sulser at Vanderbilt University in Nashville, put forward a hypothesis that the antidepressant action is due to the adaptative reaction of the noradrenergic system (so-called “beta-down-regulation”), occurring after several weeks of the administration of antidepressants (Vetulani, Stawarz, Dingell and Sulser 1976). A neuropsychological concept of the “delay” of the antidepressants postulates that these drugs may quickly change the perception of negative emotional stimuli into positive ones. However, this translates into the subjective improvement of the mood after several weeks  (Harmer and Cowen 2013). 

        A rapid antidepressant response has for several decades been observed after sleep deprivation. Although such an effect is short-lasting, however, it can be extended by the procedure of the “sleep phase advance” (Kurczewska et al, 2019). More recently, a rapid antidepressant effect was described after deep brain stimulation of the subgenual cingulate, Brodman’s area 25 (Lozano, Mayberg, Giacobbe et al. 2008). 

        Another issue connected with the antidepressant effect of ketamine is the role of the glutamatergic system in the pathogenesis and treatment of depression, and also suicidal behavior. The main mechanism of rapid antidepressant (and anti-suicidal) action of ketamine can be associated with antagonistic action on glutamatergic receptors NMDA as well as on glutamatergic receptors AMPA which can stimulate synaptogenesis (Autry et al., 2011).

        For two decades ketamine was thought to exert a negative effect on cognitive functions. The “ketamine” animal model of schizophrenia has been developed, imitating positive, negative and cognitive symptoms (Frohlich and Van Horn 2014). Also, cognitive impairment was observed in long-term ketamine users (Morgan and Curran 2012). In recent studies, depressive patients showed improvement on neuropsychological tests after one or multiple ketamine infusions (Shiroma et al. 2014; Murrough, Collins, Fields et al. 2015). In our study of bipolar depressive patients receiving mood-stabilizing drugs, there was an improvement in neuropsychological function on the third day after ketamine infusion, positively correlated with an impairment before the infusion (Permoda-Osip et al, 2015). Such a brief pro-cognitive effect of ketamine in depressive patients can be explained by its specific influence on emotional-cognitive interaction (Scheidegger, Henning, Walter et al. 2015), increased response to positive stimuli (Murrough, Collins, Fields et al. 2015) and enhanced synaptogenesis mentioned above.

        It should be also noted that recently, besides ketamine, the antidepressant effect of other psychoactive drugs has been observed (De Gregorio, Enns, Nuñez et al. 2018).

        Let me present the results of my ketamine infusion study in bipolar depression. Fifty-three patients (13 men, 40 women), aged 22-81 years (mean 47±12.6 years) with a bipolar depressive episode were included. The average age at illness onset was 31 years (±13), and the average length of the depressive episode was 4.9 (±2.0) months. Before ketamine infusion, patients were hospitalized, on average, for 21 days (±5). All the patients received at least one 1st or 2nd  generation mood-stabilizing drug: lithium carbonate - 35 patients; quetiapine - 36 patients; valproate - 11 patients; carbamazepine - 8 patients; lamotrigine - 17 patients; aripiprazole - 4 patients; and topiramate - 1 patient (Rybakowski 2018). All the patients had previously been treated with antidepressant drugs without sufficient improvement. The last antidepressant used before the infusion of ketamine was venlafaxine - 20 patients; paroxetine - 14 patients; bupropion - 9 patients; sertraline - 6 patients; mirtazapine - 3 patients; clomipramine - 2 patients; and reboxetine, fluvoxamine, fluoxetine, mianserin, escitalopram, citalopram, duloxetine or amitriptyline - 1 patient. All antidepressants were discontinued for at least seven days before infusion. On the day of the study, each patient received a 40-minute infusion of ketamine, 0.5mg/kg body weight. Psychometric evaluation was performed using the 17-item Hamilton Depression Rating Scale (HDRS).

        The intensity of depression in patients before intravenous administration of the drug, measured on the HDRS, was 23.4+4.6 points. After the administration of ketamine, a significant decrease in the HDRS score was observed. This fell to 15.6+7.4 points after 24 hours, to 14.2+7.2 points on the 3rd day, to 12.5±7.7 points on the 7th day and 11.8±8.1 points two weeks following ketamine infusion. The criteria for the response (a reduction of ≥50% on the HDRS compared with baseline) at 24 h were met by 13 patients (24,5%) and at day 7 by 27 patients (51%). The criteria for remission (intensity of depression ≤7 points on HDRS) at 24 h were met by eight patients (15%) and at day 7 by 14 patients (26%).

        In this group of patients, intravenous ketamine was relatively well tolerated. A transient increase in blood pressure occurred in about 1/3 of patients and did not correlate with the response. Also, psychiatric side effects, such as depersonalization and derealization, were experienced by 1/3 of patients only during the infusion, were not severe and did not correlate with the response to ketamine. None of the patients had a hypomanic switch within the 7 days after ketamine infusion.

        Although the study was neither randomized nor controlled we suggest that results may show that adding single ketamine infusion to mood stabilizers rapidly improves depression scores in inpatients with treatment-resistant bipolar depression (Rybakowski, Permoda-Osip and Bartkowska-Sniatkowska 2017).

        I am by no means a proponent of long-term ketamine administration. I think that it may constitute an acute option for treatment-resistant depression, also in patients with suicidal tendencies. Since long-term ketamine administration is connected with adverse health effects, the improvement after ketamine in treatment-resistant depression should be followed by the pharmacological and psychological management according to existing guidelines.



Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011; 475:91-5.

De Gregorio D, Enns JP, Nuñez NA, Posa L, Gobbi G. d-Lysergic acid diethylamide, psilocybin, and other classic hallucinogens: Mechanism of action and potential therapeutic applications in mood disorders. Prog Brain Res. 2018; 242:69-96.

Frohlich J, Van Horn JD. Reviewing the ketamine model for schizophrenia. J Psychopharmacol, 2014; 28:287-302.

Harmer CJ, Cowen PJ. 'It's the way that you look at it'--a cognitive neuropsychological account of SSRI action in depression. Philos Trans R Soc Lond B Bio Sci, 2013; 368:201-4.

Kurczewska E, Ferensztajn-Rochowiak E, Jasińska-Mikołajczyk A, Chłopocka-Woźniak M, Rybakowski JK. Augmentation of pharmacotherapy by sleep deprivation with sleep phase advance in treatment-resistant depression. Pharmacopsychiatry 2019; 52:186-92.

Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry, 2008; 64:461-7.

Morgan CJ, Curran HV; Independent Scientific Committee on Drugs. Ketamine use: a review. Addiction, 2012; 107:27-38.

Murrough JW, Collins KA, Fields J, DeWilde KE, Phillips ML, Mathew SJ, Wong E, Tang CY, Charney DS, Iosifescu DV. Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder. Transl Psychiatry, 2015; 5:e509.

Permoda-Osip A, Kisielewski J, Bartkowska-Sniatkowska A, Rybakowski JK. Single ketamine infusion and neurocognitive performance in bipolar depression. Pharmacopsychiatry 2015; 48:78-9.

Rybakowski JK, Permoda-Osip A, Bartkowska-Sniatkowska A. Ketamine augmentation rapidly improves depression scores in inpatients with treatment-resistant bipolar depression. Int J Psychiatry Clinical Pract, 2017; 21:99-103.

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

Scheidegger M, Henning A, Walter M, Boeker H, Weigand A, Seifritz E, Simone Grimm. Effects of ketamine on cognition-emotion interaction in the brain. Neuroimage, 2015; 124:8-15.

Shiroma PR, Albott CS, Johns B, Thuras P, Wels J, Lim KO. Neurocognitive performance and serial intravenous subanesthetic ketamine in treatment-resistant depression. Int J Neuropsychopharmacol 2014; 17:1805-13.

Vetulani J, Stawarz RJ, Dingell JV, Sulser F. A possible common mechanism of action of antidepressant treatments: reduction in the sensitivity of the noradrenergic cyclic AMP gererating system in the rat limbic forebrain. Naunyn Schmiedebergs Arch Pharmacol, 1976; 293:109-14.


October 29, 2020