Antianhedonic Effect of Repeated Ketamine Infusions in Patients With Treatment Resistant Depression

Wilkowska, Aleksandra; Wiglusz, Mariusz S.; Gałuszko-Węgielnik, Maria; Włodarczyk, Adam; Cubała, Wiesław Jerzy

doi:10.3389/fpsyt.2021.704330

Cited by 25 publications

(24 citation statements)

References 34 publications

(37 reference statements)

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“…Relevant to the understanding of ketamine’s efficacy in patients with MDD, ketamine infusion into the NAc protected marmosets from the anhedonic-like effects of scACC-25 overactivation for more than 1 week. This parallels results reported previously in humans, and more recently in marmosets, after systemic ketamine administration ( 8 , 21 , 28 , 29 ). Identification of the neural circuit mechanism through which ketamine acts to mediate its anti-anhedonic effects is critical for developing more effective long-term treatments for patients with MDD.…”

Section: Discussionsupporting

confidence: 91%

Chemogenetics identifies separate area 25 brain circuits involved in anhedonia and anxiety in marmosets

et al. 2023

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Poor outcomes are common in individuals with anxiety and depression, and the brain circuits underlying symptoms and treatment responses remain elusive. To elucidate these neural circuits, experimental studies must specifically manipulate them, which is only possible in animals. Here, we used a chemogenetics strategy involving engineered designer receptors exclusively activated by designer drugs (DREADDs) to activate a region of the marmoset brain that is dysfunctional in human patients with major depressive disorder, called the subcallosal anterior cingulate cortex area 25 (scACC-25). Using this DREADDs system, we identified separate scACC-25 neural circuits that underlie specific components of anhedonia and anxiety in marmosets. Activation of the neural pathway connecting the scACC-25 to the nucleus accumbens (NAc) caused blunting of anticipatory arousal (a form of anhedonia) in marmosets in response to a reward-associated conditioned stimulus in an appetitive Pavlovian discrimination test. Separately, activation of the circuit between the scACC-25 and the amygdala increased a measure of anxiety (the threat response score) when marmosets were presented with an uncertain threat (human intruder test). Using the anhedonia data, we then showed that the fast-acting antidepressant ketamine when infused into the NAc of marmosets prevented anhedonia after scACC-25 activation for more than 1 week. These neurobiological findings provide targets that could contribute to the development of new treatment strategies.

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Section: Discussionsupporting

confidence: 91%

Chemogenetics identifies separate area 25 brain circuits involved in anhedonia and anxiety in marmosets

et al. 2023

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“…Use of BZDs among patients with major depressive disorder was found to be associated with increased anhedonia but not anxiety or depression symptom levels (perhaps because BZDs mitigated anxiety) and anhedonia was the strongest predictor of BZD use in that study ( 133 ). A recent clinical study of repeated ketamine infusions in 42 patients with treatment-resistant major depression found that ketamine (an NMDA receptor antagonist) significantly reduced anhedonia (SHAPS scores) after each infusion but only among the subgroup of patients who did not use BZDs ( 134 ). Although the present study was not designed to examine BZD withdrawal and anhedonia, we did not find any significant difference in anhedonia scores between BZD misusers and never-misusers, nor between participants whose urine samples tested BZD-positive vs. BZD-negative.…”

Section: Discussionmentioning

confidence: 99%

Anhedonia modulates benzodiazepine and opioid demand among persons in treatment for opioid use disorder

et al. 2023

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BackgroundBenzodiazepine (BZD) misuse is a significant public health problem, particularly in conjunction with opioid use, due to increased risks of overdose and death. One putative mechanism underlying BZD misuse is affective dysregulation, via exaggerated negative affect (e.g., anxiety, depression, stress-reactivity) and/or impaired positive affect (anhedonia). Similar to other misused substances, BZD consumption is sensitive to price and individual differences. Although purchase tasks and demand curve analysis can shed light on determinants of substance use, few studies have examined BZD demand, nor factors related to demand.MethodsThis ongoing study is examining simulated economic demand for alprazolam (among BZD lifetime misusers based on self-report and DSM-5 diagnosis; n = 23 total; 14 male, 9 female) and each participant’s preferred-opioid/route using hypothetical purchase tasks among patients with opioid use disorder (n = 59 total; 38 male, 21 female) who are not clinically stable, i.e., defined as being early in treatment or in treatment longer but with recent substance use. Aims are to determine whether: (1) BZD misusers differ from never-misusers on preferred-opioid economic demand, affective dysregulation (using questionnaire and performance measures), insomnia/behavioral alertness, psychiatric diagnoses or medications, or urinalysis results; and (2) alprazolam demand among BZD misusers is related to affective dysregulation or other measures.ResultsLifetime BZD misuse is significantly (p < 0.05) related to current major depressive disorder diagnosis, opioid-negative and methadone-negative urinalysis, higher trait anxiety, greater self-reported affective dysregulation, and younger age, but not preferred-opioid demand or insomnia/behavioral alertness. Alprazolam and opioid demand are each significantly positively related to higher anhedonia and, to a lesser extent, depression symptoms but no other measures of negative-affective dysregulation, psychiatric conditions or medications (including opioid agonist therapy or inpatient/outpatient treatment modality), or sleep-related problems.ConclusionAnhedonia (positive-affective deficit) robustly predicted increased BZD and opioid demand; these factors could modulate treatment response. Routine assessment and effective treatment of anhedonia in populations with concurrent opioid and sedative use disorder may improve treatment outcomes.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT03696017, identifier NCT03696017.

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“…This study has several limitations. First, the model used in this study and others, in which ketamine is used to induce the manic phase, is valid, but the accuracy of this assessment has not been discussed in past years, although the aims of previous studies were to explore new methods for the improvement of treatment effects in patients with treatment-resistant depression and to rapidly reduce suicide attempts due to severe depressive symptoms in BP (Valvassori et al, 2019 ; Kim and Monteggia, 2020 ; McIntyre et al, 2020 ; Chen et al, 2021 ; Dean et al, 2021 ; Keilp et al, 2021 ; Magalhães et al, 2021 ; Nikayin and Sanacora, 2021 ; Wilkowska et al, 2021 ). A reviewer of this article led us to rethink the validity of the use of ketamine to induce the manic phase when studying BP (a physiopathological process), as drug-induced manic behavior may have different underlying mechanisms, Strictly speaking, a ketamine-induced manic phase can only represent such a phase induced by antidepressants, which is usually observed in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Brain Neural Activity Patterns in an Animal Model of Antidepressant-Induced Manic Episodes

Chen

Tian

et al. 2022

Front. Behav. Neurosci.

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Background: In the treatment of patients with bipolar disorder (BP), antidepressant-induced mania is usually observed. The rate of phase switching (from depressive to manic) in these patients exceeds 22%. The exploration of brain activity patterns during an antidepressant-induced manic phase may aid the development of strategies to reduce the phase-switching rate. The use of a murine model to explore brain activity patterns in depressive and manic phases can help us to understandthe pathological features of BP. The novel object recognition preference ratio is used to assess cognitive ability in such models.Objective: To investigate brain Ca2+ activity and behavioral expression in the depressive and manic phases in the same murine model, to aid understanding of brain activity patterns in phase switching in BP.Methods: In vivo two-photon imaging was used to observe brain activity alterations in a murine model in which induce depressive-like and manic-like behaviors were induced sequentially. The immobility time was used to assess depressive-like symptoms and the total distance traveled was used to assess manic-like symptoms.Results: In vivo two-photon imaging revealed significantly reduced brain Ca2+ activity in temporal cortex pyramidal neurons in the depressive phase in mice exposed to chronic unpredictable mild stress compared with naïve controls. The brain Ca2+ activity correlated negatively with the novel object recognition preference ratio within the immobility time. Significantly increased brain Ca2+ activity was observed in the ketamine-induced manic phase. However, this activity did not correlate with the total distance traveled. The novel object recognition preference ratio correlated negatively with the total distance traveled in the manic phase.

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Antianhedonic Effect of Repeated Ketamine Infusions in Patients With Treatment Resistant Depression

Cited by 25 publications

References 34 publications

Chemogenetics identifies separate area 25 brain circuits involved in anhedonia and anxiety in marmosets

Chemogenetics identifies separate area 25 brain circuits involved in anhedonia and anxiety in marmosets

Anhedonia modulates benzodiazepine and opioid demand among persons in treatment for opioid use disorder

Brain Neural Activity Patterns in an Animal Model of Antidepressant-Induced Manic Episodes

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