The World Journal of Biological Psychiatry
November 3, 2020
Siegfried Kasper, Wiesław Jerzy Cubała, Andrea Fagiolini et al.
84 citations
Esketamine nasal spray, an NMDA glutamate receptor antagonist, offers a fast-acting treatment option for patients with treatment-resistant depression (TRD) who have not responded to several prior therapies. A group of six European experts with clinical experience using esketamine nasal spray developed consensus statements on practical considerations before, during, and after administration. The guidance is based on their experience and available literature, aiming to help clinicians unfamiliar with the treatment. Further real-world use is expected to expand existing knowledge.
Neuropsychiatric Disease and Treatment
November 1, 2020
Alina Wilkowska, Łukasz P. Szałach, Wiesław Jerzy Cubała
31 citations
Bipolar disorder is a psychiatric illness with high morbidity, mortality, and suicide rates, a neuroprogressive course, and frequent treatment resistance, creating a need for new treatment strategies. Ketamine appears to have rapid antidepressive and antisuicidal effects. Because most available studies concern unipolar depression, this article presents a novel argument that ketamine might be a promising treatment for bipolar disorder.
Journal of Sleep Research
June 16, 2021
Nelson B. Rodrigues, Roger S. McIntyre, Orly Lipsitz et al.
28 citations
Sleep disturbances are common in treatment-resistant depression (TRD). Intravenous (IV) ketamine improved sleep symptoms, which partially mediated its antidepressant and anti-suicidal effects. In 323 adults with TRD receiving four IV ketamine infusions, self-reported improvements in insomnia, night-time restlessness, hypersomnia, early morning waking, and total sleep partially explained reductions in depression severity. Insomnia, night-time restlessness, early morning waking, and total sleep improvements also mediated reductions in suicidal ideation. Each point improvement in total sleep score was associated with 3.29 times higher odds of achieving response or remission (95% confidence interval 2.00–5.41).
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
September 1, 2024
Aleksander Kwaśny, Julia Kwaśna, Alina Wilkowska et al.
24 citations
Ketamine, a medication used for depression, may also reduce anhedonia (loss of interest or pleasure). A systematic review of 22 studies (4 randomized-controlled trials and 18 open-label trials) found that all reported alleviation of anhedonia symptoms after ketamine or esketamine administration, regardless of the number of infusions. Neuroimaging studies showed changes in functional connectivity linked to improvement. However, limitations include few placebo-controlled trials. The review suggests a potential anti-anhedonic effect of ketamine in depressed patients, likely through neuroplastic changes.
Cells
February 12, 2022
Alina Wilkowska, Mariusz S. Wiglusz, Katarzyna Jakuszkowiak‐wojten et al.
23 citations
A review of animal and human studies on combining ketamine with lamotrigine found that animal models suggested a synergistic antidepressant effect, while studies in healthy humans showed lamotrigine pretreatment reduced ketamine-induced dissociative symptoms. In a study of depressed patients, a single ketamine infusion combined with lamotrigine did not produce a stronger antidepressant effect than ketamine alone. A case series described antidepressant and anti-suicidal effects in two bipolar patients. Clinical studies in mood disorder patients did not support lamotrigine reducing ketamine-induced dissociation. The available evidence was insufficient to answer the review's questions, but pointed to future research directions, including controlled studies in bipolar patients with multiple ketamine infusions.
Medicina
February 9, 2020
Adam Włodarczyk, Wiesław Jerzy Cubała
22 citations
Current treatments for major depression focus on monoaminergic drugs, which fail many patients. Treatment-resistant bipolar depression (TRBD) affects up to 33% of treated depressive patients. Ketamine, an NMDA receptor antagonist, shows promise, with effects emerging minutes to hours after a single dose. However, little data exist on ketamine's performance in TRBD patients with somatic comorbidities like cardiovascular disease, diabetes, obesity, stroke, epilepsy, or in the elderly. The literature indicates ketamine is efficacious and safe; most adverse drug reactions are mild and resolve within 30 minutes to 2 hours of administration.
Brain Sciences
January 13, 2023
Maria Gałuszko‐węgielnik, Zuzanna Chmielewska, Katarzyna Jakuszkowiak‐wojten et al.
20 citations
Psychotic treatment-resistant depression is a severe form of major depressive disorder involving hallucinations or delusions, often underdiagnosed and undertreated. Ketamine has shown rapid antidepressant effects, and its enantiomer esketamine was approved for treatment-resistant depression in 2019. This report describes four inpatients with treatment-resistant depression and psychotic features, including one in severe suicidal crisis, who received a single 0.5 mg/kg intravenous infusion of ketamine as an add-on to standard care. Monitoring showed no worsening of psychotic symptoms in short or long term, and all patients achieved stable remission with an immediate antisuicidal effect. Ketamine may benefit individuals with this condition.
Bipolar Disorders
February 4, 2024
Alina Wilkowska, Mariusz S. Wiglusz, Aleksandra Arciszewska et al.
17 citations
In patients with treatment-resistant bipolar depression, adding ketamine infusions to ongoing treatment reduced anhedonia, a debilitating symptom linked to suicidality and poor treatment response. Improvement was seen on both patient-reported and clinician-rated measures of anhedonia, and anxiety and mood/cognition symptoms also improved, but sleep symptoms did not. No serious adverse events occurred. The findings suggest ketamine may be a useful option for anhedonia in this population, though further research is needed.
International Journal of Molecular Sciences
November 23, 2022
Alina Wilkowska, Wiesław Jerzy Cubała
17 citations
Treatment-resistant depression affects about 30% of people with depression, and the likelihood of remission drops with each subsequent episode. This condition contributes heavily to global disease burden, raises morbidity and mortality, and lowers quality of life. It involves repeated difficult-to-treat episodes, with resistance growing over time. Staging captures how these changes lead to worsening treatment resistance and overall functioning. Ketamine, a rapid-acting antidepressant that can promote neuroplasticity, is argued here to be able to reverse this worsening process when used as an add-on treatment, offering hope and countering therapeutic nihilism.
Neuropsychiatric Disease and Treatment
October 1, 2020
Joanna Szarmach, Wiesław Jerzy Cubała, Adam Włodarczyk et al.
15 citations
In patients with treatment-resistant depression, intravenous ketamine is generally safe and well-tolerated when added to existing psychiatric medications. Blood pressure and heart rate returned to baseline within 90 minutes after each infusion, with no lasting complications. However, larger temporary increases in blood pressure occurred in patients also taking SSRIs, and heart rate decreases were greater in those not taking mood stabilizers. Risks were more pronounced in patients with coexisting high blood pressure or diabetes. The study included 35 people with major depressive disorder and 14 with bipolar disorder.
Medicina
March 16, 2021
Joanna Szarmach, Wiesław Jerzy Cubała, Adam Włodarczyk et al.
14 citations
Ketamine treatment for treatment-resistant depression has a good safety and tolerability profile, but patients with metabolic and cardiovascular comorbidities require risk mitigation. In a naturalistic observational study of 49 inpatients with major depressive disorder or bipolar disorder, those with hypertension showed a greater increase in systolic blood pressure after the second infusion compared to those without hypertension. Patients with diabetes mellitus had significant differences in heart rate after infusions 2, 7, and 8, and a higher increase in diastolic blood pressure. Hyperlipidemic patients experienced a greater decrease in heart rate after infusion 5 and systolic blood pressure after infusion 4. Stroke survivors had higher increases in diastolic blood pressure after infusions 4 and 6. Epilepsy patients had a greater decrease in systolic blood pressure after the 8th infusion.
Klinik Psikofarmakoloji Bülteni-Bulletin of Clinical Psychopharmacology
June 1, 2014
Wiesław Jerzy Cubała, Alexandra Gabrielsson
11 citations
Zolpidem, a non-benzodiazepine hypnotic introduced in 1988, is widely prescribed for short-term insomnia due to its lower abuse potential than benzodiazepines. This systematic review of 47 case reports from 1966–2012 found that sleep-related amnestic behaviors, such as complex actions without memory, occur as an adverse drug reaction. Women were more frequently affected, and individuals with mood disorders or those taking concomitant monoaminergic drugs were more prone. Alcohol or other substance use was reported in only a minority of cases. The findings suggest that physicians should assess risk factors—especially female sex and concurrent monoaminergic medication—before prescribing zolpidem.
Frontiers in psychiatry
January 1, 2024
Aleksander Kwaśny, Alina Wilkowska, Wiesław Jerzy Cubała
10 citations
A systematic review of clinical trials on 5-MeO-DMT, an atypical psychedelic being studied as a rapid-acting antidepressant, found that the drug has a good short-term safety and tolerability profile. Three trials involving 78 participants (two with healthy volunteers, one with treatment-resistant depression patients) reported no serious adverse events and no drop-outs. The authors conclude that 5-MeO-DMT administration in humans is safe in the short term, but call for larger, placebo-controlled trials with longer follow-up to assess potential chronic adverse events.
Frontiers in Psychiatry
December 8, 2023
Alina Wilkowska, Wiesław Jerzy Cubała
10 citations
Bipolar depression is a serious psychiatric condition linked to high suicide risk, treatment resistance, chronicity, and poor quality of life. Approved treatments are limited and often insufficient, creating an urgent need for new strategies. Intranasal esketamine, a ketamine enantiomer, is a rapid-acting antidepressant proven effective for treatment-resistant depression. Research on bipolar depression, though less extensive, suggests esketamine may be a safe alternative with low risk of mood polarity shifts. Reports indicate ketamine treatment may reduce suicidal thoughts, anhedonia, and anxiety. Ketamine's potential mood-stabilizing properties are hypothesized. This narrative review examines ketamine as an add-on to standard medication for acute bipolar depression.
Pharmaceuticals
January 24, 2023
Adam Włodarczyk, Alicja Dywel, Wiesław Jerzy Cubała
10 citations
In patients with treatment-resistant depression, intravenous ketamine may elevate psychotic symptoms in those with epilepsy. Among 49 inpatients with major depressive or bipolar depression treated with ketamine, the presence of epilepsy was significantly associated with an increase in Brief Psychiatric Rating Scale scores over time. For the subgroup with epilepsy (6 patients), substantial fluctuations occurred across all administrations. Psychotic symptoms for other comorbid conditions were not significant. The findings indicate that careful consideration of comorbidities and close clinical supervision are needed during ketamine treatment.
The World Journal of Biological Psychiatry
June 20, 2023
Maria Gałuszko‐węgielnik, Katarzyna Jakuszkowiak‐wojten, Alina Wilkowska et al.
9 citations
A woman with both bipolar disorder and borderline personality disorder received intravenous ketamine for acute depression. While ketamine initially improved her depressed mood, continued treatment led to increased nonsuicidal self-injury, impulsive behavior, and worsening dissociative symptoms. Treatment was stopped and replaced with a different medication that proved helpful. The authors conclude that ketamine's effects on emotional dysregulation and impulsivity are unclear and differ from its antidepressant effects, highlighting the need for more safety and effectiveness studies in this patient group.
Frontiers in Psychiatry
June 3, 2020
Alina Wilkowska, Łukasz P. Szałach, Jakub Słupski et al.
9 citations
Ketamine can rapidly reduce depression in people with treatment-resistant bipolar disorder, but it also carries a risk of triggering mania. This case describes a patient with bipolar I disorder who, after eight low doses of oral ketamine added to their usual treatment, switched from a depressive episode to a manic episode with mixed features. The manic symptoms began two days before the switch became full-blown. The finding highlights the need for careful monitoring of mood changes when using ketamine in bipolar depression.
Asian journal of psychiatry
September 1, 2024
Michał Pastuszak, Wiesław Jerzy Cubała, Aleksander Kwaśny
8 citations
In patients with treatment-resistant bipolar depression receiving eight intravenous ketamine infusions while continuing their usual medications, the most common new symptoms that appeared included decreased appetite, weight gain, excessive sleep, and mood changes that varied throughout the day. Feelings of sadness, hopelessness about the future, reduced sexual interest, and physical discomfort did not emerge. However, 13.6% of patients reported new thoughts of death or suicide. Larger studies using both clinician and patient reports are needed to better understand these treatment-emergent symptoms, and clearer definitions would improve future research.
Frontiers in Neuroscience
July 11, 2023
Maria Gałuszko‐węgielnik, Katarzyna Jakuszkowiak‐wojten, Mariusz S. Wiglusz et al.
8 citations
In patients with treatment-resistant unipolar or bipolar depression with psychotic features, eight intravenous infusions of 0.5 mg/kg ketamine given twice a week over 4 weeks did not worsen psychotic or dissociative symptoms. No statistically significant changes occurred in depressive, dissociative, or psychomimetic symptom scores across the whole group during treatment. However, within the unipolar and bipolar subgroups separately, significant improvements in these symptom scores were observed. The findings support the safety and tolerability of ketamine in this population, showing no exacerbation of psychotic symptoms.
Therapeutic Advances in Psychopharmacology
January 1, 2021
Adam Włodarczyk, Wiesław Jerzy Cubała, Maria Gałuszko‐węgielnik et al.
8 citations
In treatment-resistant inpatients with major depressive disorder (MDD) or bipolar disorder (BP), intravenous ketamine was generally well-tolerated with no lasting neurological harm. However, certain concurrent medications were linked to more psychomimetic and dissociative symptoms. Patients taking the antidepressant citalopram reported greater psychomimetic effects. Classic mood stabilizers—lamotrigine, valproate, and lithium—were each significantly associated with increased scores on the Brief Psychiatric Rating Scale. No long-term adverse effects were observed. The findings suggest that ketamine treatment requires careful monitoring for dissociative and psychomimetic symptoms, especially when combined with specific psychotropic drugs.
Magnesium Research
April 1, 2018
Natalia Górska, Wiesław Jerzy Cubała, Jakub Słupski et al.
8 citations
Depression is a leading cause of disability, and many adults with major depression do not achieve remission with first-line treatments. Magnesium influences several neurotransmitter systems involved in emotional processes, including serotonergic, noradrenergic, dopaminergic, GABAergic, and glutamatergic systems. The mechanism of antidepressants' action involves the glutamatergic system, and magnesium ions may play a role in major depressive disorder pathophysiology by blocking the N-methyl-D-aspartate receptor (NMDAR). Ketamine, an NMDAR antagonist, has fast-acting antidepressant and antisuicidal effects. The evidence discussed suggests a possible synergistic interaction between magnesium and ketamine's pharmacodynamic activity in mood disorders.
Frontiers in psychiatry
January 1, 2024
Aleksander Kwaśny, Wiesław Jerzy Cubała, Adam Włodarczyk
7 citations
Anhedonia, a reduced ability to experience pleasure, is a core depression symptom that often persists despite standard treatments. Ketamine appears to have antianhedonic effects. In a naturalistic study of 28 inpatients with treatment-resistant depression, both responders and non-responders to ketamine therapy showed significant reductions in anhedonia over time, as measured by the Snaith-Hamilton Pleasure Scale. Non-responders also reported significant improvement in self-reported depression at the seventh infusion, but not at follow-up. Changes in depressive symptoms and anhedonia did not fully overlap, suggesting ketamine may alleviate anhedonia as a separate symptom domain regardless of overall treatment response.
Brain Sciences
December 11, 2020
Jakub Słupski, Wiesław Jerzy Cubała, Natalia Górska et al.
7 citations
Serum copper concentration changes during ketamine treatment in patients with treatment-resistant depression, but no clear link between copper levels and treatment response was found. Patients with major depressive or bipolar disorder received weekly ketamine infusions, and copper levels were measured before, during, and after treatment. Copper concentration was significantly higher before treatment than after the fifth infusion, and also higher after the full course than after the fifth infusion. However, changes in copper levels did not correlate with scores on depression or mania rating scales, nor with somatic comorbidities. The findings provide data on copper's role in short-term ketamine therapy but do not support copper as a marker of treatment response.
Journal of Psychopharmacology
July 11, 2025
Aleksander Kwaśny, Patrycja Ciurkowska, Wiesław Jerzy Cubała et al.
6 citations
In interventional clinical trials of psilocybin and LSD, participants are overwhelmingly White, raising concerns about whether these therapies are safe and effective for diverse populations. A cross-sectional analysis of nine eligible trials (eight psilocybin, one LSD) registered on ClinicalTrials.gov through January 2025 found that among 501 psilocybin participants, 87.2% were White, 3.0% Black, and 5.0% Asian; ethnicity was reported in only four trials, with 13.4% identifying as Hispanic or Latino. The single LSD trial of 11 older adults reported no race or origin data. Participation-to-population ratios for U.S.-only trials confirmed underrepresentation of Black and Asian individuals. The authors conclude that broader recruitment and standardized reporting are essential to ensure equity and establish safety and efficacy across groups.
Psychiatry research
August 1, 2025
Damian Swieczkowski, Aleksander Kwaśny, Krzysztof Sadko et al.
5 citations
A cross-sectional evaluation of 40 clinical trials on ketamine and its enantiomers, esketamine and arketamine, for treatment-resistant depression reveals significant methodological inconsistencies. Key issues include inadequate blinding due to ketamine's dissociative effects, poor management of expectancy bias, and insufficient safety monitoring. Placebo response, accounting for a large portion of treatment effects, was inconsistently handled, and long-term follow-up was lacking in most trials, limiting understanding of extended safety. The findings call for harmonized, rigorous frameworks to improve regulatory approval and therapeutic success, with lessons applicable to other psychedelics under investigation for mental health disorders.