Repeated ketamine injections in synergy with antidepressants for treating refractory depression: A case showing 6-month improvement

Major depressive disorder imposes a large global burden and a substantial minority of patients—commonly estimated at around 30%—meet criteria for treatment‑resistant depression (TRD). Earlier research has shown that ketamine produces rapid antidepressant effects across multiple routes of administration, but optimal dosing remains uncertain: some studies report greater benefit with doses above the frequently used 0.5 mg/kg intravenous bolus, while others find 0.5 mg/kg numerically superior to higher doses. Long‑term intravenous regimens have been proposed to extend the brief response after single doses, but chronic ketamine use raises safety concerns such as addiction and cognitive impairment. Wang and colleagues present a single‑patient case report intended to illustrate the clinical course, tolerability and durability of effect following repeated, rapidly administered, high‑dose intravenous ketamine given alongside ongoing antidepressant therapy. The report addresses the open question of whether escalation above 0.5 mg/kg and repeated rapid injections can be both tolerated and associated with sustained improvement in a person with longstanding, refractory major depression.

This paper is a single case report of a Chinese woman with a long history of recurrent depressive episodes beginning in 1991, multiple prior psychiatric admissions, and persistent symptoms despite prior treatments. At the index admission in 2018 she presented with severe depressive symptoms including suicidal ideation and two suicide attempts earlier that year. Routine laboratory, cardiac, gynaecological and neuroimaging tests were reported as within normal limits. Diagnosis was made using the Structured Clinical Interview for DSM‑IV as recurrent depressive disorder, current episode severe without psychotic features; bipolar disorder was screened out by a Mood Disorder Questionnaire score of 4. The patient and family denied alcohol or illicit substance misuse and family history for mental illness was negative. Mood and anxiety were monitored with the Hamilton Depression Scale‑24 (HAMD‑24) and the Hamilton Anxiety Scale (HAMA). Cognitive function was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) at admission, every 4 weeks during hospitalisation, and every 3 months after discharge. Pharmacotherapy during ketamine treatment consisted of venlafaxine extended‑release up to 225 mg daily and escitalopram 20 mg daily, continued throughout the course. After informed consent and under monitoring with pulse oximetry, electrocardiography and blood pressure measurement, ketamine was administered intravenously. Initial dosing used 0.5 mg/kg delivered in 20 mL saline over 20 seconds with supplemental oxygen at 5 L/min. When response to the low dose was inadequate, the investigators escalated to 1 mg/kg given intravenously over 1 minute. The extract indicates repeated injections were given and later notes a total of eight injections, but the precise timing and interval between injections is not clearly reported in the extracted text. The patient was observed in the operating room after each injection and vital signs and acute adverse effects were recorded.

At baseline during the index admission the patient had severe symptoms with HAMD‑24 36 and HAMA 21. The first rapid intravenous 0.5 mg/kg ketamine dose produced an acute cardiovascular reaction with blood pressure rising to 180/110 mm Hg and heart rate to 130 bpm; she awoke 10 minutes later and was observed for 1 hour without other abnormalities. That initial low dose did not meaningfully improve depressive symptoms and she relapsed by the next morning. After subsequent injections the patient’s depressive symptoms progressively lessened; after the third injection symptoms were reduced and after the final injection reported in the extract her HAMD‑24 was 8 and HAMA 11. The treatment course comprised eight ketamine injections in total (the extract does not specify the inter‑injection schedule). By week 9 of admission she was discharged in good emotional state. At 6‑month outpatient follow‑up she reported no suicidal ideation or depressive symptoms and was able to work normally; she remained on venlafaxine 225 mg and escitalopram 20 mg. Adverse effects during treatment were described as mild and transient, consisting of short‑lived exacerbations of dissociative symptoms and episodic blood pressure elevation. Cognitive testing with CANTAB was reported to show improvement on several domains after treatment, though the extract does not provide the specific cognitive scores or the numerical CANTAB results. The authors note that some tabulated data were referenced but are not available in the extracted text.

Wang and colleagues interpret the case as suggesting that when standard low‑dose ketamine (0.5 mg/kg) fails to produce sustained benefit, repeated and more rapidly administered higher‑dose intravenous ketamine (1 mg/kg) given adjunctively with conventional antidepressants may be both tolerated and associated with prolonged remission. They explain their rationale for the rapid bolus approach as an attempt to accelerate ketamine crossing of the blood–brain barrier and to attain higher central exposure, and they justify dose escalation on the hypothesis that higher doses may block a greater fraction of NMDA receptors. The authors note that ketamine’s mechanism in TRD remains unclear. The investigators also propose a potential synergistic effect between ketamine and ongoing antidepressants, citing prior reports of enhanced durability when medications are combined with ketamine infusions; one referenced study reported response in a subset of subjects for up to 4 weeks with such combinations. Cognitive outcomes are discussed cautiously: in this case CANTAB testing indicated improvements in several domains, but the authors acknowledge contrasting literature that documents cognitive deficits during and shortly after ketamine infusion and that venlafaxine itself may have contributed to cognitive gains. They reiterate known safety concerns about chronic ketamine exposure—addiction and cognitive impairment—but report only transient dissociative effects and blood pressure elevations in this patient. Limitations and uncertainties are recognised implicitly: this is a single case, the mechanistic basis for the observed durability is uncertain, and some detailed numerical data and timing of injections are not clearly reported in the extracted text. The authors suggest that their observations warrant further study to determine whether repeated, higher‑dose rapid ketamine injections can be replicated safely and effectively in larger samples and over longer follow‑up.