Authors' objectives: Background: In severe cases of depression and obsessive-compulsive disorder (OCD), the tricyclic antidepressant clomipramine is sometimes administered parenterally, especially in treatment-resistant conditions and inpatient care. Arguments for parenteral compared to oral administration include a more predictable bioavailability, a higher parent to metabolite ratio with serotonergic activity being more pronounced in the parent drug, reaching steady state faster, reduced compliance problems, and a potential placebo effect related to the administration. Question at issue: In patients with depression or OCD, is parenteral administration of clomipramine superior to oral clomipramine, other treatments, or placebo in terms of reducing depressive symptoms and OCD symptoms within two weeks, as well as other important outcome measures?

Authors' results and conclusions: Results: Fourteen randomised controlled trials (RCTs) including a total of 418 patients fulfilled the inclusion criteria, whereof ten were assessed not to have a high risk of bias. No RCTs compared parenteral clomipramine with the beforehand determined relevant comparisons electroconvulsive therapy (ECT) and ketamine. No RCTs provided information regarding the outcomes suicide attempts, all-cause mortality, suicidal ideation, global functioning, length of hospital stay, or health-related quality of life. Depression For the comparison of intravenous versus oral clomipramine, five double-blind RCTs (n=170) formed the basis for the conclusion. Results from three RCTs could be pooled, resulting in a mean difference of change in Hamilton depression rating scale (HDRS) scores of -1.27 (95% confidence interval (CI): -3.09 to 0.54; minimum clinically important difference: 2). Thus, intravenous clomipramine may not be superior to oral administration in terms of reducing depressive symptoms within two weeks, but a clinically relevant effect cannot be excluded (low certainty of evidence). Further, there may be no difference regarding change in HDRS scores after more than two weeks and treatment discontinuation. Regarding adverse events related to administration via injection or infusion, no conclusions could be drawn based on available RCTs, but infusion-related adverse event rates like thrombophlebitis and hypotension occurred and were in line with rates described in the summary of product characteristics. For the comparison of intravenous clomipramine versus other treatments, the available RCTs did not allow for conclusions, or no RCTs were available. For the comparison of intravenous clomipramine versus placebo, one double-blind RCT (n=16; mean difference of change in HDRS scores: -6.0 (95% CI: -0.9 to -11) formed the basis for the conclusion that intravenous clomipramine may be superior to placebo in terms of reducing depressive symptoms within two weeks (low certainty of evidence; this assessment does not concern the efficacy of clomipramine as an active substance). Obsessive-compulsive disorder For the comparison of intravenous versus oral clomipramine, no conclusion could be drawn based on available RCTs (very low certainty of evidence). For the comparison of intravenous clomipramine versus other treatments, no RCTs were available. For the comparison of intravenous clomipramine versus placebo in patients with OCD, one double-blind RCT (54 patients poorly responsive to oral clomipramine; mean difference of change in Yale-Brown obsessive compulsive scale scores: -2.5 (95% CI: -5.6 to 0.6; minimum clinically important difference: 4.9)) formed the basis for the conclusion that in patients with OCD refractory to oral clomipramine, intravenous clomipramine may not be superior to placebo regarding effects on OCD symptoms at two weeks, but a clinically relevant effect cannot be excluded (low certainty of evidence). Conclusion: In patients with depression, parenteral administration of clomipramine may not be favourable compared to oral administration. In patients with OCD, parenteral clomipramine may not be favourable when oral treatment has failed. For other critical and important outcomes and comparisons, evidence is either absent or does not allow for conclusions, but administration-related adverse reactions can occur with parenteral clomipramine. Given these findings and the high cost of the injectable formulation, ethical concerns may be raised, and further research including ECT or ketamine can be considered warranted.

Authors' methods: Methods: Two authors performed literature searches (September 2024) in Medline, Embase, the Cochrane Library and PsycInfo. They independently assessed the abstracts and, in consensus, selected full-text articles that were not clearly out of scope to be sent to the other authors, who then decided in consensus whether the inclusion criteria were fulfilled, i.e., whether information regarding the question at issue was provided. The included studies were critically appraised, and data were extracted. Studies without a high risk of bias formed the primary basis for the conclusions. Meta-analyses were performed when applicable. Certainty of evidence was assessed according to GRADE. The study protocol was preregistered with PROSPERO (CRD420250654029).

Project Status: Completed

Year Published: 2025

URL for published report: https://mellanarkiv-offentlig.vgregion.se/alfresco/s/archive/stream/public/v1/source/available/sofia/su4372-2081313122-159/native/2025_144%20HTA-rapport%20Parenteral%20Clomipramine%202025-07-02.pdf

English language abstract: An English language summary is available

Publication Type: Full HTA

Organisation Name: The Regional Health Technology Assessment Centre

Contact Address: The Regional Health Technology Assessment Centre, Region Vastra Gotaland, HTA-centrum, Roda Straket 8, Sahlgrenska Universitetssjukhuset, 413 45 GOTHENBORG, Sweden

Contact Name: hta-centrum@vgregion.se

Contact Email: hta-centrum@vgregion.se