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• In depression, parenteral clomipramine does not show clear short- or long-term advantages over oral clomipramine in symptom reduction or treatment discontinuation, although a short-term benefit cannot be ruled out due to imprecision of effect estimates.
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• In obsessive-compulsive disorder(OCD), current randomised trials provide very uncertain evidence, and no superiority of parenteral clomipramine over oral clomipramine or placebo has been demonstrated.
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• The certainty of the evidence is predominantly low or very low, mainly due to small sample sizes, few events, and wide confidence intervals(CIs) in the included randomised controlled trials(RCTs).
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• Important clinically relevant outcomes such as suicidality, functioning, hospital length of stay, and quality of life are lacking.
Introduction
The tricyclic antidepressant (TCA) clomipramine has been administered parenterally for decades because of hypothesised advantages over oral formulations and other treatments. Arguments for parenteral over oral administration include more predictable bioavailability; a higher parent-to-metabolite ratio with serotonergic activity being more prominent in the parent drug; faster achievement of steady state, potentially leading to a quicker onset of action; fewer compliance issues; and a potential placebo effect related to the mode of administration (Evans et al., Reference Evans, Bett, Cox, Dubois and Van Hees1980; Balant-Gorgia et al., Reference Balant-Gorgia, Gex-Fabry and Balant1991; Hendset et al., Reference Hendset, Haslemo, Rudberg, Refsum and Molden2006; Jones et al., Reference Jones, Razza, Weissman, Karbi, Vine, Mulsant, Brunoni, Husain, Mulsant, Blumberger and Daskalakis2021; Peciña et al., Reference Peciña, Heffernan, Wilson, Zubieta and Dombrovski2018). This may be particularly relevant in inpatient care, where rapid symptom relief and reduction of suicide risk are critical treatment goals (Zisler et al., Reference Zisler, Meule, Endres, Schennach, Jelinek and Voderholzer2024; Abdolizadeh et al., Reference Abdolizadeh, Jones, Hosseini Kupaei, Shah, Rodak, Farooqui, Husain, Weissman, Zaheer, Gratzer, Blumberger and Husain2025). Furthermore, it has been suggested that TCAs may be more effective than selective serotonin reuptake inhibitors (SSRIs) in treating depression and obsessive–compulsive disorder (OCD) (Anderson, Reference Anderson2000; Cohen et al., Reference Cohen, Zantvoord, Storosum, Mattila, Daams, Wezenberg, de Boer and Denys2024b).
Guidelines acknowledge the potential of parenteral clomipramine (Katzman et al., Reference Katzman, Bleau, Blier, Chokka, Kjernisted and Van Ameringen2014). However, its global use remains unclear. A recent nationwide survey showed that 31 of 37 responding Swedish clinics had used parenteral clomipramine during the past three years, and 29 clinics (78%) reported considering it an alternative to electroconvulsive therapy (ECT) in certain cases (Ioannou et al., Reference Ioannou, Falk, Gustavsson, Kahn, Nilsson, Sjögren, Steingrimsson, Svanberg, Szabó and Wallerstedt2025). Patients receiving this treatment, therefore, likely represent particularly challenging cases for clinical decision-making. In Sahlgrenska University Hospital, serving 1.8 million inhabitants in the second largest region in Sweden, 4.1% of adult patients admitted for at least six days with a depressive state between 2016 and 2022 received such treatment (Ioannou et al., Reference Ioannou, Falk, Gustavsson, Kahn, Nilsson, Sjögren, Steingrimsson, Svanberg, Szabó and Wallerstedt2025).
Despite decades of clinical use, critical evidence gaps regarding the clinical effects of parenteral clomipramine persist. To our knowledge, compilations of evidence regarding the efficacy in depression and OCD are limited to older publications that lack meta-analyses, do not assess the risk of bias in the included studies, and do not evaluate the certainty of the evidence (Moukaddam & Hirschfeld, Reference Moukaddam and Hirschfeld2004; Ravindran et al., Reference Ravindran, Jung and Ravindran2010). This systematic review aimed to fill these gaps by examining whether parenteral clomipramine is more effective than oral clomipramine, other treatments, or placebo in reducing depression or OCD symptoms and other outcomes in patients with these conditions.
Methods
The current systematic review was conducted as part of a health technology assessment (HTA), intended to provide information for regional evidence-based decision-making and also including, for instance, the number of patients at issue in the region as well as economic aspects (Ioannou et al., Reference Ioannou, Falk, Gustavsson, Kahn, Nilsson, Sjögren, Steingrimsson, Svanberg, Szabó and Wallerstedt2025). It is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Page et al., Reference Page, McKenzie, Bossuyt, Boutron, Hoffmann, Mulrow, Shamseer, Tetzlaff, Akl, Brennan, Chou, Glanville, Grimshaw, Hróbjartsson, Lalu, Li, Loder, Mayo-Wilson, McDonald, McGuinness, Stewart, Thomas, Tricco, Welch, Whiting and Moher2021) and was registered with PROSPERO (CRD420250654029).
The research question was formulated using the PICO framework. Accordingly, participants (P) were patients with depression (P1) or OCD (P2). Predefined subgroups of P were (i) older patients (≥65 years) and (ii) severe depression with melancholic or psychotic symptoms. The intervention (I) was parenteral clomipramine. Predefined subgroups of I were monotherapy and add-on therapy. The comparison (C) was oral clomipramine (C1), other treatment (C2), or placebo (C3). Predefined subgroups of C2 were ECT and ketamine. Although a placebo is not a clinically relevant treatment alternative, we included this comparison to capture the entire evidence base for parenteral clomipramine. The main outcomes (O) were depressive symptoms (P1) or OCD symptoms (P2) within two weeks. Additional outcomes were long-term (>2 weeks) depressive symptoms (P1) or OCD symptoms (P2), suicide attempt, all-cause mortality, suicidal ideation, global functioning, treatment discontinuation, length of hospital stay, health-related quality of life (HRQL), and adverse events related to administration via injection/infusion (e.g., thrombophlebitis, infection, or anaphylaxis). Publications were restricted to RCTs, and languages were limited to English, Swedish, Danish, and Norwegian.
Literature search and study selection
On 20 September 2024, two experienced medical librarians (J.G. and T.S.) conducted systematic searches in Medline, Embase, the Cochrane Library, and PsycInfo. Search strategies are provided in the supplement. Websites of Scandinavian national and regional HTA organisations were visited in April 2025. A citation search – both backward and forward – of all included articles, as well as a selection of excluded systematic reviews, was conducted in Web of Science Core Collection.
The titles and abstracts retrieved in the systematic literature search were independently screened by two authors (J.G. and T.S.) regarding eligibility for full-text retrieval, i.e., those not clearly outside the scope of this systematic review. This screening process was conducted using the Rayyan tool (Ouzzani et al., Reference Ouzzani, Hammady, Fedorowicz and Elmagarmid2016). Any disagreements were resolved through consensus discussions. All retrieved full-text reports were independently read by at least two authors (J.G. and T.S., or M.I., Ö.F., J.N., P.S., S.S., and S.M.W.). In a consensus meeting, we made the final decision on which reports to include in this systematic review, i.e., those that fulfilled the PICO criteria. For articles excluded in consensus, after full-text reading, reasons for exclusion were noted.
A search on Clinicaltrials.gov (March 4, 2025), using the search terms (chlorimipramine OR chlomipramine OR anafranil OR hydiphen OR clomipramine), identified 37 trials, none of which met the PICO criteria.
Data extraction and study assessments
Data from the included studies were independently extracted by three authors (S.M.W., M.I., and J.N.), and any discrepancies were resolved through consensus discussions. Data collection included study design, participant details, characteristics of individuals in the intervention and control groups, treatment regimen information, and results related to the outcomes of interest.
For the outcome regarding depressive and OCD symptoms within two weeks, we chose to extract the results closest to one week and two weeks, pooling the latter if data were available; otherwise, we used the former. For the outcome regarding depressive and OCD symptoms after more than two weeks, we chose to extract the results that were closest to four weeks and pooled them if possible. For P1, the change in the Hamilton Depression Rating Scale (HDRS) was beforehand determined to be the primary basis for conclusions. Similarly, for P2, the change in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was the primary basis for conclusions. When mean scores were not provided, we calculated them from individual data if available. When exact scores were not available in the text, we estimated them from figures if available. When the standard deviation (SD) for the change was not provided, we estimated this figure using the following formula: sqrt(((n-1)×SDpre2 + (n-1)×SDpost2)/(2n/2)). When the change in summarised HDRS scores was not available, we extracted separate HDRS scores or Montgomery Åsberg Depression Rating Scale (MADRS) scores. We did not request additional data from the study investigators.
Each study was independently assessed by at least five authors regarding the risk of bias and directness (M.I., J.N., P.S., S.M.W., and either Ö.F., S.S., or Z.S.), followed by consensus discussions. We used the Cochrane risk of bias tool for randomised trials (RoB 2) (Sterne et al., Reference Sterne, Savović, Page, Elbers, Blencowe, Boutron, Cates, Cheng, Corbett, Eldridge, Emberson, Hernán, Hopewell, Hróbjartsson, Junqueira, Jüni, Kirkham, Lasserson, Li, McAleenan, Reeves, Shepperd, Shrier, Stewart, Tilling, White, Whiting and Higgins2019). Beforehand, we decided not to judge RCTs too harshly on reporting aspects that were not applicable at the time of conduct, such as reporting of random sequence generation. Directness was assessed based on a checklist developed regionally, including questions about each component of the PICO, and the extent to which the assessed study corresponded to this (Center for Health Technology Assessment 2021). The reasons behind the consensus assessments of risk of bias and directness were recorded.
The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Atkins et al., Reference Atkins, Best, Briss, Eccles, Falck-Ytter, Flottorp, Guyatt, Harbour, Haugh, Henry, Hill, Jaeschke, Leng, Liberati, Magrini, Mason, Middleton, Mrukowicz, O’Connell, Oxman, Phillips, Schünemann, Edejer, Varonen, Vist, Williams and Zaza2004). Beforehand, we decided that studies without a high risk of bias would constitute the primary basis for conclusions. In assessments regarding precision, we took into account whether the 95% confidence interval (CI) included the minimum clinically important difference (MCID) of 2 for HDRS scores (Hengartner & Plöderl, Reference Hengartner and Plöderl2022) and 4.9 for Y-BOCS scores (Cohen et al., Reference Cohen, Zantvoord, Mattila, Storosum, de Boer and Denys2024a). Informative statements according to GRADE guidelines were used to summarise the results (Santesso et al., Reference Santesso, Glenton, Dahm, Garner, Akl, Alper, Brignardello-Petersen, Carrasco-Labra, De Beer, Hultcrantz, Kuijpers, Meerpohl, Morgan, Mustafa, Skoetz, Sultan, Wiysonge, Guyatt and Schünemann2020).
Meta-analysis
When two or more studies provided data that could be pooled, random effects meta-analyses were performed to obtain weighted mean differences, including 95% CI, using the Review Manager (RevMan) version 5.4.1 software (Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). We pooled HDRS data if a summarised result, including the items at issue, was reported, irrespective of abbreviations and item selections that were used, representing the development of this scale over the years. For dichotomous outcomes, the Peto odds ratio was used in case of zero-event arms, as this method does not require corrections (Higgins et al., Reference Higgins, Thomas, Chandler, Cumpston, Li, Page and Welch2024). Heterogeneity was assessed with I2 statistics.
Results
After removal of duplicates, the literature search identified 4,973 unique publications, 14 of which met the PICO criteria of this systematic review (Figure 1)
PRISMA flowchart.
(Escobar et al., Reference Escobar, Flemenbaum and Schiele1973; Hordern et al., Reference Hordern, Seldrup and Scient1979; Lecrubier et al., Reference Lecrubier, Puech, Jouvent, Simon and Widlocher1980; de Cuyper et al., Reference de Cuyper, van Praag, Mulder-Hajonides, Westenberg and de Zeeuw1981; Drago et al., Reference Drago, Motta and Grossi1983; Fähndrich, Reference Fähndrich1983; Faravelli et al., Reference Faravelli, Broadhurst, Ambonetti, Ballerini, De Biase, La Malfa and Das1983; Pollock et al., Reference Pollock, Perel, Nathan and Kupfer1989; Spreux-Varoquaux et al., Reference Spreux-Varoquaux, Gailledreau, Vanier, Bothua, Plas, Chevalier, Advenier, Pays and Brion1996; Koran et al., Reference Koran, Sallee and Pallanti1997, Reference Koran, Aboujaoude, Ward, Shapira, Sallee, Gamel and Elliott2006; Sallee et al., Reference Sallee, Vrindavanam, Deas-Nesmith, Carson and Sethuraman1997; Fallon et al., Reference Fallon, Liebowitz, Campeas, Schneier, Marshall, Davies, Goetz and Klein1998; Altamura et al., Reference Altamura, Dell’Osso, Buoli, Zanoni and Mundo2008). Publications excluded after full-text reading, as well as the reasons for excluding them, are presented in Table S1.
Study characteristics
The included RCTs, published between 1973 and 2008, are summarised in Table 1. They were performed in the United States (Escobar et al., Reference Escobar, Flemenbaum and Schiele1973; Pollock et al., Reference Pollock, Perel, Nathan and Kupfer1989; Koran et al., Reference Koran, Sallee and Pallanti1997, Reference Koran, Aboujaoude, Ward, Shapira, Sallee, Gamel and Elliott2006; Sallee et al., Reference Sallee, Vrindavanam, Deas-Nesmith, Carson and Sethuraman1997; Fallon et al., Reference Fallon, Liebowitz, Campeas, Schneier, Marshall, Davies, Goetz and Klein1998), Italy (Drago et al., Reference Drago, Motta and Grossi1983; Faravelli et al., Reference Faravelli, Broadhurst, Ambonetti, Ballerini, De Biase, La Malfa and Das1983; Altamura et al., Reference Altamura, Dell’Osso, Buoli, Zanoni and Mundo2008), France (Lecrubier et al., Reference Lecrubier, Puech, Jouvent, Simon and Widlocher1980; Spreux-Varoquaux et al., Reference Spreux-Varoquaux, Gailledreau, Vanier, Bothua, Plas, Chevalier, Advenier, Pays and Brion1996), Belgium (de Cuyper et al., Reference de Cuyper, van Praag, Mulder-Hajonides, Westenberg and de Zeeuw1981), Germany (Fähndrich, Reference Fähndrich1983),and the United Kingdom (Hordern et al., Reference Hordern, Seldrup and Scient1979). Ten RCTs were double-blind (Escobar et al., Reference Escobar, Flemenbaum and Schiele1973; Hordern et al., Reference Hordern, Seldrup and Scient1979; Drago et al., Reference Drago, Motta and Grossi1983; Faravelli et al., Reference Faravelli, Broadhurst, Ambonetti, Ballerini, De Biase, La Malfa and Das1983; Pollock et al., Reference Pollock, Perel, Nathan and Kupfer1989; Spreux-Varoquaux et al., Reference Spreux-Varoquaux, Gailledreau, Vanier, Bothua, Plas, Chevalier, Advenier, Pays and Brion1996; Koran et al., Reference Koran, Sallee and Pallanti1997, Reference Koran, Aboujaoude, Ward, Shapira, Sallee, Gamel and Elliott2006; Sallee et al., Reference Sallee, Vrindavanam, Deas-Nesmith, Carson and Sethuraman1997; Fallon et al., Reference Fallon, Liebowitz, Campeas, Schneier, Marshall, Davies, Goetz and Klein1998), two were single-blind (Lecrubier et al., Reference Lecrubier, Puech, Jouvent, Simon and Widlocher1980; Altamura et al., Reference Altamura, Dell’Osso, Buoli, Zanoni and Mundo2008), and two were open-label (de Cuyper et al., Reference de Cuyper, van Praag, Mulder-Hajonides, Westenberg and de Zeeuw1981; Fähndrich, Reference Fähndrich1983).
Summary of study characteristics and findings of the included studies
BPD, bipolar disorder; C, comparison; C1: clomipramine non-parenterally; C2: other treatment for the condition; C3: placebo; HADS, Hamilton depression scale; HAM-D17, Hamilton depression rating scale, 17 items; HAM-D21, Hamilton depression rating scale, 21 items; HDRS17, Hamilton depression rating scale, first 17 items; HDS, Hamilton depression scale; HRS, Hamilton rating scale; I, intervention; IM, intramuscular; IV, intravenous, MADRS, Montgomery-Åsberg depression rating scale, MDD, major depressive disorder, MDE, major depressive episode, NA, not applicable; NR, not reported; PO, per os; RCT, randomised controlled trial; SD, standard deviation; SRI, serotonin reuptake inhibitor; Y-BOCS, Yale-Brown obsessive- compulsive scale.
The intervention was intravenous (IV) clomipramine with gradual titration in eight RCTs (Escobar et al., Reference Escobar, Flemenbaum and Schiele1973; Hordern et al., Reference Hordern, Seldrup and Scient1979; Lecrubier et al., Reference Lecrubier, Puech, Jouvent, Simon and Widlocher1980; de Cuyper et al., Reference de Cuyper, van Praag, Mulder-Hajonides, Westenberg and de Zeeuw1981; Fähndrich, Reference Fähndrich1983; Faravelli et al., Reference Faravelli, Broadhurst, Ambonetti, Ballerini, De Biase, La Malfa and Das1983; Spreux-Varoquaux et al., Reference Spreux-Varoquaux, Gailledreau, Vanier, Bothua, Plas, Chevalier, Advenier, Pays and Brion1996; Fallon et al., Reference Fallon, Liebowitz, Campeas, Schneier, Marshall, Davies, Goetz and Klein1998), with pulse loading in four RCTs (Pollock et al., Reference Pollock, Perel, Nathan and Kupfer1989; Koran et al., Reference Koran, Sallee and Pallanti1997, Reference Koran, Aboujaoude, Ward, Shapira, Sallee, Gamel and Elliott2006; Sallee et al., Reference Sallee, Vrindavanam, Deas-Nesmith, Carson and Sethuraman1997), and with a fixed dose in two RCTs (Drago et al., Reference Drago, Motta and Grossi1983; Altamura et al., Reference Altamura, Dell’Osso, Buoli, Zanoni and Mundo2008). The comparison was oral clomipramine (C1) in eight RCTs (Escobar et al., Reference Escobar, Flemenbaum and Schiele1973; Hordern et al., Reference Hordern, Seldrup and Scient1979; de Cuyper et al., Reference de Cuyper, van Praag, Mulder-Hajonides, Westenberg and de Zeeuw1981; Faravelli et al., Reference Faravelli, Broadhurst, Ambonetti, Ballerini, De Biase, La Malfa and Das1983; Pollock et al., Reference Pollock, Perel, Nathan and Kupfer1989; Spreux-Varoquaux et al., Reference Spreux-Varoquaux, Gailledreau, Vanier, Bothua, Plas, Chevalier, Advenier, Pays and Brion1996; Koran et al., Reference Koran, Sallee and Pallanti1997, Reference Koran, Aboujaoude, Ward, Shapira, Sallee, Gamel and Elliott2006), another medication (C2) in four RCTs (Lecrubier et al., Reference Lecrubier, Puech, Jouvent, Simon and Widlocher1980; Drago et al., Reference Drago, Motta and Grossi1983; Fähndrich, Reference Fähndrich1983; Altamura et al., Reference Altamura, Dell’Osso, Buoli, Zanoni and Mundo2008), and placebo (C3) in two RCTs (Sallee et al., Reference Sallee, Vrindavanam, Deas-Nesmith, Carson and Sethuraman1997; Fallon et al., Reference Fallon, Liebowitz, Campeas, Schneier, Marshall, Davies, Goetz and Klein1998). ECT and ketamine were not used as a comparison in any RCT. Ten RCTs were assessed as not having a high risk of bias (Escobar et al., Reference Escobar, Flemenbaum and Schiele1973; Hordern et al., Reference Hordern, Seldrup and Scient1979; Drago et al., Reference Drago, Motta and Grossi1983; Faravelli et al., Reference Faravelli, Broadhurst, Ambonetti, Ballerini, De Biase, La Malfa and Das1983; Pollock et al., Reference Pollock, Perel, Nathan and Kupfer1989; Spreux-Varoquaux et al., Reference Spreux-Varoquaux, Gailledreau, Vanier, Bothua, Plas, Chevalier, Advenier, Pays and Brion1996; Koran et al., Reference Koran, Sallee and Pallanti1997, Reference Koran, Aboujaoude, Ward, Shapira, Sallee, Gamel and Elliott2006; Sallee et al., Reference Sallee, Vrindavanam, Deas-Nesmith, Carson and Sethuraman1997; Fallon et al., Reference Fallon, Liebowitz, Campeas, Schneier, Marshall, Davies, Goetz and Klein1998). Reasons underlying the directness and risk of bias assessments are outlined in Table S2.
A summary of our findings, including reasons for downgrading according to GRADE, is presented in Table 2. No studies reported results for the outcomes suicide attempt, all-cause mortality, suicidal ideation, global functioning, length of hospital stay, or HRQL.
Summary of findings for patients with depression and patients with OCD
C, comparison; C1, oral clomipramine; C2, other treatment; C3, placebo; CI, confidence interval; HDRS, Hamilton depression rating scale; HRQL, health-related quality of life; I, intervention; NA, not applicable; OCD, obsessive-compulsive disorder.
1 Serious imprecision, some study limitations, some uncertainty regarding directness.
2 Very serious imprecision, some study limitations, some uncertainty regarding directness.
3 Serious indirectness, serious imprecision.
4 Serious study limitations, serious inconsistency, uncertain precision, some uncertainty regarding directness.
5 Serious study limitations, very serious indirectness, very serious imprecision.
6 Very serious inconsistency, serious imprecision, some study limitations, some uncertainty regarding directness.
Patients with depression (P1)
Eleven RCTs, including a total of 317 patients, investigated parenteral clomipramine in patients with depression (Escobar et al., Reference Escobar, Flemenbaum and Schiele1973; Hordern et al., Reference Hordern, Seldrup and Scient1979; Lecrubier et al., Reference Lecrubier, Puech, Jouvent, Simon and Widlocher1980; de Cuyper et al., Reference de Cuyper, van Praag, Mulder-Hajonides, Westenberg and de Zeeuw1981; Drago et al., Reference Drago, Motta and Grossi1983; Fähndrich, Reference Fähndrich1983; Faravelli et al., Reference Faravelli, Broadhurst, Ambonetti, Ballerini, De Biase, La Malfa and Das1983; Pollock et al., Reference Pollock, Perel, Nathan and Kupfer1989; Spreux-Varoquaux et al., Reference Spreux-Varoquaux, Gailledreau, Vanier, Bothua, Plas, Chevalier, Advenier, Pays and Brion1996; Sallee et al., Reference Sallee, Vrindavanam, Deas-Nesmith, Carson and Sethuraman1997; Altamura et al., Reference Altamura, Dell’Osso, Buoli, Zanoni and Mundo2008).
Depressive symptoms
For the comparison between parenteral and oral clomipramine (C1), six RCTs provided data regarding depressive symptoms within two weeks (Escobar et al., Reference Escobar, Flemenbaum and Schiele1973; Hordern et al., Reference Hordern, Seldrup and Scient1979; de Cuyper et al., Reference de Cuyper, van Praag, Mulder-Hajonides, Westenberg and de Zeeuw1981; Faravelli et al., Reference Faravelli, Broadhurst, Ambonetti, Ballerini, De Biase, La Malfa and Das1983; Pollock et al., Reference Pollock, Perel, Nathan and Kupfer1989; Spreux-Varoquaux et al., Reference Spreux-Varoquaux, Gailledreau, Vanier, Bothua, Plas, Chevalier, Advenier, Pays and Brion1996). Five double-blind RCTs were assessed not to have a high risk of bias and included a total of 170 patients (Escobar et al., Reference Escobar, Flemenbaum and Schiele1973; Hordern et al., Reference Hordern, Seldrup and Scient1979; Faravelli et al., Reference Faravelli, Broadhurst, Ambonetti, Ballerini, De Biase, La Malfa and Das1983; Pollock et al., Reference Pollock, Perel, Nathan and Kupfer1989; Spreux-Varoquaux et al., Reference Spreux-Varoquaux, Gailledreau, Vanier, Bothua, Plas, Chevalier, Advenier, Pays and Brion1996). Two of these could not be pooled; one did not report a summarised HDRS result (Escobar et al., Reference Escobar, Flemenbaum and Schiele1973) and the other used MADRS (Spreux-Varoquaux et al., Reference Spreux-Varoquaux, Gailledreau, Vanier, Bothua, Plas, Chevalier, Advenier, Pays and Brion1996). A forest plot of the changes in HDRS scores at two weeks for the remaining RCTs is presented in Figure 1A, with a pooled result of −1.27 (95% CI: −3.09 to 0.54; I2 = 22%). At one week, a meta-analysis of these studies revealed a mean difference of −0.71 (95% CI: −3.20 to 1.77; I2 = 62%). In the RCT reporting results using MADRS, the difference in change was −2.9 (95% CI: −13.3 to 7.5).
Five RCTs provided data regarding long-term depressive symptoms in patients with parenteral or oral clomipramine (Escobar et al., Reference Escobar, Flemenbaum and Schiele1973; Hordern et al., Reference Hordern, Seldrup and Scient1979; de Cuyper et al., Reference de Cuyper, van Praag, Mulder-Hajonides, Westenberg and de Zeeuw1981; Faravelli et al., Reference Faravelli, Broadhurst, Ambonetti, Ballerini, De Biase, La Malfa and Das1983; Pollock et al., Reference Pollock, Perel, Nathan and Kupfer1989). Four double-blind RCTs were assessed not to have a high risk of bias and included a total of 143 patients(Escobar et al., Reference Escobar, Flemenbaum and Schiele1973; Hordern et al., Reference Hordern, Seldrup and Scient1979; Faravelli et al., Reference Faravelli, Broadhurst, Ambonetti, Ballerini, De Biase, La Malfa and Das1983; Pollock et al., Reference Pollock, Perel, Nathan and Kupfer1989). One of these did not report a summarised HDRS result (Escobar et al., Reference Escobar, Flemenbaum and Schiele1973). A meta-analysis of the changes in HDRS scores for the remaining RCTs is presented in Figure 2B, with a pooled result of −1.06 (95% CI: −4.70 to 2.58; I2 = 72%).
Forest plot and meta-analysis of changes in Hamilton depression rating scale (HDRS) scores at two (A) and four (B) weeks for the comparison intravenous (IV) versus oral (PO) clomipramine.
For the comparison between parenteral clomipramine and other treatments (C2), three RCTs contributed results regarding depressive symptoms within two weeks. The comparison was either maprotiline, citalopram (Altamura et al., Reference Altamura, Dell’Osso, Buoli, Zanoni and Mundo2008), or salbutamol (Lecrubier et al., Reference Lecrubier, Puech, Jouvent, Simon and Widlocher1980; Drago et al., Reference Drago, Motta and Grossi1983), all administered intravenously. One of them, comparing IV clomipramine with IV maprotiline, was assessed not to have a high risk of bias, included a total of 40 patients, and reported ‘no significant differences in the two groups’ (Drago et al., Reference Drago, Motta and Grossi1983).
Two RCTs contributed data regarding long-term depressive symptoms in patients with parenteral clomipramine or another treatment, either IV maprotiline (Fähndrich, Reference Fähndrich1983) or IV salbutamol (Lecrubier et al., Reference Lecrubier, Puech, Jouvent, Simon and Widlocher1980). Both were assessed to have a high risk of bias. The mean difference favoured IV salbutamol in one RCT: 7.6 (95% CI: 5.6 to 9.6) (Lecrubier et al., Reference Lecrubier, Puech, Jouvent, Simon and Widlocher1980). The other RCT reported similar response rates in both randomisation groups (Fähndrich, Reference Fähndrich1983).
For the comparison between parenteral clomipramine and placebo (C3), one RCT contributed results regarding depressive symptoms within two weeks (Sallee et al., Reference Sallee, Vrindavanam, Deas-Nesmith, Carson and Sethuraman1997). It was assessed not to have a high risk of bias and included 16 adolescents. The reduction in HDRS scores at day 6 was larger in the intervention group, mean difference: −6.0 (95% CI: −0.9 to −11). No RCT contributed data regarding long-term depressive symptoms.
Treatment discontinuation
For the comparison between parenteral and oral clomipramine (C1), three double-blind RCTs contributed data regarding treatment discontinuation (Hordern et al., Reference Hordern, Seldrup and Scient1979; Faravelli et al., Reference Faravelli, Broadhurst, Ambonetti, Ballerini, De Biase, La Malfa and Das1983; Pollock et al., Reference Pollock, Perel, Nathan and Kupfer1989).They were all assessed not to have a high risk of bias and included a total of 112 patients. One RCT did not clearly report randomisation group allocation for one treatment discontinuation (Pollock et al., Reference Pollock, Perel, Nathan and Kupfer1989) and could therefore not be pooled. A meta-analysis including the two RCTs providing poolable data is presented in Figure 3A, with a Peto odds ratio of 1.05 (95% CI: 0.30 to 3.71, I2 = 7%).
Forest plot and meta-analysis of treatment discontinuation (A) and forest plot of adverse events related to administration via injection/infusion (B; no meta-analysis was performed because of clinical heterogeneity of adverse events) for the comparison of intravenous (IV) versus oral (PO) clomipramine.
For the comparison between parenteral clomipramine and other treatments (C2), one RCT, using IV citalopram as the comparison and with a high risk of bias contributed the information that none of the 36 participants discontinued (Altamura et al., Reference Altamura, Dell’Osso, Buoli, Zanoni and Mundo2008).
No RCT contributed data regarding treatment discontinuation for the comparison between parenteral clomipramine and placebo (C3).
Adverse events related to administration via injection/infusion
For the comparison between parenteral and oral clomipramine (C1), three double-blind RCTs contributed data regarding infusion-related adverse events (Escobar et al., Reference Escobar, Flemenbaum and Schiele1973; Hordern et al., Reference Hordern, Seldrup and Scient1979; Faravelli et al., Reference Faravelli, Broadhurst, Ambonetti, Ballerini, De Biase, La Malfa and Das1983). They were all assessed not to have a high risk of bias and included a total of 121 patients. As all RCTs had a double dummy design, procedure-related adverse events could occur in both randomisation groups; one versus one event of thrombophlebitis occurred in these RCTs. In all, five versus two events related to the cardiovascular system occurred in the randomisation groups, whereof four versus two events were hypotension. These adverse events are in line with those described in the summary of product characteristics (SPC). A forest plot of all adverse events related to administration via injection/infusion is presented in Figure 3B. No meta-analysis was performed because of the clinical heterogeneity of the adverse events.
No RCT contributed data regarding infusion-related adverse events for the comparison between parenteral clomipramine and other treatments (C2) or placebo (C3),
Patients with OCD (P2)
Three RCTs, including a total of 101 patients, investigated parenteral clomipramine in patients with OCD (Koran et al., Reference Koran, Sallee and Pallanti1997, Reference Koran, Aboujaoude, Ward, Shapira, Sallee, Gamel and Elliott2006; Fallon et al., Reference Fallon, Liebowitz, Campeas, Schneier, Marshall, Davies, Goetz and Klein1998).
OCD symptoms
For the comparison between parenteral and oral clomipramine (C1), two double-blind RCTs contributed data regarding OCD symptoms within two weeks (Koran et al., Reference Koran, Sallee and Pallanti1997, Reference Koran, Aboujaoude, Ward, Shapira, Sallee, Gamel and Elliott2006). They were both assessed not to have a high risk of bias and included a total of 47 patients. One RCT included patients who had previously not responded to serotonin reuptake inhibitors including clomipramine (Koran et al., Reference Koran, Aboujaoude, Ward, Shapira, Sallee, Gamel and Elliott2006). A forest plot of changes in Y-BOCS scores at one week is presented in Figure 4. Because of clinical heterogeneity, we refrained from performing a meta-analysis.
Forest plot of changes in Yale-Brown obsessive-compulsive scale (Y-BOCS) scores at one week for the comparison of intravenous (IV) versus oral (PO) clomipramine (no meta-analysis was performed because of clinical heterogeneity).
One double-blind RCT provided data regarding long-term OCD symptoms in patients with parenteral or oral clomipramine (Koran et al., Reference Koran, Sallee and Pallanti1997). It was assessed not to have a high risk of bias, included 15 patients, and reported a non-significant change in Y-BOCS scores: −4.5 (95% CI: −16.5 to 7.5).
No RCT contributed data regarding OCD symptoms within two weeks or in the long-term for the comparison between parenteral clomipramine and other treatments (C2).
For the comparison between parenteral clomipramine and placebo (C3), one RCT contributed data regarding OCD symptoms within two weeks (Fallon et al., Reference Fallon, Liebowitz, Campeas, Schneier, Marshall, Davies, Goetz and Klein1998). It was assessed not to have a high risk of bias, included 54 patients that were refractory to oral clomipramine, and reported no significant difference in Y-BOCS scores among those who completed the entire treatment (14 infusions): mean difference: −2.5 (95% CI: −5.6 to 0.6). Regarding long-term OCD symptoms, no RCT contributed data.
Treatment discontinuation
For the comparison between parenteral and oral clomipramine (C1), one double-blind RCT, contributed data regarding treatment discontinuation (Koran et al., Reference Koran, Aboujaoude, Ward, Shapira, Sallee, Gamel and Elliott2006). It was assessed not to have a high risk of bias, included 32 patients, and reported three versus five events (out of 16 in each randomisation group).
No RCT contributed data regarding treatment discontinuation for the comparison between parenteral clomipramine and other treatments (C2) or placebo (C3).
Adverse events related to administration via injection/infusion
For the comparison between parenteral and oral clomipramine (C1), one double-blind RCT contributed data regarding infusion-related adverse events (Koran et al., Reference Koran, Aboujaoude, Ward, Shapira, Sallee, Gamel and Elliott2006). It was assessed not to have a high risk of bias, included 32 patients, and reported that two patients in each randomisation group experienced adverse events related to the infusion. All events were related to the cardiovascular system.
No RCT contributed data regarding infusion-related adverse events for the comparison between parenteral clomipramine and other treatments (C2) or placebo (C3).
Discussion
This systematic review shows that in patients with depression, parenteral clomipramine may not be superior to oral administration in terms of reducing depressive symptoms within two weeks. Given the MCID of 2 for HDRS (Hengartner and Plöderl, Reference Hengartner and Plöderl2021) and as the upper confidence limit for symptom reduction exceeded 3, a clinically relevant effect of parenteral over oral clomipramine cannot be excluded. In the long term, there may be no difference. The same applies to treatment discontinuation rates. In patients with OCD overall, the evidence regarding potential differences in symptom alleviation between parenteral and oral clomipramine is too uncertain for conclusions. In the subgroup of patients with OCD refractory to oral clomipramine, parenteral clomipramine may not be superior to placebo, but a clinically relevant effect cannot be excluded. Across both conditions, data on key outcomes, including suicide attempts, all-cause mortality, suicidal ideation, global functioning, length of hospital stay, and HRQL, are lacking. Based on very low certainty of evidence, infusion-related adverse event rates reported in available RCTs are in line with the known safety profile.
Since low certainty evidence did not demonstrate benefits of parenteral compared to oral clomipramine in patients with depression, and infusion-related adverse events occurred, the benefit-risk balance may be unfavourable. A negative benefit-risk balance for parenteral clomipramine may also apply to patients with OCD, both in general and in those who have not responded to oral treatment. It is important to note that these results specifically pertain to parenteral administration, not to the substance clomipramine itself. In fact, both randomisation groups in the depression studies showed a clinically relevant reduction in depressive symptoms, regardless of how the medication was administered. However, clomipramine was ranked lower than other antidepressants in a comprehensive network analysis (Cipriani et al., Reference Cipriani, Furukawa, Salanti, Chaimani, Atkinson, Ogawa, Leucht, Ruhe, Turner, Higgins, Egger, Takeshima, Hayasaka, Imai, Shinohara, Tajika, Ioannidis and Geddes2018). A plausible explanation may be the lack of sedative and appetite-inducing effects of clomipramine, unlike medications such as amitriptyline and mirtazapine (Hieronymus et al., Reference Hieronymus, Lisinski and Eriksson2024). In the case of OCD, on the other hand, a clinically relevant effect on OCD symptoms was not consistent across the randomisation groups of the studies included in the current evidence synthesis.
One of the underlying arguments for parenteral instead of oral administration of clomipramine is to bypass the hepatic first-pass metabolism, which results in lower levels of its main metabolite, desmethylclomipramine. This may be relevant because clomipramine is a potent serotonin reuptake inhibitor, while its metabolite primarily inhibits noradrenaline reuptake (Gillman, Reference Gillman2007). However, a recent study reported that a higher ratio of desmethylclomipramine to clomipramine, in patients with depression, was more frequently observed in responders than non-responders (Vos et al., Reference Vos, Coenen, Ter Hark, Aarnoutse, Schellekens and Janzing2024). This finding suggests that the metabolism rationale for parenteral administration of clomipramine – namely, the purportedly more prominent serotonergic activity due to a higher parent-to-metabolite ratio – may not be applicable, consistent with our findings of no difference between parenteral and oral administration.
Many RCTs in the current evidence compilation were conducted during the 1980s. Their setting may thus not fully reflect current practices. Indeed, changes in the conceptualisation of depression have added complexity to comparing findings across different time periods (Parker et al., Reference Parker, Fink, Shorter, Taylor, Akiskal, Berrios, Bolwig, Brown, Carroll, Healy, Klein, Koukopoulos, Michels, Paris, Rubin, Spitzer and Swartz2010; Ghaemi et al., Reference Ghaemi, Vöhringer and Vergne2012). The prevalence of severe depression, however, has remained relatively stable (Fugger et al., Reference Fugger, Waldhör, Hinterbuchinger, Pruckner, König, Gmeiner, Vyssoki, Vyssoki and Fellinger2020) despite increased admission rates for mental, behavioural, and neurodevelopmental disorders (Naser et al., Reference Naser, Dahmash, Alqahtani, Alsairafi, Alsaleh and Alwafi2022). In the current systematic review, we intentionally used a broad definition in the PICO, including both unipolar and bipolar subtypes and without any age limits. This approach reflects real-world clinical practice, aiming to include the full spectrum of patients. However, since most RCTs included patients with severe depression, our findings may primarily be applicable to this subgroup.
For several outcomes selected for this systematic review due to their relevance for patients and healthcare, no data were available. For instance, results regarding the length of hospital stay could have added information, being a surrogate measure of short-term symptom reduction. Furthermore, no RCT studied the role of parenteral clomipramine as an alternative or adjunct to other rapid-acting interventions, such as ECT or ketamine, which are relevant in modern psychiatric care. Moving forward, more studies with relevant comparisons are warranted, particularly in depression, where the low certainty evidence does not rule out a short-term positive effect.
From a clinical decision-making perspective, our findings suggest that parenteral clomipramine should generally not be considered for the treatment of depression or OCD. The absence of clear short- or long-term advantages in symptom reduction in depression and the lack of convincing benefits over oral clomipramine or placebo in OCD, together with the infusion-related risks and resource requirements, make oral treatment preferable for most patients. Nevertheless, as a potential favourable effect cannot be entirely ruled out, parenteral clomipramine may be considered in highly selected cases, such as severely depressed inpatients who cannot reliably take oral medication or in whom rapid titration is more feasible via the IV route.
An important strength of this systematic review is that it provides a synthesis of currently available scientific evidence regarding the clinical value of parenteral clomipramine. Another major strength is the thorough and transparent performance, in line with the state-of-the art standards for this research design. Important limitations include that for both conditions studied – and particularly for OCD – the certainty of evidence was low or very low due to small sample sizes and few events. Further, our predefined primary outcome was symptom change within two weeks, which is shorter than the time frame typically required to observe full antidepressant or anti-obsessional effects. Moreover, the included RCTs had methodological shortcomings, such as unclear reporting of patient recruitment and randomisation procedure, the latter not uncommon at the time (Altman & Doré, Reference Altman and Doré1990). Importantly, no RCT provided separate results for the HDRS ‘depressed mood’ item, which reportedly detects antidepressant effects more sensitively than the overall HDRS scores (Hieronymus et al., Reference Hieronymus, Emilsson, Nilsson and Eriksson2016). In addition, we pooled data from studies using different versions of the HDRS, an aspect that needs to be considered when pooled mean differences are interpreted. Similarly, the limitations associated with the Y-BOCS scale must be acknowledged (Storch et al., Reference Storch, De Nadai, Conceição do Rosário, Shavitt, Torres, Ferrão, Miguel, Lewin and Fontenelle2015; Cohen et al., Reference Cohen, Zantvoord, Mattila, Storosum, de Boer and Denys2024a), although it is a widely used tool for measuring longitudinal change. Finally, this systematic review does not address aspects like patient preferences, logistical and resource implications, or cost-effectiveness.
Conclusion
The current evidence compilation shows that parenteral clomipramine may not be superior to oral administration in any respect, however, a short-term benefit in depression cannot be excluded.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/neu.2026.10074.
Acknowledgements
None.
Data availability
No additional data are available.
Author contributions
Michael Ioannou: Study conception and design, literature search coordination, data analysis and interpretation, manuscript writing and revision. Örjan Falk: Study conception, data extraction and assessment, manuscript revision. Joss Gustavsson: Study conception, literature search and screening, manuscript revision. Johan Nilsson: Study conception, data extraction and assessment, data analysis, manuscript revision. Petteri Sjögren: Study conception, methodology, data assessment, manuscript revision. Steinn Steingrimsson: Study conception, data assessment, manuscript revision. Therese Svanberg: Study conception, literature search and screening, manuscript revision. Zoltan Szabó: Study conception, data assessment, manuscript revision. Susanna M Wallerstedt: Study conception, methodology, literature search, data extraction, analysis, and interpretation, manuscript writing, and revision.
Funding statement
The results reported in this article emerge from a regional HTA in Region Västra Götaland, Sweden, performed within the authors’ employment in Sahlgrenska University Hospital, Gothenburg, Sweden. The study was funded by the Swedish state under the ALF agreement between the Swedish government and the county councils (ALFGBG-998256).
Competing interests
Michael Ioannou, Örjan Falk, Joss Gustavsson, Petteri Sjögren, Therese Svanberg, Zoltan Szabó, and Susanna M Wallerstedt have no conflicts of interest to disclose. Steinn Steingrimsson has received consulting fees from a start-up company developing a computer game as an adjunctive treatment. Johan Nilsson holds a part-time position at Clinical Trial Consultants (CTC), which is a clinical research organisation specialising in early-phase studies; he does not receive any direct compensation from the sponsor (e.g., a pharmaceutical company); and he does not hold any ownership shares in CTC.
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