Table 1 –
Elements defining Treatment-Resistant Mania (TRM) in 47 peer-reviewed publications
| Authors and Year of publication | N (only those presenting with mania) | Mania severity criteria | Mania duration criteria | Treatment criteria | Intervention |
|---|---|---|---|---|---|
| Case reports | |||||
| Mahmood et al., 1997 25 | 1 | Severe mania with aggression requiring hospitalization | Unspecified (at least 6 months based on pharmacotherapy tried) | Lack of response to therapeutic dosages of at least three antipsychotics | Clozapine monotherapy |
| Chanpattana et al., 2000 26 | 1 | “Uncontrolled manic symptoms” | “About one year” | Lack of response to a combination of two or three mood stabilizers or antipsychotics for at least two weeks, followed by ECT | Acute ECT combined with clozapine |
| Dunayevich & Strakowski, 2000 27 | 1 | Mania with psychosis requiring hospitalization | Not discussed | Lack of response to high dosages and therapeutic levels of lithium and divalproex and a typical antipsychotic (with lack of response to ECT in the past) | Quetiapine, initially combined with both mood stabilizers and typical antipsychotic, then combined with lithium only |
| Malhi et al., 2001 28 | 1 | Mild to severe “unremitting chronic mania” (with 15 hospitalizations) | 15 years | Lack of response to several combinations of therapeutic levels or dosages of one mood stabilizer plus one antipsychotic (including clozapine) for weeks to months, and three trials of ECT plus clozapine | -- |
| Tsao et al., 2004 29 | 1 | Nine manic relapses | Two years | Lack of response, rapid manic relapse, or inability to tolerate mood stabilizers or antipsychotics (including clozapine) used alone or in combination | Acute ECT followed by maintenance ECT |
| Chen et al., 2005 30 | 1 | Index YMRS = 48 Long (“one-year”) manic episodes alternation with rapid-cycling with severe mania (with 50 hospitalizations) for close to 20 years) | Close to 20 years | Lack of response to 24 combinations of therapeutic dosages of one or two mood stabilizers plus one or two antipsychotics (including clozapine) | Topiramate plus clozapine |
| Nascimiento et al., 2006 31 | 1 | Severe manic episodes with five hospitalizations and lack of full remission between episodes over five years | Five years | Lack of response to combinations of therapeutic dosages of one or two mood stabilizers plus one antipsychotic | Acute ECT followed by maintenance ECT |
| Huang et al., 2008 32 | 1 | Five hospitalizations due to manic relapses | Six months | Rapid manic relapse despite a combination of two mood stabilizers (at therapeutic level) plus an antipsychotic (at high dosage) | Addition of estrogen-progesterone combination |
| Robinson et al., 2011 33 | 1 | Mania with psychosis and violence requiring two hospitalizations | More than 15 months | Lack of response to, or inability to tolerate four combinations of therapeutic dosages of one mood stabilizer plus one or two antipsychotics, plus a benzodiazepine | Acute ECT followed by combination of lithium plus perphenazine |
| Kohli & Singh, 2013 34 | 1 | Mania with psychosis and violence requiring hospitalization (in the context of multiple relapses on various medications in the past) | Four weeks | Lack of response to a combination of therapeutic dosages of divalproex, olanzapine, levomepromazine, plus lorazepam | Asenapine initially combined with divalproex and then monotherapy |
| Lally & McDonald, 2013 20 | 1 | Mania with psychosis and violence requiring seclusion | Seven weeks | Lack of response to several combinations of one mood stabilizer (at therapeutic level), an antipsychotic (at high dosage), and a benzodiazepine (at high dosage) | Acute ECT |
| Eloff & Esterhuysen 2014 35 | 1 | Severe mania requiring hospitalization | 18 months | Lack of response to several combinations of one or two mood stabilizers (at therapeutic level) and an antipsychotic (at high dosage), including clozapine | Adjunctive treatment with reserpine |
| Muneer, 2014 36 | 1 | Severe mania requiring hospitalization | Three months | Lack of full response to two combinations of therapeutic dosages of one mood stabilizer plus one antipsychotic plus one benzodiazepine | Combination of divalproex, aripiprazole, alprazolam, and gabapentin |
| Keat et al., 2016 37 | 1 | Severe mania with psychosis requiring several hospitalizations | Three months | Lack of full response to combinations of therapeutic dosages of one or two mood stabilizers plus one or two antipsychotics and 12 sessions of ECT | Clozapine in combination with lithium and divalproex |
| Modak et al., 2017 38 | 1 | Severe mania requiring hospitalization | Four months | Lack of response to two combinations of therapeutic dosages of one or two mood stabilizers plus one or two antipsychotics, and one trial of ECT | Combination of two mood stabilizers (lithium and valproate) plus chlorpromazine |
| Enokida et al., 2022 39 | 1 | Severe mania with aggression (YMRS = 44) requiring hospitalization | One year | Lack of response or inability to tolerate three antipsychotics (used consecutively) combined with low dosage of lithium | ECT acutely followed by maintenance with divalproex monotherapy |
| Case series | |||||
| Antonacci & Swartz, 1995 41 | 4 | Severe mania with psychosis requiring hospitalization | Weeks to 14 years | Lack of response to therapeutic dosages of several mood stabilizers (alone or in combination) combined with one to three antipsychotics (sequentially). Additional lack of response to ECT in one of the four cases. | Clozapine alone or in combination |
| Goodnick, 1995 42 | 2 | Acute mania with psychosis, “ | One week in one case; unspecified in the other case | Lack of response to therapeutic dosage of lithium and one antipsychotic for one week in one case; intolerance to lithium “in the past” in another case | Risperidone |
| Zarate et al., 1995 43 | 9 | Multiple hospitalizations | Not discussed | Lack of response or intolerance to “lithium, VPA, CBZ, neuroleptics, combinations of these, and ECT” | Clozapine monotherapy |
| Poyurovsky & Weizman, 1996 44 | 2 | Mania and “failure to improve” | Not discussed | First level: lack of response to a mood stabilizer, first-generation antipsychotic, or their combination Second level: ECT |
Acute ECT combined with clozapine |
| Burt et al., 1999 13 | 4 | Outpatient with unspecified manic symptoms | Not discussed | Lack of response or partial response to, or inability to tolerate “at least two prior approved treatments for BD | Addition of donepezil |
| Britto de Macedo-Soares et al., 2005 17 | 3 | YMRS > 16 | Not discussed | Lack of response to at least two adequate antimanic trials, defined as lasting at least six weeks with either a combination of a mood stabilizer (at therapeutic level) plus an antipsychotic (at therapeutic dosage) or a combination of two mood stabilizers (at therapeutic level) | Acute ECT |
| Van Riel et al., 2008 50 | 517 | Not discussed | 12 months | Some unspecified treatment with no specific or minimum number of treatment strategies | --- |
| Ifteni et al., 2014 46 | 25 | Inpatient admission for mania | Not discussed | Lack of response to two or more combinations of one mood stabilizer (lithium or DVP) plus one antipsychotic | Clozapine monotherapy or combined with DVP |
| Benzoni et al. 2015 48 | 5 | Inpatient admission for DSM-IV manic episode | “At least six months” | Lack of response to “at least three different pharmacological treatments in the last six months” | ECT |
| Kumar et al. 2015 49 | 20 | Inpatient admission for mania with psychosis | Not discussed | Poor response to at least two mood stabilizers (used singly or combined) | Clozapine monotherapy |
| Askoy Poyraz et al. 2015 47 | 3 | Severe mania with agitation, aggression, or psychosis requiring hospitalization | Days to several months | Lack of response to therapeutic dosages of one or more mood stabilizers or antipsychotics (alone or in combination). Additional lack of response to ECT in one of the three cases | Addition of rapidly titrated clozapine |
| Open-label non-controlled trials | |||||
| Kramlinger & Post, 1989 51 | 7 | “Moderately severe mania” | Mean (SD): 30 (9) days (median: 32.5; range: 14–39) | Prior non-response to, or relapse on, lithium monotherapy and lack of response to monotherapy with therapeutic dosages of CBZ | Combination of CBZ plus lithium |
| Baumgartner et al., 1994 52 | 3 | “Severe manic episodes that […] required hospitalization” | At least six months | Lack of response to combinations of mood stabilizers and antipsychotics | Addition of supraphysiological dosage of thyroxine |
| Calabrese et al., 1996 53 | 10 | “Moderately severe episode of mania” | At least 24 weeks | Lack of response to, or tolerability of, therapeutic levels for 6 weeks of lithium and either CBZ or VPA, and therapeutic dosages for 6 weeks of at least two typical antipsychotics | Monotherapy with clozapine |
| Sajatovic et al., 1999 54 | 5 | YMRS ≥25 with psychotic symptoms | At least two manic episodes in the past two years or continuous manic psychosis for the past two months | Lack of response to, or tolerability of, therapeutic levels for at least 6 weeks of lithium and either CBZ or VPA, and typical antipsychotics | Monotherapy with risperidone |
| Green et al., 2000 55 | 22 | 24-item BPRS score ≥21 (using a 0–6 scale) and a CGI score ≥3 (using a 0–6 scale) | Three episodes of mania with psychosis in the past 2 years or a 6-month history of mania with psychosis | Lack of response to a 6-week trial of 500 mg/day of chlorpromazine or its equivalent and lack of response or tolerability to a 6-week trial of therapeutic levels of lithium | Monotherapy with clozapine |
| Vieta et al., 2002 56 | 17 | YMRS score ≥ 12 and at least moderately ill on the CGI | None required | Lack of response to at least two mood-stabilizers (lithium, CBZ, or VPA), either in monotherapy or in combination | Addition of topiramate |
| Chen et al., 2011 57 | 18 | YMRS score ≥20 | None required | Irrespective of dosage or duration, prior lack of response or tolerability: (i) lithium; (ii) CBZ or valproate; and (iii) two or more typical or atypical antipsychotics | Monotherapy with olanzapine |
| Manhas et al., 2016 58 | 11 | Not discussed | 6 weeks or more | Lack of response to a combination of two “standard medications” for at least 6 weeks | ECT |
| Randomized clinical trials | |||||
| Suppes et al., 1999 59 | 7 | “Persistent symptoms” or “intolerance of medications” | Not discussed | Documented lack of full response (or intolerance) to therapeutic levels of a combination of two mood stabilizers (lithium, VPA, CBZ) plus a typical antipsychotic if the patient had psychotic symptoms). | Randomized to continuation of usual care vs. addition of clozapine |
| Evins et al., 2006 60 | 12 | YMRS ≥15 | 2 weeks | Lack of response to therapeutic levels of lithium, VPA, or CBZ | Randomized to addition of donepezil vs. placebo |
| Vik et al., 2013 61 | 39 | Hospitalized; YMRS ≥16 | 3 weeks | Lack of response to therapeutic levels of lithium or DVP, moderate to high dosage of an antipsychotic, or their combination | Randomized to addition of calcitonin vs. placebo |
| Laboratory study | |||||
| Bulut et al., 2019 62 | 60 | YMRS ≥18; CGI-S ≥ 4; decrease in YMRS < 50% | Not discussed | During previous manic episodes, lack of response or intolerance to (i) lithium carbonate, (ii) VPA or CBZ, and (iii) two or more typical or atypical antipsychotics | NA |
| Narrative reviews | |||||
| Gerner, 1993 63 | NA | -- | -- | “Lack of return to the patient’s best previous level of functioning” | NA |
| Sachs, 1996 12 | NA | -- | -- | Lack of remission after 6 weeks of adequate treatment with at least two antimanic agents (i.e., mood stabilizers and antipsychotics) in the absence of antidepressant or other mood-elevating agents | NA |
| Tohen & Gannon, 1998 64 | NA | “Acute mania” (see text) | -- | No “amelioration of symptoms” of acute mania after 6 weeks of treatment with an adequate dosage of lithium, anticonvulsant, or antipsychotic | NA |
| Keck & McElroy, 2001 67 | NA | -- | -- | Lack of response to one adequate trial of lithium or a mood stabilizer (“primary resistance”) or sequential use of two (“secondary resistance”), or three (“tertiary resistance”) adequate trials of mood stabilizer or antipsychotics Adequate trials are defined based on specified blood levels or dosages given for a minimal duration of 2 weeks (“probable adequacy”) or 3 weeks (“definite adequacy”) |
NA |
| Gitlin, 2006 15 | NA | < 50% reduction in YMRS score | -- | Acute TRM: lack of response to two or three “treatments that are generally considered effective” Maintenance TRM: continued cycling despite previously demonstrated effective treatments |
NA |
| Gajwani, 2009 68 | NA | < 50% reduction in YMRS score | -- | Stage I: lack of response to adequate dosage and duration monotherapy with lithium, an anticonvulsant, or an atypical antipsychotic Stage II: Stage I plus lack of response to combination of a mood stabilizer and an atypical antipsychotic Stage III: Stage II plus lack of response to several evidence-based adjunctive agents Stage IV: Stage III plus lack of response to neurostimulation |
-- |
| Fountoulakis, 2012 65 | NA | No significant reduction in YMRS or MRS scores (without a significant increase in MADRS or HDRS scores, or these scores staying below 7) | -- | Lack of response after 8-10 weeks of treatment with adequate dosage of “an effective agent” | NA |
| Poon et al., 2012 66 | NA | -- | -- | Unsatisfactory response to at least two “dissimilar” treatments with adequate dosages for at least 6 weeks. | NA |
| Systematic review | |||||
| Fountoulakis et al., 2020 10 | NA | No significant reduction in YMRS or MRS scores (without a significant increase in MADRS or HDRS scores, or these scores staying below 7) | -- | Lack of response after evidence-based treatment for 8-10 weeks, as recommended by the CINP or CANMAT guidelines for the treatment of acute mania | NA |
BPRS: Brief Psychiatric Rating Scale; CANMAT: Canadian Network for Mood and Anxiety Treatments; CBZ: Carbamazepine; CGI: Clinical Global Impression Scale; CGI-S: Clinical Global Impression Scale; Severity, CINP: International College of Neuropsychopharmacology; DVP: Divalproex; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; ECT: Electroconvulsive Therapy; GAS: Global Assessment Scale; MADRS: Montgomery-Asberg Rating Scale; HAM-D: Hamilton Depression Rating Scale; MRS: Mania Rating Scale; NA: Not Applicable; SD: Standard Deviation; VPA: Valproic Acid; YMRS: Young Mania Rating Scale