Review and meta-analysis of add-on tranylcypromine with antipsychotic drugs for the treatment of schizophrenia with predominant negative symptoms: a restoration of evidence

Figures & data

Figure 1. Flowchart of included studies.

Table 1. Characteristics of controlled studies of add-on tranylcypromine (TCP) with antipsychotic drugs in negative schizophrenia.

Study	Patients	Sex (% male)	Age^f (years)	TCP dose^g (mg/day)	Antipsychotic drug dose^g (mg/day)	Duration (weeks)	Comedication	Anticholinergics	Milieu effects	Randomized	Doubleblind	Run-in of TCP/anti- psychotic^d
Buffaloe et al.^36	Chronic anerg schizophrenic patients, 13–33 years treatment.	m (100)	48 (36–56)	30 (nv)	20 (2–30) TFP (v)	5	No	n.d.	Inpatients, remotivation program with outside recreatio-nal and occupational activities, however, remained at plateau	No^a	Yes	No/Yes (5 weeks)
Vogt^32	Chronic retarded patients, >5 years ill, 78% schizophrenics, socially and symptomatically seriously ill, treatment with tranquilizers and ECT.	m (100)	ca. 40	30 (nv)	40 TFP (v)	12	No	Yes (n = 18)	Inpatients, constant ward program	n.d.	Yes	No/Yes (2 weeks)
Hordern et al.^33	Chronic schizophrenic patients, apathetic, withdrawn, >2 years in clinic.	f (0)	50 (21–65)	40 (v)^i	40 TFP (v)^i	9	n.d.	Yes (n = 36)	Inpatients, hospital ward with minimal milieu influences	No^b	Yes	No/No (5 weeks)
Schiele et al.^34	Chronic schizophrenic patients, anerg, depressive, retarded, treated with phenothiazines, mean duration of illness 5.9 years and 2.4 years in clinic, severly ill.	n.d.	36	10–60 (v)	5–50 TFP (v)	8	No	Yes (n = 28)	Inpatients, usual hospital care, no other special treatment	Yes	Yes	No/Yes (2 weeks)
Mena et al.^37	Chronic pseudoneurotic schizo-phrenics, long unsuccessfull treatment with antipsychotics and antidepressants.	n.d.	46.5	40 (nv)	4 TFP (nv)	4	No	n.d.	Outpatients	Yes	Yes	No/No (4 days)
Hedberg et al.^38	Chronic (51%), acute (16%) and paranoid (29%) schizophrenic patients, 31% pseudoneurotic schizophrenics among chronic schizophrenics.	m/f (50)	16–50	30 (v)	32 TFP (v)	8	Methyprylon, chloral	Yes^h (n.d.)	Inpatients, n.d.	n.d.	Yes	No/No (>2 days)^e
Bucci^35	Chronic schizophrenic patients with negative asymptoms and depression, treatment with antipsychotics, last inpatient treatment >3 years, moderately severe.	m/f (47)	36.6 (26–50)	20 (nv)	300 CPZ (nv)	16	n.d.	Yes (n = 5)	Outpatients	No^c	No^j	No/No (2 weeks)

^aPairwise matching according to initial ratings of Hospital Assessment Scale, ^bpairwise matching according to age, chronicity, severity of disease, and ratability, ^cmatching patients according to age and symptoms, ^d“No” means a wash-out, ^ecross-over study: data for first sequence, no wash-out before second and third sequences, ^fmean, mean (range), or range, ^gmaximum target dose or range for variable doses, ^hcases of emergency, ⁱthis study included a third treatment with both TCP and TFP placebos, ^jone of two raters blind; studies written bold and italic are included in the primary meta-analysis. Abbreviations. TFP, trifluoperazine; CPZ, chlorpromazine; m, male; f, female; v, variable dose; nv, fixed (non-variable) dose; n.d., not defined.

Figure 2. Forest plot of the primary meta-analysis of controlled studies of add-on tranylcypromine (TCP) with antipsychotic drug vs. antipsychotic drug monotherapy in negative schizophrenia (TFP trifluoperazine, CPZ chlorpromazine).

Table 2. Primary meta-analysis of add-on tranylcypromine (TCP) with antipsychotic drug vs. antipsychotic drug monotherapy in negative schizophrenia.

Study	Response criteria applied	Add-on TCP with antipsychotic drug			Antipsychotic drug monotherapy			logOR	LL(logOR)	UL(logOR)
		%R	R^a	NR^a	%R	R^a	NR^a
Vogt^32	Much improved/improved (R) vs. no change (NR) according to global assessment	79.2	19	5	69.2	18	8	0.524	−0.766	1.814
Hordern et al.^33	Marked/clear improvement (R) vs. no change/clear worsening/marked worsening (NR) according to change in 20 schizophrenia items of the VAMSRPP rated independently by two physicians^b	60.0	15	10	32.0	8	17	1.159	−0.001	2.320
Schiele et al.^34	Positive (R) vs. zero/negative (NR) improvement score according to MMPI profiles before and after treatment	69.6	16	7	45.8	11	13	0.994	−0.204	2.191
Bucci^35	Gradual and progressive improvement which became quite noticeable (R) vs. no improvement (NR) with BPRS-ratings by two physicians	73.3	11	4	0	0	15	4.372	1.353	7.392
Mean ± s.d.		70.5 ± 8.0			36.8 ± 28.9

^aOnly one study provided information on drop-outs, 5 in each treatment group [34]. All responder data were analyzed therefore for per protocol (PP) outcome. ^bInterrater reliability correlation r = 0.88. Abbreviations. logOR, natural logarithm of odds ratio; LL, lower limit; UL, upper limit; s.d., standard deviation; R, responder; NR, non-responder; BPRS, Brief Psychiatric Rating Scale; MMPI, Minnesota Multiphasic Personality Inventory; VAMSRPP, Veterans Administration Multidimensional Scale for Rating Psychiatric Patients.

Table 3. Results of extrapyramidal adverse effects (EPS) in controlled studies of add-on tranylcypromine (TCP) with antipsychotic drugs in negative schizophrenia (ratio of patients with EPS per treatment group).

Study	Assay/reporting of EPS	Add-on TCP with antipsychotic drug	Antipsychotic drug	Fisher’s exact test
Vogt^32	Symptoms found in spite of application of anticholinergics	33.3%	0.0%	p < .01
Hordern et al.^33	Symptoms found before application of anticholinergics	84.0%	84.0%	n.s.
Schiele et al.^34	Application of anticholinergics as a surrogate of EPS	60.9%	58.3%	n.s.
Bucci^35	Application of anticholinergics as a surrogate of EPS	0.0%	33.3%	p = .04

Abbreviation. n.s., not significant.

Table 4. Clinical data of non-controlled studies of add-on tranylcypromine (TCP) with antipsychotic drugs in negative schizophrenia.

Study	Patients (n)	Prior medication	TCP dose (mg/day)	Antipsychotic drug: dose (mg/day)	Duration (Weeks)	General psychopathology^a	Positive symptoms	Depression	Adverse effects
Kruse^41	40	TFP, CPZ, add-on imipramine	20–30	28 TFP: 20–30, 12 CPZ: n.d.	12	9 Much improved (8 TCP/TFP, 1 TCP/CPZ), onset improvement week 5–9, 31 no change	3 Improved, 0 worse	n.d.	n.d.
Singh et al.^42	25^b	FGA, other treatments	30–80	TFP: 4–10	6	4 Much improved, 9 improved, 2 no change, 2 worse (8 drop-outs)	Drop-out: 1 exacerbation	n.d.	Drop-outs: 4 hypotension, 3 aP increased; mild: agitation, insomnia, akathisia, hypotension, drowsiness, micturition disorder
Barsa et al.^43	70	FGA	10–60	PTZ^c: n.d.	16–32	7 Remission, 10 improved, 8 slightly improved, 25 no change or worse	20 Worse (9 drop-out), reversibel 5–10 days after discontinuation of TCP	n.d.	Orthostatic dysregulation during first month, reversible with decreased TCP-dose (18 mild, 3 moderate to severe), no other severe adverse effects
Barsa et al.^44	26	n.d.	n.d.	PTZ: n.d.	4–80	8 Moderately , 5 slightly, 8 not improved, 5 worse	n.d.	n.d.	4 Orthostatic dysregulation, reversible after dose reduction
Langner^45	13	FGA	10–30	TFP^d: 1–3, PTZ^e: n.d.	4–52	8 Moderately , 2 slightly, 3 not improved	n.d.	n.d.	2 insomnia, 1 headache, 1 mild repeated tyramine reactions (flush, nausea, palpitations)
Bucci^35^f	15	CPZ	20	CPZ: 300	16	13 With gradual but progressive improvement	n.d.	Depression improved	No hypertensive crises, anticholinergic drug for the 5 patients with EPS no longer needed
Roesch-Ely et al.^19	53	49 SGA, 4 FGA, 15 SSRI, 7 TCA, 7 VFX	20–50	52 SGA^g: n.d., 1 FGA: n.d.	1–19	23 Improved, 30 no change, 0 worse	2 Improved, 0 worse	11 Improved, 42 no change, 0 worse	No hypertensive crises, 1 orthostatic dysregulation, 1 insomnia, 1 akathisia, 2 EPS, 23 increased weight (6 with 5–10 kg, 3 with > 10 kg)

^aMay be put on a level with improvement of negative symptoms, ^b14 negative schizophrenia, 11 several other withdrawn psychiatric states, improvement in negative schizophrenia: 2 much improved, 5 improved, 2 no change, 1 worse, ^cmainly levomepromazine (n = 21), 12 CPZ, 17 combined CPZ/TFP, 10 combined levomepromazine/TFP, ^dTFP 1–3 mg as component of a fixed-dose drug combination with TCP, ^e3 thioridazine, 2 TFP, 2 chlorprothixene, ^ffollow-up of CPZ-monotherapy group of controlled study, ^g28 olanzapine, 2 sulpiride, 10 aripiprazole, 5 amisulpride, 8 quetiapine, 2 risperidone, 6 ziprasidone, 9 clozapine (incl. more than one SGA per patient). Abbreviations. aP, Alkaline phosphatase; EPS, extrapyramidal symptoms; FGA, first-generation antipsychotic drug; PTZ, phenothiazine; SGA, second-generation antipsychotic drug; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressants; VFX, venlafaxine; n.d., not defined (no data), for other abbreviations see Table 1.

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Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article. The authors may be contacted for further data sharing.