a. General characteristics of the included reports and patients
Figure 1 shows the flow diagram according to the PRISMA protocol for the studies included in this systematic review of case reports. Initially, 3416 articles were identified; 1837 duplicates were eliminated, and 1579 publications remained. Subsequently, 1531 articles were removed after reviewing the titles and abstracts because of irrelevance to the study objective. Of the remaining 48 articles, 24 could not be retrieved and were excluded, and 3 articles were excluded since the reported patients were underage. Finally, 21 articles were assessed with the JBI tool after the screening. One article (35) was excluded from the quality assessment process due to the low quality of information presented and the high risk of bias.
A total of 20 articles (36–55) met the inclusion criteria and survived the quality process, encompassing 22 patients from 8 different countries (Table 1) and most patients from India (10 patients, 45.45% of the cases included). One of the articles was published in Spanish (53) and another in Japanese (37), while the rest were published in English.
Of the 22 patients included in the case reports, 15 (68.18%) were male, and 7 (31.82%) were female patients. Additionally, the mean age (standard deviation) among the participants was 31.45 (10.88) years.
Regarding past medical history, 15 (68.18%) had no medical conditions. However, 2 (9.09%) patients had diabetes mellitus as comorbidity, 1 (4.54%) had hypothyroidism, 1 (4.54%) had an episode of meningeal tuberculosis in the past, and 1 (4.54%) had suicide attempts during TB therapy. In this patient’s case, the study authors reported no relevant psychiatric history. Of the included studies, one patient had a family history of psychiatric disorders (major depression and bipolar disorder), and one patient had a family history of alcoholism; however, there were no reports of medical comorbidities for both patients. Finally, 19 (86.36%) reported having no illegal drug, alcohol, or nicotine dependency. However, 3 (13.64%) participants reported having used alcohol regularly in the past, and one (4.54%) patient reported the last use of cannabis and cocaine 9 weeks before admission. No reported patient consumed concomitantly illegal drugs or alcohol during the treatment with CS.
b. Clinical characteristics of DR-TB patients and CS-induced psychosis
Concerning the type of DR-TB patients, 21 of 22 patients (95.45%) had multidrug-resistant TB (MDR-TB), and one patient (4.54%) had renal tuberculosis (Table 1). Moreover, there were no patients with extreme drug-resistant TB (XDR-TB). Concerning the CS therapy, the mean dose (standard deviation) of CS given as treatment was 631.58 (174.17) mg/die, and the mean duration of CS treatment (standard deviation) until the onset of psychotic symptoms was 169.09 (239.52) days. Within the antitubercular treatment, the reported patients included in this systematic review received mostly drugs, such as pyrazinamide (14 patients, 63.60%), levofloxacin (12 patients, 54.50%), ethionamide (12 patients, 54.50%), kanamycin (11 patients, 50.00%) and pyridoxine (10 patients, 45.50%) (Table 1).
Table 1 also mentions the details of the clinical presentations of the patients in the included case reports with MDR-TB and cycloserine-induced psychosis. Regarding the duration of psychosis, the median duration of psychosis during treatment with cycloserine was 13 days (39 − 4 days; interquartile range: 35). The most common symptoms reported in patients with MDR-TB and cycloserine-induced psychosis were delusions (15 patients; 68.20%), followed by aggressiveness (15 patients; 68.20%), insomnia/decreased sleep (13 patients; 59.10%), hallucinations (12 patients; 54.50%), irritability (10 patients; 45.50%) and incoherent or disorganized speech (10 patients; 45.50%). Concerning the aggression observed in the case reports, 14 of 22 reported patients presented aggressive behavior, mostly against other persons, while one of the 22 included patients presented self-aggression (Table 2). In this last case, the patient died as a result of suicide due to exsanguination as a cause of self-injury cuts in the peripheral vessels.
Table 2
Main characteristics of psychiatric symptoms in patients with cycloserine-associated psychosis.
Symptoms
|
n
|
Percentage
|
Delusions
|
15
|
|
Participants with one delusion
|
9
|
|
Paranoid/persecution
|
7
|
77.80%
|
Delusions of grandeur
|
1
|
11.11%
|
Jealousy
|
1
|
11.11%
|
Participants with two delusions
|
6
|
|
Paranoid/persecution and delusion of grandeur
|
4
|
66.67%
|
Paranoid/persecution and delusions of reference
|
2
|
33.33%
|
Agressiveness
|
14
|
|
Aggresiveness against others
|
13
|
59.10%
|
Self-aggressiveness
|
1
|
4.54%
|
Formal thought disorders (FTD)
|
13
|
|
Participants with one FTD
|
10
|
|
Incoherent/disorganized speech
|
7
|
36.80%
|
Monologues
|
2
|
10.50%
|
Accelerated speech
|
1
|
5.30%
|
Participants with two FTDs
|
3
|
|
Incoherent/disorganized speech and monologues
|
2
|
66.67%
|
Incoherent/disorganized speech and accelerated speech
|
1
|
33.33%
|
Hallucinations
|
12
|
|
Visual and acoustic hallucinations
|
5
|
22.70%
|
Only visual hallucinations
|
2
|
9.10%
|
Only acoustic hallucinations
|
1
|
4.54%
|
Not specified/not described
|
4
|
18.20%
|
In the case of the registry of the type of hallucinations, there are records of 12 (54.50%) patients reported in the included clinical cases. Of these, two (9.10%) of the patients presented visual hallucinations, one (4.54%) presented auditory hallucinations, five (22.70%) a combination of both, and in four cases (18.20%), the hallucination type was not specified (Table 2).
Concerning the type of delusions, 7 of 9 patients (77.80%) reported persecutory/paranoid delusions, one of 9 patients (11.11%) reported delusions of grandeur and 1 of 9 patients (11.11%) reported jealous delusions. Finally, 6 patients reported two delusional symptoms (Table 2). Of them, four of 6 patients (66.67%) reference and persecutory/paranoid delusions, and two of 6 patients (33.33%) had persecutory/paranoid and delusions of grandeur (Table 2).
c. Clinical treatment of MDR-TB patients with CS-induced psychosis
Treatment of cycloserine-induced psychosis varied between reported patients. Of the 22 patients reported, only 4 (18.20%) did not receive antipsychotic treatment. Of the remaining 18 (81.80%) patients reported, the majority (10 patients; 45.50%) received monotherapy with one antipsychotic (2 participants received risperidone, four olanzapine, two haloperidol, 1 received quetiapine, and 1 received chlorpromazine). Of the patients who received a combination of 2 antipsychotics (4 patients, 18.20%), two received a combination with olanzapine and haloperidol, 1 received chlorpromazine and haloperidol, and one patient received olanzapine and quetiapine. Finally, four patients (18.20%) received a combination of three antipsychotics: 2 of them received chlorpromazine + risperidone + haloperidol, 1 of them received haloperidol + promethazine + olanzapine, and 1 of them received haloperidol + chlorpromazine + olanzapine.
Of the adjuvant treatments to antipsychotic therapy, six (27.20%) patients received benzodiazepines (lorazepam, nitrazepam, and clonazepam), 3 (13.60%) patients received anticholinergic agents (benzhexol), and 1 (4.54%) received valproic acid.
Parallel to psychopharmacological therapy, 11 (50.00%) of the reported patients stopped receiving CS, while 2 (9.19%) continued CS treatment, and 2 (9.19%) reported patients the dose of CS was reduced (Table 1). Additionally, two reported patients (9.19%) had their cycloserine dose wholly suspended for a defined period (Table 1). Finally, in 3 (13.60%) reported cases, the antitubercular therapy (including CS) was withheld (Table 1).
Finally, 20 of the 22 reported patients (90.90%) presented a clinical improvement of psychotic symptoms with the reported therapeutic strategies. On the other hand, only one patient reported partial symptom improvement with low-grade labile mood and psychosis (Table 1). Finally, in the case of one patient, suicide was committed by exsanguination by cutting himself in different regions of the body and did not present an improvement in psychotic symptoms despite treatment (Table 1).
d. Quality assessment of case reports: CS-induced psychosis in DR-TB patients
In general, the quality of the case reports was good, showing that the vast majority of the articles had a low risk of bias (supplement material 2). In this sense, it was determined that 17 (85.00%) of the reports presented a very low risk, while 3 (15.00%) presented a low risk. A total of 3 (15.00%) studies did not report the number of doses of cycloserine used in patients with MDR-TB. On the other hand, in the case of the record of symptoms, of the reported cases that described the presence of hallucinations, 4 (20.00%) studies did not specify what type of hallucinations they were (e.g., visual or auditory). Finally, only one study described the use of cycloserine for treating MDR-TB after using other antibiotics. At the same time, the rest of the reported cases indicate a concomitant use of cycloserine with other antibiotics. The quality assessment of the individual studies is in detail in supplement material 2.
In the case of the probability of the reaction to an adverse event, in this case, psychosis induced by cycloserine, a total of 6 articles used the Naranjo algorithm in patients who use cycloserine. In case this algorithm had not been described in the case reports, the score was established according to the information presented in the article. Of the reported articles, 18 showed a “probable” Naranjo index for cycloserine-induced psychosis (5 to 8 points), while the rest scored as “possible” (1 to 4 points).