- Email: [email protected]
Methylene blue excretion in depression
x50
k3IOLPSYCHIATRY l')X9:26:84785X
C’orrespondence
m interpreting seizure duration SR- I EEG instrumentation.
using the MECTA Bat-p H. Guze Edward H. Lisron
University of California Neuropsychiatric Institute and Hospital 760 Westwood Plaza Los Angeles, CA 90024
References Guze BH, Liston EH, Baxter LR, et al. (1989): Poor interrater reliability of MECTA EEG recording of ECT seizure duration. J Clin Psychiatp 50: 140142. Ries RK (1985): Poor interrater reliability of MECTA EEG seizure duration measurement during ECT. Biol Psychiatry l&121-126.
Methylene Blue Excretion in Depression To the Editor: Methylene blue has been used extensively in medicine for the treatment of methaemoglobinemia and as a contrast dye in a variety of surgical and diagnostic procedures. In recent times it has also been under investigation for the treatment of therapy-resistant manic depressive illness with some beneficial effects noted (Narsapur and Naylor 1983; Thomas and Callander 1985; Naylor et al. 1986). Elevated vanadium levels in biological fluids may be of etiological significance in manic depressive psychosis (Naylor et al. 1984) and it has been suggested that the effects
Table 1. Mean 24-Hour Excretion of Methylene
of vanadium in these subjects could be counteracted by the therapeutic use of methylene blue to reduce vanadate ions to less pathotoxic vanadyl ions (Naylor et al 1981). As no studies on the disposition and fate of the substance during chronic administration have been undertaken, trials of methylene blue in depression offered a useful opportunity to monitor whole blood levels and urinary excretion during continuous treatment. During a 3-week trial on high-dose (300 mg/day) versus low-dose (15 mg/day) methylene blue in depressed female psychiatric in-patients in the Metabolic Unit at the Royal Dundee Liff Hospital, 9:OO AM fasting blood samples and 24.hr urine collections were made at 7. 14, and 21 days after commencing
Blue During Chronic Therapy
Low dose (15 mg) Days
High dose (300 mg)
Mean
SD
N
MCUI
SD
N
Free
(%I (mg)
41.0 6. 1
IS.2 2.3
7 7
14.6 43.9
5.3 16 0
h” 6
Total
(9) Img) (%I
88.6 13.3 35 .o
23.5 3.5 5.7
7 7 7
20.7 62.2 4. I 12.2
6“ h 6
I
Free
Cm@
5.3
0.9
I
39.8 119.4 13.7 41.1
hh
14 Total Free
(%) (mgt (%I (mg)
88.6 13.3 40.6 6.1
22.3 3.3 13.8 2. I
7 7 7 7
37.6 112.7 IS.1 45.2
17.9 53.6 3.9 11.7
6” 6 6” 6
(%) (mg)
83.5 12.5
22.1 3.3
7 7
35.2 105.6
15.5 46.3
h” 6
21 Total
‘p -c 0.005. %I-c0.001
BIOLPSYCHIATRY 1989;26:847-858
Correspondence
851
Table 2. Forty-eight-Hour Excretion of Methylene Blue Following Single Oral Doses in a Male Subject Dose (mg) 25 50 100
Total mg
Free mg (” SEM)
8
(k SEM)
8
14.9 2 0.2 28.1 c 0.2 33.5 2 0.1
59.6 56.2 33.5
17.7 ” 0.2 30.8 2 1.3 39.5 + 1.0
70.8 61.5 39.5
therapy. In a second experiment, a 52-year-old male patient took oral doses of 25, 50, and 100 mg of methylene blue in multiples of 25 mg tablets at 9:oO AM at weekly intervals with urine collections for 48hr urine dosage. Whole blood and urinary methylene blue were measured according to the methods of Di Santo and Wagner (1972a). All concentrations of methylene blue in whole blood were below the limits of detection for the method (0.05 mg/liter). Nevertheless, the substance was well absorbed in the low-dose group with average urinary recoveries of 84%-89% (Table 1). Recoveries for the high-dose group were appreciably lower, amounting to only 35%-40% of oral intake. These differences were statistically significant at the p < 0.005 and p < 0.001 levels (two-tailed f-test). After single oral doses of methylene blue were given to a male subject, total urinary recoveries in 48-hr ranged from 39.5% to 70.8% (Table 2) with the lowest recoveries associated with the highest dosage. The distinctive differences in urinary elimination of methylene blue between patients on low and high doses and the corroborative evidence from singledose studies suggest that there are ph~aco~neti~ differences in the handling of low and high oral doses and possibly physiological constraints on effective dose levels when given by mouth. The mechanism involved is open to question. When given to volunteers in modest oral doses, Di Santo and Wagner (1972b) demonstrated effective though erratic absorption of methylene blue from the gastrointestinal tract whereas in animals, tissue uptake from the circulation is both rapid and extensive (Di Santo and Wagner 1972~). Owing to the possibility of an enterohepatic circulation for methylene blue (Blass and Fung 1976), incompleteness of absorption cannot be inferred from urine recoveries alone. If there are physiological limitations on gastrointestinal absorption there may be advantages in using frequent small oral doses rather than large bduses. There is a need for better methods
of analysis for whole blood to help resolve some of the issues raised by this study. J.P. M.?udy SM. Allan A.H. W. Smith G.J. Naybr Departments of Biochemical Medicine and Psychiatry University of Dundee Dundee DDI 9SY Gt. Britain
References Blass, Fung F (1976): Dyed but not dead methylene blue overdose. Anaesthesiology 45:458-459. Di Santo AR, Wagner JG (1982a): Ph~aco~netics of highly ionized drugs I: Methylene blue-whole blood, urine and tissues assays. JPhannSci 61:598602. Di Santo AR, Wagner JG (1972b): Ph~~okinetics of highly ionized drugs II: Methylene blue-absorption, metabolism and excretion in man and dog after oral administration. IBID 61:1086-1090. Di Santa AR, Wagner JG (1972~): Ph~aco~netics of highly ionized drugs III: Blood levels in the dog and tissue levels in the rat following intravenous administration. IBID 61: 1090-1094. Narsapnr SL, Nayior GJ (1983): Methylene blue: A possible treatment for manic depressive psychosis. J Affect Dis 5:155-161. Naylor GJ, Dick DAT, Johnston BB, et al. (1981): Possible explanation for therapeutic action of lithium and a possible substitute (methylene blue). Lancer 2: 1175-l 176. Naylor GJ, Mattin B, Hopwocd SE, Watson JY (1986): A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic depressive psychosis. Biol Psychiatry 211:915-920.
RIOL PSYCHIATRI /989,26:X47 X5X
f
‘orrespondenct.
Naylor GJ. Smith AHW, Brycc D, Ward NI ( 1984): Tissue vanadium levels in manic depressive psy. chosis. Psycho1 Meri 14:767--7X.
Thomas RD. Callander K ( 1985): Methylene blue in treatment of bipolar illness. Ric71P,y-hintry 20: 120Ill
Headache in Schizophrenia and Seasonality of Births
phrenia began, did the person complain of headaches?’ Of the 2013 completed questionnaires, 18% answered “yes,” 74% <‘no,” and 8% “do not remember.” When those answering “yes” were compared with those answering “no” in regard to gender, family history of schizophrenia, or age of onset, no significant difference was found. When the month of birth was examined and compared to all general births in the United States for 1941-1960, it was found that those with no history of headache showed a significant January-April birth excess (p = 0.027, chisquare) similar to the winter-spring birth excess reported for persons with schizophrenia in over 20 other studies. Those with a history of headache, however. showed no trend toward winter-spring births and did not differ from the genera1 U.S. birth pattern. As considerable evidence has accumulated that some cases of schizophrenia are associated with adverse perinatal events (McNeil 1987), these p~limina~ obse~ations suggest that a history of headache at the onset of schizophrenia might help differentiate those cases associated with perinatal pathology (headache absent) from those without such pathology (headache present). This note needs to be followed by a methodolop&ally correct study of patients who have been more carefully diagnosed, with suitable precautions against bias with validation of onset and pain, and with controls. It is suggested that clinicians should routinely ask newly diagnosed patients with schizophrenia about headache, and the results should be compared with patients suffering from bipolar disorder or other psychiatric conditions. It might also be useful to do a prospective follow-up of patients with headache at onset to ascertain whether they develop a different course.
To The Editor: Headache is a common but often overlooked early symptom of schizophrenia and was described by both Kraepelin and Bleuler. Attempts to ascertain its incidence have yielded remarkably consistent results: Hinterhuber (1975) reported that 17% of patients had severe headache at the time of onset of their disease and Varsamis and Adamson (1976) found that 23% of “recently hospitalized schizophrenic patients” complained of headache. In a study of patients with chronic schizophrenia, Watson et al. ( 198 1) claimed that 17% complained of headache and Gittelson ( 196 1) observed that “patients suffering from schizop~enia or schizoaffective psychosis showed an improvement in the headache which paralleled the change in psy~hopa~ology ,” In order to ascertain the incidence of headache at the onset of schizophrenia and its possible relationship to other aspects of the disease. a question about headache was included in a 15-item questionnaire in a 1984 newsletter of the National Alliance for the Mentally Ill (NAMI). Most questions concerned perinatal events and childhood illnesses in individuals who subsequently developed schizophrenia or schizoaffective disorder. The NAM1 newsletter at the time went to approximately 20,000 families, and 2,013 completed questionnaires were returned; it is reasonable to assume that there was a self-selection of those who returned the questionnaire toward families who believed perinatal and early childhood biological factors were causally related to their relative’s disease. No effort was made to verify that the subject of the questionnaire did have schizophrenia or schizoaffective disorder; it is known, however, that NAM1 members are self-selected toward those with family members who are more severely affected with serious mental illnesses. The question read: “Around the time the schizo-
Twin Study Unit Neur(~psychiat~ Research Hospital
k3IOLPSYCHIATRY l')X9:26:84785X
C’orrespondence
m interpreting seizure duration SR- I EEG instrumentation.
using the MECTA Bat-p H. Guze Edward H. Lisron
University of California Neuropsychiatric Institute and Hospital 760 Westwood Plaza Los Angeles, CA 90024
References Guze BH, Liston EH, Baxter LR, et al. (1989): Poor interrater reliability of MECTA EEG recording of ECT seizure duration. J Clin Psychiatp 50: 140142. Ries RK (1985): Poor interrater reliability of MECTA EEG seizure duration measurement during ECT. Biol Psychiatry l&121-126.
Methylene Blue Excretion in Depression To the Editor: Methylene blue has been used extensively in medicine for the treatment of methaemoglobinemia and as a contrast dye in a variety of surgical and diagnostic procedures. In recent times it has also been under investigation for the treatment of therapy-resistant manic depressive illness with some beneficial effects noted (Narsapur and Naylor 1983; Thomas and Callander 1985; Naylor et al. 1986). Elevated vanadium levels in biological fluids may be of etiological significance in manic depressive psychosis (Naylor et al. 1984) and it has been suggested that the effects
Table 1. Mean 24-Hour Excretion of Methylene
of vanadium in these subjects could be counteracted by the therapeutic use of methylene blue to reduce vanadate ions to less pathotoxic vanadyl ions (Naylor et al 1981). As no studies on the disposition and fate of the substance during chronic administration have been undertaken, trials of methylene blue in depression offered a useful opportunity to monitor whole blood levels and urinary excretion during continuous treatment. During a 3-week trial on high-dose (300 mg/day) versus low-dose (15 mg/day) methylene blue in depressed female psychiatric in-patients in the Metabolic Unit at the Royal Dundee Liff Hospital, 9:OO AM fasting blood samples and 24.hr urine collections were made at 7. 14, and 21 days after commencing
Blue During Chronic Therapy
Low dose (15 mg) Days
High dose (300 mg)
Mean
SD
N
MCUI
SD
N
Free
(%I (mg)
41.0 6. 1
IS.2 2.3
7 7
14.6 43.9
5.3 16 0
h” 6
Total
(9) Img) (%I
88.6 13.3 35 .o
23.5 3.5 5.7
7 7 7
20.7 62.2 4. I 12.2
6“ h 6
I
Free
Cm@
5.3
0.9
I
39.8 119.4 13.7 41.1
hh
14 Total Free
(%) (mgt (%I (mg)
88.6 13.3 40.6 6.1
22.3 3.3 13.8 2. I
7 7 7 7
37.6 112.7 IS.1 45.2
17.9 53.6 3.9 11.7
6” 6 6” 6
(%) (mg)
83.5 12.5
22.1 3.3
7 7
35.2 105.6
15.5 46.3
h” 6
21 Total
‘p -c 0.005. %I-c0.001
BIOLPSYCHIATRY 1989;26:847-858
Correspondence
851
Table 2. Forty-eight-Hour Excretion of Methylene Blue Following Single Oral Doses in a Male Subject Dose (mg) 25 50 100
Total mg
Free mg (” SEM)
8
(k SEM)
8
14.9 2 0.2 28.1 c 0.2 33.5 2 0.1
59.6 56.2 33.5
17.7 ” 0.2 30.8 2 1.3 39.5 + 1.0
70.8 61.5 39.5
therapy. In a second experiment, a 52-year-old male patient took oral doses of 25, 50, and 100 mg of methylene blue in multiples of 25 mg tablets at 9:oO AM at weekly intervals with urine collections for 48hr urine dosage. Whole blood and urinary methylene blue were measured according to the methods of Di Santo and Wagner (1972a). All concentrations of methylene blue in whole blood were below the limits of detection for the method (0.05 mg/liter). Nevertheless, the substance was well absorbed in the low-dose group with average urinary recoveries of 84%-89% (Table 1). Recoveries for the high-dose group were appreciably lower, amounting to only 35%-40% of oral intake. These differences were statistically significant at the p < 0.005 and p < 0.001 levels (two-tailed f-test). After single oral doses of methylene blue were given to a male subject, total urinary recoveries in 48-hr ranged from 39.5% to 70.8% (Table 2) with the lowest recoveries associated with the highest dosage. The distinctive differences in urinary elimination of methylene blue between patients on low and high doses and the corroborative evidence from singledose studies suggest that there are ph~aco~neti~ differences in the handling of low and high oral doses and possibly physiological constraints on effective dose levels when given by mouth. The mechanism involved is open to question. When given to volunteers in modest oral doses, Di Santo and Wagner (1972b) demonstrated effective though erratic absorption of methylene blue from the gastrointestinal tract whereas in animals, tissue uptake from the circulation is both rapid and extensive (Di Santo and Wagner 1972~). Owing to the possibility of an enterohepatic circulation for methylene blue (Blass and Fung 1976), incompleteness of absorption cannot be inferred from urine recoveries alone. If there are physiological limitations on gastrointestinal absorption there may be advantages in using frequent small oral doses rather than large bduses. There is a need for better methods
of analysis for whole blood to help resolve some of the issues raised by this study. J.P. M.?udy SM. Allan A.H. W. Smith G.J. Naybr Departments of Biochemical Medicine and Psychiatry University of Dundee Dundee DDI 9SY Gt. Britain
References Blass, Fung F (1976): Dyed but not dead methylene blue overdose. Anaesthesiology 45:458-459. Di Santo AR, Wagner JG (1982a): Ph~aco~netics of highly ionized drugs I: Methylene blue-whole blood, urine and tissues assays. JPhannSci 61:598602. Di Santo AR, Wagner JG (1972b): Ph~~okinetics of highly ionized drugs II: Methylene blue-absorption, metabolism and excretion in man and dog after oral administration. IBID 61:1086-1090. Di Santa AR, Wagner JG (1972~): Ph~aco~netics of highly ionized drugs III: Blood levels in the dog and tissue levels in the rat following intravenous administration. IBID 61: 1090-1094. Narsapnr SL, Nayior GJ (1983): Methylene blue: A possible treatment for manic depressive psychosis. J Affect Dis 5:155-161. Naylor GJ, Dick DAT, Johnston BB, et al. (1981): Possible explanation for therapeutic action of lithium and a possible substitute (methylene blue). Lancer 2: 1175-l 176. Naylor GJ, Mattin B, Hopwocd SE, Watson JY (1986): A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic depressive psychosis. Biol Psychiatry 211:915-920.
RIOL PSYCHIATRI /989,26:X47 X5X
f
‘orrespondenct.
Naylor GJ. Smith AHW, Brycc D, Ward NI ( 1984): Tissue vanadium levels in manic depressive psy. chosis. Psycho1 Meri 14:767--7X.
Thomas RD. Callander K ( 1985): Methylene blue in treatment of bipolar illness. Ric71P,y-hintry 20: 120Ill
Headache in Schizophrenia and Seasonality of Births
phrenia began, did the person complain of headaches?’ Of the 2013 completed questionnaires, 18% answered “yes,” 74% <‘no,” and 8% “do not remember.” When those answering “yes” were compared with those answering “no” in regard to gender, family history of schizophrenia, or age of onset, no significant difference was found. When the month of birth was examined and compared to all general births in the United States for 1941-1960, it was found that those with no history of headache showed a significant January-April birth excess (p = 0.027, chisquare) similar to the winter-spring birth excess reported for persons with schizophrenia in over 20 other studies. Those with a history of headache, however. showed no trend toward winter-spring births and did not differ from the genera1 U.S. birth pattern. As considerable evidence has accumulated that some cases of schizophrenia are associated with adverse perinatal events (McNeil 1987), these p~limina~ obse~ations suggest that a history of headache at the onset of schizophrenia might help differentiate those cases associated with perinatal pathology (headache absent) from those without such pathology (headache present). This note needs to be followed by a methodolop&ally correct study of patients who have been more carefully diagnosed, with suitable precautions against bias with validation of onset and pain, and with controls. It is suggested that clinicians should routinely ask newly diagnosed patients with schizophrenia about headache, and the results should be compared with patients suffering from bipolar disorder or other psychiatric conditions. It might also be useful to do a prospective follow-up of patients with headache at onset to ascertain whether they develop a different course.
To The Editor: Headache is a common but often overlooked early symptom of schizophrenia and was described by both Kraepelin and Bleuler. Attempts to ascertain its incidence have yielded remarkably consistent results: Hinterhuber (1975) reported that 17% of patients had severe headache at the time of onset of their disease and Varsamis and Adamson (1976) found that 23% of “recently hospitalized schizophrenic patients” complained of headache. In a study of patients with chronic schizophrenia, Watson et al. ( 198 1) claimed that 17% complained of headache and Gittelson ( 196 1) observed that “patients suffering from schizop~enia or schizoaffective psychosis showed an improvement in the headache which paralleled the change in psy~hopa~ology ,” In order to ascertain the incidence of headache at the onset of schizophrenia and its possible relationship to other aspects of the disease. a question about headache was included in a 15-item questionnaire in a 1984 newsletter of the National Alliance for the Mentally Ill (NAMI). Most questions concerned perinatal events and childhood illnesses in individuals who subsequently developed schizophrenia or schizoaffective disorder. The NAM1 newsletter at the time went to approximately 20,000 families, and 2,013 completed questionnaires were returned; it is reasonable to assume that there was a self-selection of those who returned the questionnaire toward families who believed perinatal and early childhood biological factors were causally related to their relative’s disease. No effort was made to verify that the subject of the questionnaire did have schizophrenia or schizoaffective disorder; it is known, however, that NAM1 members are self-selected toward those with family members who are more severely affected with serious mental illnesses. The question read: “Around the time the schizo-
Twin Study Unit Neur(~psychiat~ Research Hospital