Haloperidol Improves Membrane Phospholipid Abnormalities in Temporal Lobes of Schizophrenic Patients Hiroshi Fukuzako, M.D., Tsuyoshi Fukuzako, M.D., Satoshi Kodama, M.D., Tomo Hashiguchi, M.D., Morikuni Takigawa, M.D., and Toshiro Fujimoto, M.D.

Using 31P magnetic resonance spectroscopy, we examined than in controls. Treatment was associated with a decline in changes in the levels of phosphorus metabolites in the the total symptom score according to the Brief Psychiatric temporal lobes of 13 schizophrenic patients before and 12 Rating Scale and the score for positive symptoms showed a weeks after initiating treatment. Spectra were relatively high correlation with reduction in PDE level in obtained from a volume of interest positioned in each the left . These preliminary results suggest temporal lobe. Findings were compared with those in 13 that haloperidol may partially normalize disturbed age- and gender-matched healthy subjects. Prior to metabolism or abnormalities in components of membrane treatment the patients showed higher levels of phospholipids in the left temporal lobe of untreated phosphodiesters (PDE) in both temporal lobes than healthy schizophrenic patients, paralleling symptom alleviation. subjects. Haloperidol administration significantly reduced [Neuropsychopharmacology 21:542–549, 1999] the excess of PDE in the left temporal lobe, although the © 1999 American College of Neuropsychopharmacology. PDE concentration remained somewhat higher bilaterally Published by Elsevier Science Inc.

KEY WORDS: ; Magnetic resonance et al. 1994; Deicken et al. 1995), whereas temporal lobe spectroscopy; Haloperidol; Temporal lobe; Phosphorus dysfunction may be related to “positive” symptoms metabolites (Fukuzako et al. 1996; Klemm et al. 1996; Nordahl et al. Functional neuroimaging studies have revealed abnor- 1996; Sabri et al. 1997). The effects of neuroleptic treat- malities in the brains of schizophrenic patients, espe- ment on regional cerebral blood flow (rCBF) and me- cially in the frontal and temporal lobes, basal ganglia, tabolism are not yet clear (Miller et al. 1997). Several re- and thalamus (Bertolino et al. 1996; Andreasen et al. searchers have found, however, that neuroleptic 1997; Egan and Weinberger 1997; McClure et al. 1998). treatment produced changes in rCBF in the frontal and dysfunction generally has been associated temporal lobes of schizophrenic patients. Nilsson et al. with “negative” symptoms and the disorganization (1977) demonstrated a widespread reduction in cortical syndrome (Liddle et al. 1992; Kaplan et al. 1993; Shioiri perfusion, especially in frontotemporal regions, after several weeks of treatment with haloperidol. Changes From the Department of Neuropsychiatry (HF, TF[T. Fukuzako], in positive symptom scores correlated well with SK, TH, MT), Faculty of Medicine, Kagoshima University, Kagoshima, changes in both frontal and temporal CBF (Berman et Japan; and South Japan Health Science Center (TF[T. Fujimoto]), Miyazaki, Japan. al. 1996). Single-dose haloperidol administration in Address correspondence to: Hiroshi Fukuzako, M.D., Depart- schizophrenic patients ameliorated hypoactivity in the ment of Neuropsychiatry, Faculty of Medicine, Kagoshima Univer- frontal lobes and suppressed hyperactivity in the tem- sity, 8–35–1 Sakuragaoka, Kagoshima 890–8520, Japan. Received September 17, 1998; revised January 12, 1999; accepted poral lobe and adjacent occipital and parietal areas April 5, 1999. (Matsuda et al. 1991). These CBF changes were not de-

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tected when the drug was administered to normal vol- nia or schizophreniform disorder (American Psychiat- unteers. These observations suggest that neuroleptics ric Association 1987) and were right-handed according alleviate schizophrenic symptoms by actions in the to the Edinburgh Handedness Inventory (Oldfield 1971; frontal and temporal lobes. Schachter et al. 1987) were recruited from the outpa-

Phospholipase A2 (PLA2) is a key enzyme in the me- tient clinics of Fujimoto Hospital and Kagoshima Uni- tabolism of phospholipids that also affects receptor versity Hospital between 1991 and 1996. All patients function and signal transduction (Farooqui et al. 1992). gave their written informed consent for participation in In a biochemical study, Gattaz et al. (1995) found plate- the study. None had a recent history of alcohol or drug let PLA2 activity to be greater in schizophrenic patients abuse. than in healthy controls; this elevation was reduced by Sixteen patients of the 25 completed adequate MRS neuroleptic treatment. Neuroleptics may alter brain studies before and after 12 weeks of treatment with ha- phospholipid metabolism and composition by regulat- loperidol. The dose of haloperidol given each patient ing PLA2 activity in a manner similar to that seen in was determined by the treating psychiatrist. The aver- platelets and red blood cells. Possible effects of neuro- age total dose of haloperidol administered during the leptics like haloperidol on membrane phospholipid me- 12-week period was 470 Ϯ 223 mg. All patients were tabolism and composition are under investigation. In treated in the two institutions, and their diagnoses were one study, haloperidol was found to reduce synthesis of reevaluated one year following the first scan. Three pa- various phospholipids in rat brain (Singh and Shankar tients were excluded from data analysis because their 1996). diagnosis remained schizophreniform disorder at this Disturbed phospholipid metabolism has been pro- follow-up estimation. As a result, data from the 13 pa- posed as a neurodevelopmental pathogenesis of schizo- tients (7 men and 6 women aged 16 to 32 years; mean phrenia (Horrobin 1998). In vivo 31phosphorus magnetic 22.6), who were diagnosed with schizophrenia, were resonance spectroscopy (31P-MRS) is able to quantitate analyzed. They had been ill for 7.4 Ϯ 6.5 months at the membrane phospholipids and high-energy phosphate time of the first scan. A neuropsychiatrist (T. Fukuzako) metabolism in the brain (Maier 1995; McClure et al. evaluated the patients using the Oxford version of the 1998). Therefore, 31P-MRS may represent a direct test Brief Psychiatric Rating Scale (BPRS, range 0 to 6) (Kola- for such a hypothesis. With 31P-MRS, increased levels of kowska 1976) before and after treatment. The sum of phosphodiesters (PDE) and decreased levels of phosph- scores for conceptual disorganization, suspiciousness, omonoesters (PME) have been observed in the frontal hallucinatory behavior, mannerisms and posturing, and lobes of drug-naive schizophrenic patients compared unusual thought content was taken as the subscale with levels in healthy subjects (Pettegrew et al. 1991; score for positive symptoms. Negative symptom scores Stanley et al. 1995). Increased ␤-phosphates of 5’-ade- were estimated based on emotional withdrawal, motor nosine triphosphate (␤-ATP) and decreased inorganic retardation, uncooperativeness, and blunted affect. This orthophosphate (Pi) also have been reported (Pettegrew selection criteria was based on the results of Kitamura et al. 1991). Evidence of changes in phosphorus metabo- et al. (1990). lites has been sought after treatment with neuroleptic Thirteen age- and gender-matched healthy subjects medication only in the study of Keshavan et al. (1995), who served as controls (ages 15 to 31 years; mean 22.2) with negative results. However, no previous report has were relatives of hospital staff members and students at investigated metabolite changes in the temporal lobes the University. They underwent MRS twice, with the of drug-naive schizophrenic patients and subsequent same interval between scans as in the patient group. All alterations in metabolite levels with neuroleptic treat- subjects were right-handed according to the Edinburgh ment. In our previous study, the association between inventory (Oldfield 1971); a laterality score greater than membrane phospholipid abnormality in the temporal 80 was considered evidence of right-handedness lobe and positive symptoms was reported in medicated (Schachter et al. 1987). schizophrenic patients (Fukuzako et al. 1996). In the The method of MRS data acquisition and processing present study, we performed 31P-MRS to investigate has been described in our earlier report (Fukuzako et al. metabolite changes in the temporal lobes of schizo- 1996). Spectroscopy was performed on a Siemens-Asahi phrenic patients induced by the administration of halo- Meditec MR system (Erlangen, Germany) with a mag- peridol for 12 weeks and its relations to specific symptoms. netic field strength of 2.0 tesla. A circular polarizing head coil was tuned to 84.5 MHz for proton imaging and to 34.2 MHz for in vivo multivoxel 31P-MRS (two-

MATERIALS AND METHODS dimensional chemical shift imaging; 2DCSI). T1-weighted spin-echo images with a repetition time of 500 msec and Twenty-five first-episode, drug-naive Japanese patients an echo time of 15 msec were acquired for the voxel (14 men and 11 women aged 16 to 32 years; mean 23.1) placement. The field of view was 24 cm with an 8 x 8 who met DSM-III-R diagnostic criteria for schizophre- data matrix and a 4-cm section thickness. The volume of

544 H. Fukuzako et al. NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 4

each voxel was 36 ml. We sought to make the location Repeated-measures analysis of variance (ANOVA) of the voxels investigated as near to identical as possi- was performed separately for patients and controls, ble between the two MRS scans. On the midsagittal with scan (pre- and posttreatment) analyzed and side slice, placement of voxels was determined as the pos- (left and right) as within-subject factors. Subsequently, terior limit of the volume of interest (VOI) passing two-way ANOVA with a between-subject factor of di- through the superior and inferior colliculus. On the agnosis and a within-subject factor of side was per- coronal slice, the placement of the voxels was deter- formed on data obtained before and after haloperidol mined as the midline of voxels passing through the in- treatment, and was followed by Scheffé multiple-com- terhemispheric fissure and third ventricle. In addition, parison method to establish statistically significant dif- the inferior limit of the VOIs was placed on a line pass- ferences (p Ͻ .05). Pairwise comparisons were made: ing through the inferior aspect of both temporal lobes. the second scan to the first scan in each patient or con- The spectra from the two VOIs, each consisting of two trol group; patient to control at the time of the first scan voxels, were produced by recalculating the signals al- or the second scan; and left to right for the first scan or ready obtained. These VOIs contained mainly the tem- the second scan in each group. Phosphorus metabolites poral lobes and small part of the frontal and parietal were analyzed in an exploratory manner without cor- lobes. The time of repetition was 2 sec; the number of rection for multiple comparison, in spite of the in- sample points was 1024; and the acquisition delay was creased risk of a Type I error. Pearson’s product mo- 1.72 msec. Twelve measurements were obtained for ment correlation coefficient (r) was used to test each spectrum. Data were processed with Fourier trans- relationships between the two types of values. formation and exponential multiplication (16 Hz) and then phase-corrected for the constant phase and linear frequency dependent phase. RESULTS Spectral peaks were obtained for PME, Pi, PDE, phosphocreatine (PCr), and ␥-, ␣-, and ␤-ATP. The No obvious morphologic abnormalities were detected spectra were quantified by peak area measurements. on magnetic resonance images of patients or healthy An automated baseline correction technique removed subjects. Mole percentages of metabolites in controls, in the sinc-wiggle-like distortion from the baseline of the the drug-naive patients, and in patients after 12 weeks spectra. The technique minimized the square error be- of haloperidol treatment are shown in Table 1. In the tween the theoretically derived spectrum and the cor- patient group, ANOVA revealed significant effects of rected spectrum. After baseline correction, peak param- scan (pre- vs. post-treatment) and side for levels of PME ϭ ϭ ϭ ϭ eters such as height, position, and width were obtained (F3, 36 3.42; p .028) and PDE (F3, 36 5.21; p .004). by a Lorentzian curve-fitting procedure. This process In the control group, no significant effects were ob- was performed automatically after the number of peaks served for any metabolite. was determined. For each spectrum, the integrated ar- Subsequent repeated-measures ANOVA showed a ␥ ␣ ␤ ϭ eas for PME, Pi, PDE, and PCr, and for -, -, and - significant effect of diagnosis for levels of PME (F1, 24 ϭ ϭ Ͻ ATP were measured, and percentages of total phospho- 4.75; p .039) and PDE (F1, 24 20.0; p .001) in drug- rus signal (mole percentages) were calculated. The ␤- naive patients compared with healthy subjects. A sig- ATP peak was adopted as an ATP reference because ␥- nificant diagnosis-by-side interaction was observed for ␣ ϭ ϭ and -ATP peaks contain other phosphate metabolites PCr (F1, 24 5.05; p .034). Post hoc multiple compari- such as adenosine diphosphate and dinucleotide phos- son revealed a significant elevation of PDE on both phate. Coefficients of variation (CVs) for controls in this sides in drug-naive patients compared to the control study for each metabolite ranged from 6.5% to 17.6% group (left, p Ͻ .001; right, p ϭ .004) (Table 1). Haloperi- (PME, lt 12.0%, rt 14.8%; Pi, lt 15.4%, rt 17.6%; PDE, lt dol administration significantly reduced the excess of 6.5%, rt 6.6%; PCr, lt 15.0%, rt 12.4%; ␤-ATP, lt 10.5%, rt PDE in the left temporal lobe of schizophrenic patients 10.7%; ␥-ATP, lt 11.1%, rt 16.2%; and ␣-ATP, lt 10.2%, rt (p ϭ .028) (Table 1, Figure 1). 10.1%). These CVs were less than those we had previ- The total BPRS score declined with haloperidol treat- ously calculated based on one voxel (36 ml, range 8.7% ment, from an average of 35.3 to 13.4 (paired t-test: t ϭ to 27.9%) (Fukuzako et al. 1996). We investigated 9.79, p Ͻ .001). After 12 weeks of treatment with halo- changes between two scans performed one to two peridol, only the PDE level showed a remaining trend weeks apart in five schizophrenic patients who under- toward an excess in comparison to levels in healthy went long-term medication and five healthy volunteers. subjects (lt, p ϭ .065; rt, p ϭ .073). Relationships be- No significant metabolite changes were demonstrated tween changes in symptom score and metabolite level between the two scans by a paired t test, although the were tested for PME and PDE on both sides separately sample size was very small. In addition, the CVs in the because the level of PDE in the left temporal lobe was patients and controls in the previous study of small changed significantly by haloperidol treatment, sample were comparable to those in the present one. whereas both levels of PME on the left (p ϭ .061) and of

NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 4 Phosphorus Metabolite Changes by Haloperidol 545

Table 1. Phosphorus Metabolites in Temporal Lobes before and after Haloperidol Treatment

Schizophrenic Patients (N ϭ 13) Controls (N ϭ 13)

Metabolite Before Treatment After Treatment First Scan Second Scan

PME lt 9.4 Ϯ 1.7 10.5 Ϯ 1.2 10.7 Ϯ 1.7 10.3 Ϯ 1.3 rt 9.5 Ϯ 1.7 10.3 Ϯ 1.2 10.6 Ϯ 2.0 10.3 Ϯ 1.6 Pi lt 5.6 Ϯ 1.5 5.9 Ϯ 1.0 6.3 Ϯ 1.0 5.6 Ϯ 1.1 rt 5.3 Ϯ 1.3 5.6 Ϯ 0.8 5.9 Ϯ 1.5 5.9 Ϯ 1.1 PDE lt 41.8 Ϯ 2.7a 39.9 Ϯ 1.5b 37.8 Ϯ 2.3 38.6 Ϯ 1.9 rt 41.1 Ϯ 2.4a 39.7 Ϯ 1.8 37.7 Ϯ 2.6 37.8 Ϯ 3.5 PCr lt 11.5 Ϯ 1.3 10.7 Ϯ 1.2 10.5 Ϯ 1.5 11.0 Ϯ 1.4 rt 10.4 Ϯ 1.2 10.9 Ϯ 1.0 10.9 Ϯ 1.3 11.1 Ϯ 1.9 ␤-ATP lt 10.1 Ϯ 1.5 9.6 Ϯ 2.0 11.0 Ϯ 1.3 10.9 Ϯ 1.4 rt 10.6 Ϯ 1.5 10.5 Ϯ 1.3 11.0 Ϯ 1.3 10.6 Ϯ 1.2 ␥-ATP lt 9.5 Ϯ 1.9 10.4 Ϯ 2.8 11.0 Ϯ 1.3 10.5 Ϯ 1.9 rt 10.5 Ϯ 2.1 10.5 Ϯ 1.9 10.9 Ϯ 2.3 11.0 Ϯ 2.1 ␣-ATP lt 12.0 Ϯ 1.8 12.9 Ϯ 2.3 12.8 Ϯ 2.1 13.2 Ϯ 1.8 rt 12.7 Ϯ 2.6 12.6 Ϯ 2.9 13.0 Ϯ 2.0 13.4 Ϯ 1.9

a p Ͻ .005; post-hoc Scheffé test (compared to control under untreated condition). b p Ͻ .05; post-hoc Scheffé test (compared to the condition before haloperidol treatment).

PDE on the right (p ϭ .095) tended to be altered by the 0.73, p ϭ .003) (Figure 2). The PDE reduction in the right medication. Reduction in PDE level in the left temporal temporal lobe showed a weak correlation with the de- lobe correlated well with decline of total BPRS score (r ϭ cline in positive symptom score (r ϭ 0.59, p ϭ .031). The 0.69, p ϭ .007) and the score for positive symptoms (r ϭ total amount of haloperidol did not correlate signifi- cantly with changes in the level of any metabolite. The decline in BPRS score did not correlate with levels of any metabolite prior to haloperidol treatment.

DISCUSSION

In this study, 31P-MRS detected an elevation of PDE in the temporal lobes of drug-naive schizophrenic patients compared with healthy subjects. These results are in part consistent with previous observations reported in the of schizophrenic patients (Pette- grew et al. 1991; Stanley et al. 1995). A recent prelimi- nary study of 31P-MRS in the temporal lobes of post- mortem brains has shown a nonsignificant decrease in phosphoethanolamine (PE) and increases in glycero- phosphoethanolamine (GPE) and glycerophosphocho- line (GPC) in schizophrenic subjects, changes smaller but otherwise similar to our own findings (Williamson et al. 1996). Pettegrew et al. (1991) have speculated that increased PDE in the frontal lobes of schizophrenic pa- tients may reflect increased breakdown of membrane phospholipids. The pre-acquisition delay time of 1.72 msec in our study makes interpretation of increased PDE difficult. The PDE resonance obtained from our Figure 1. Mole percentages of phosphodiesters (PDE) in 31 the left and right temporal region of schizophrenic patients P-MRS method arises from free mobile PDE (GPC, before (drug-naive) and after (12-week haloperidol) receiv- GPE) and mobile PDE moieties (small membrane phos- ing haloperidol for 12 weeks. Mean values (Ϯ SD) in healthy pholipid structures such as micelles and vesicles) (Mur- controls and long-term medicated patients also are shown phy et al. 1989; McNamara et al. 1994; Stanley et al. (data from our previous study: Fukuzako et al. 1996). 1997; McClure et al. 1998). The longer pre-acquisition 546 H. Fukuzako et al. NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 4

Figure 2. Correlations between changes in phosphodiesters (PDE) and changes in total Brief Psychiatric Rating Scale (BPRS) score and score for positive symptoms after 12 weeks of haloperidol treatment. delay time might yield different results (Stanley et al. determination of the origins of increased PDE is diffi- 1997). PDE are more concentrated in white matter than cult, disturbed metabolism or abnormalities in compo- in gray (Kilby et al. 1990). However, a decreased gray- nents of membrane phospholipids may not be re- to-white matter ratio would be an unlikely cause of in- stricted to the frontal lobe in the manner of the gray creased PDE level, since haloperidol treatment for 10 matter volume reduction observed in first-episode and months does not alter volumes of gray and white mat- long-term medicated schizophrenic patients (Lawrie ter (Keshavan et al. 1994). Therefore, the increase in and Abukmeil 1998; Zipursky et al. 1998). PDE may reflect an increase in GPC, GPE, and/or small In the present study an elevated level of PDE, espe- membrane phospholipid structures (McClure et al. cially in the left temporal lobe, was decreased by treat- 1998). ment with haloperidol, in contrast to the report of Ke- Several recent studies have used 1H-decoupled 31P- shavan et al. (1995), who reported increased levels of MRS to try to determine which PDE components con- PDE on pretreatment imaging but no significant tribute to the changes in PDE resonance observed in changes after four weeks of haloperidol treatment. The schizophrenic patients (Potwarka et al. 1996; Blüml et discrepancy between their results and ours may have al. 1998). A preliminary study has shown that mem- resulted from differences in patient characteristics, loca- brane or mobile phospholipids are increased in the tion of the VOI, or the MRS techniques. Only nine of the frontal lobes of medicated schizophrenic patients, sug- 15 patients studied by Keshavan group were diagnosed gesting abnormal membrane structures (Potwarka et al. with schizophrenia, while the remaining six had other 1996). Recent reports suggest that schizophrenia is asso- psychotic disorders. The VOI was located in the pre- ciated with a deficiency of arachidonic acid and docosa- frontal cortex in their study; in ours the VOI was placed hexaenoic acid in cell membranes (Horrobin 1998; Puri in the temporal lobe, which has been associated with and Richardson 1998). On the other hand, Blüml et al. positive symptoms representing reality distortion that (1998) have demonstrated elevation of GPC and GPE are alleviated substantially by administration of neuro- concentrations in the parietal lobes of young medicated leptics (Fukuzako et al. 1996; Klemm et al. 1996; Nor- schizophrenic patients compared with healthy controls dahl et al. 1996; Sabri et al. 1997). In contrast, the frontal and elderly schizophrenic patients. Although definitive lobe reportedly has been associated with negative NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 4 Phosphorus Metabolite Changes by Haloperidol 547

symptoms (psychomotor poverty) and disorganization roleptics and other therapies. Further studies regarding syndromes that often resist neuroleptic treatment (Lid- changes in metabolites with treatment using recently dle et al. 1992; Kaplan et al. 1993; Shioiri et al. 1994; De- developed in vivo 31P- and 1H-MRS techniques (Ber- icken et al. 1995). A relatively high correlation between tolino et al. 1996; Stanley et al. 1997; Blüml et al. 1998; reductions in PDE level and in scores for positive symp- Deicken et al. 1998) will help to assess such possibilities. toms lends support to VOI location as the reason for in- terstudy differences. Also, the depth-resolved surface coil spectroscopy used by the Keshavan group did not ACKNOWLEDGMENTS eliminate signals originating from the skull and cranial muscles, while our method of 2DCSI was virtually free This study was partially supported by grants from the Minis- of such artifacts. Finally, the period of haloperidol ad- try of Science, Culture, and Education (05770735 and ministration between the two scans was three times 06770764) and the National Center of Psychiatry and Neurol- longer in our study than in theirs. ogy of the Ministry of Health and Welfare (3A-5) of Japan (Dr. Administration of haloperidol for 12 weeks reduced H. Fukuzako). the level of PDE to that found in patients receiving neu- roleptic medication over long periods. However, the resonance representing PDE in the medicated patients REFERENCES still had a trend toward increase, compared with those in healthy subjects. These in vivo results may be consis- American Psychiatric Association (1987): Diagnostic and tent with biochemical findings demonstrating that in- Statistical Manual of Mental Disorders, 3rd ed, revised. 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