Psychosomatic Medicine 61:618-629 (1999)
© 1999 American Psychosomatic Society
SPECIAL ISSUE: PSYCHOPHARMACOLOGY AND PSYCHOSOMATIC RESEARCH |
Influences of Biological Rhythms on the Effects of Psychotropic Drugs
Haruo Nagayama, MD, PhD
From the Department of Neuropsychiatry, Oita Medical University, Oita, Japan.
Address reprint requests to: Haruo Nagayama, MD, PhD, Department of Neuropsychiatry, Oita Medical University, Hasama-machi, Oita-gun, Oita 879-5593, Japan. Email: nagayama{at}Oita-med.ac.jp
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ABSTRACT
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The efficacy of psychotropic drugs varies depending on the time of administration. This phenomenon is observed with antipsychotics, antidepressants, mood stabilizers, benzodiazepines, barbiturates, and psychostimulants. The presence or absence of this phenomenon and the rhythm phase in the efficacy of each drug varies depending on the drug, dose, parameter measured, animal species, and strain. A recent study demonstrating circannual changes in the phases of circadian rhythm of drug efficacy suggests that discrepancies between studies may be considerably explained by the presence of a circannual rhythm. The rhythms in drug effects are suggested not to be due to rhythmic changes in the pharmacokinetics of the drugs but rather to an endogenous rhythm in drug susceptibility resulting from a circadian rhythm in the intracerebral neurotransmission system. The presence of this phenomenon and its law have been demonstrated to a considerable extent in animals, but corresponding clinical reports in humans remain insufficient despite its clinical importance. Further study in humans is certainly warranted.
Key Words: psychotropic drug • circadian rhythm • chronopharmacology • biological rhythm • neurotransmitter • receptor
Abbreviations: DOI = 2,5-dimethoxy-4-iodophenyl-2-aminopropane hydrochloride; GABA = 
-aminobutyric acid; 5-HIAA = 5-hydroxyindole aceticacid; 5-HT = serotonin; 5-MeODMT =5-methoxy-N,N-dimethyotryptamine; 8-OH-DPAT =8-hydroxy-2-(di-N-propylamino)tetralin.
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INTRODUCTION
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Most physiologic functions have a rhythm with a period of approximately 24 hours. Drug efficacy also varies markedly within the 24-hour period depending on the time of administration (1). This phenomenon is extremely significant for pharmacologic studies and clinical practice and applies to psychotropic drugs, such as antipsychotics, antidepressants, mood stabilizers, benzodiazepines, barbiturates, psychostimulants, and a variety of neurotransmitter agonists. Presented here is a review of the rhythmicity of the effects of psychotropic drugs depending on the time of administration and the underlying mechanism of the rhythm.
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RHYTHMS IN THE EFFICACY OF PSYCHOTROPIC DRUGS
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Antipsychotics
Rhythms in drug efficacy that are dependent on the time of administration have been reported for chlorpromazine, haloperidol, tetrabenazine, reserpine, spiperone, and pimozide (see Table 1). The waveform, or rhythm phase, varies with drug, dose, and the measured parameter. In rats, the optimal time of administration for maximum antiapomorphine effects (expressed as the "peak time" below) is in the early dark period for chlorpromazine (2) and in the early light period for haloperidol (3). Furthermore, the maximum effect for spiperone is in the early light or early dark period (unpublished data) and for pimozide, in the middle dark period (unpublished data). Thus, the rhythm phase in drug efficacy is different among drugs, even when the same parameters are compared.
The peak time for the sedative effect of chlorpromazine (4) at a dose of 2.5 to 5 mg/kg is the middle light period, whereas for a dose of 10 mg/kg, the peak time shifts to the middle dark period. A similar tendency is observed for haloperidol (3); ie, at 0.5 to 1 mg/kg, the peak time is the early light period, and at 2 to 8 mg/kg, it is the middle dark period, indicating that the rhythm phase varies with the dose even for the same drug. Generally, the peak time shifts forward as a function of increased dose. This tendency in the rhythm of drug efficacy, however, is dependent on the parameter measured. A dose-dependent shift of the peak time for the antiapomorphine effects is not observed for either chlorpromazine (2) or haloperidol (3).
The peak time for the sedative effects of chlorpromazine is the middle light or middle dark period (4); for antiapomorphine effects, the early dark period (2); and for hypothermic effects, the middle light period (5). The peak time for the sedative effects of haloperidol is either the early light period or the middle dark period, whereas it is the early light period for the antiapomorphine effects (3). These results indicate that the rhythm phase varies with the parameter measured, even for the same drug.
Antidepressants and Mood Stabilizers
The rhythms in drug effects have been clinically applied using antidepressants (Tables 1 and 2). Lofepramine has been shown to have a greater antidepressant effect during a 3-week course of therapy when administered at 2400 than when administered 0800 or 1600 (6). Furthermore, the antidepressant effects of clomipramine during 4 weeks of therapy varied depending on the time of administration (7). In this case, administration at noon was more effective than administration in the morning or evening, suggesting that the phase of rhythm in the efficacy was different from that of lofepramine.
In animal studies, fluoxetine suppressed the intake of carbohydrates only when administered in the early dark period but not at the other two times examined (8). The effects on feeding behavior have been investigated with the 5-HT1A receptor agonist, 8-OH-DPAT (9), and L-norepinephrine (10), neither of which is an antidepressant. Feeding behavior decreased after administration of 8-OH-DPAT in the early dark period but increased after administration in the middle dark period or the latter half of the dark period. Also, feeding behavior was decreased by L-norepinephrine administered in the early dark period but was increased after administration in the latter half of the light period. The fact that there are not only quantitative differences in drug effects but also opposite effects depending on the time of administration further emphasizes the significance of this phenomenon.
Benzodiazepines and Barbiturates
The results of rotarod tests in mice conducted after administration of lorazepam are different depending on the time of administration (11) (see Tables 1 and 2).
Many animal studies of the sleep duration effects of pentobarbital (12–15) and hexobarbital (16–18) have been conducted. Most of these studies produced the consistent result that maximum effects were obtained after administration in the latter half of the light period to the early dark period. Intracerebral dopamine levels after administration of phenobarbital (19) vary within the regions of the brain; ie, for the caudate and midbrain, the peak time is the early light period and latter half of the light period, respectively, and for the cerebellum and cortex, the peak time is in the final light to middle dark period (Table 1).
Psychostimulants
Most of the animal studies of amphetamines (5, 20, 21) have consistently concluded that the peak time is the latter half of the dark period, but one report (5) indicated the presence of another peak time in the latter half of the light period (see Tables 1 and 2).
Agonists and Related Compounds
For subcutaneous injection of 8-OH-DPAT in rats, the peak time is the middle dark period for the 5-HT syndrome (22) or hypothermia (23); the peak time for intraventricular injection is the same (24) (see Table 1). These results strongly suggest that the peak efficacy times of the subcutaneous injection are not due to pharmacokinetics (eg, drug absorption, excretion, metabolism, and distribution) but rather to a rhythm in the susceptibility of the postsynaptic 5-HT1A receptor, which is the site of action for 8-OH-DPAT. However, results of one study indicate that there is no rhythm in the hypothermic effects of the drug (25). This discrepancy may be due to the subjects used in these studies; rats were used in the first study, and mice were used in the second. 8-OH-DPAT acts postsynaptically on the 5-HT1A receptor in the rat but on other sites in the mouse.
The effects of 5-HT (26), 5-hydroxytryptophan (27), 5-MeODMT (a nonselective 5-HT receptor agonist) (28, 29), p-chloroamphetamine (29), and DOI (a selective 5-HT2A/2C agonist) (30) on the 5-HT system undergo rhythmic changes depending on the time of administration, although there is some controversy. These discrepancies may be related to the receptor specificity of individual drugs. The efficacy of apomorphine, a dopamine agonist, peaks in the light period for both stereotypy (21, 31) and hypothermia (32) and in the dark period for locomotion (21).
In addition to the studies described above, there are several studies that have used only two administration times. In general, when a difference is observed between results obtained at two time points in a study in which only two time points were used without any special setting, there is a slight possibility that a circadian rhythm exists. If, however, no difference is observed between the results at two time points, the presence or absence of a rhythm cannot be judged. In this review, animal studies were included only if four or more time points were analyzed; human studies that analyzed three or more time points were also included, but studies using only two time points are also included in Table 2 for reference.
Endogenicity of Circadian Rhythm in the Effect of Psychotropic Drugs
In general, there are two types of periodic changes with a 24-hour cycle. One is an endogenous circadian rhythm, and the other is an exogenous factor–induced rhythm-like phenomenon. Experimental methods using constant conditions have been performed to discriminate between the two phenomena. Rhythmicity in the effects of psychotropic drugs has been demonstrated even under constant conditions (33, 34), suggesting that it is an endogenous rhythm, ie, a circadian rhythm in a narrow sense.
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RHYTHMS IN THE PHARMACOKINETICS OF PSYCHOTROPIC DRUGS
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There are many reports on the changes in the pharmacokinetics of psychotropic drugs depending on the time of administration. In all of the human studies, however, the effects of administration time have been compared between only two time points. Therefore, there is not enough information to determine whether a circadian rhythm is present in the pharmacokinetics.
In animal experiments (Table 3 ), rhythms are observed in enzyme activities for drug metabolism in the liver for imipramine (35) and hexobarbital (16–18, 35). The rhythms of those enzyme activities might help to elucidate the underlying mechanism of the rhythms in the drug effect. Rhythms in enzyme activity must be reflected, however, by the blood levels of a drug in order for the reflection of the rhythms in enzyme activity to be considered one of the drug’s effects. The results of studies comparing drug levels among four or more different administration times are controversial (5, 36–39). Peak time is the time of administration for maximum effects. AUC = area under the curve; ka = absorption rate constant; MRT = mean resident time; Vdss = steady-state volume of distribution.
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Table 3. Circadian Rhythms in Blood and Brain Concentration, Hepatic Metabolism, and Clearance of Psychotropic Drugs, Animal Studies
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To prove that the rhythm in drug efficacy is induced by a rhythm in pharmacokinetics, including absorption, metabolism, excretion, and distribution of the drug, it is necessary to demonstrate rhythmic changes in drug concentrations in both blood and brain. In addition, it is necessary to demonstrate a reasonable relation between the waveforms of the rhythms of the drug levels and in the effects. Many authors have investigated the rhythm in the drug efficacy in relation to the drug concentration in the brain, and all of the studies denied a correlation between the rhythm in the drug efficacy and the intracerebral drug level (3–5, 11, 15, 40–42) (Table 3). There were no significant differences in the intracerebral drug concentration among different administration times that resulted in a different effect. Thus, the hypothesis that the rhythm in the effect of psychotropic drugs might be induced by the rhythm of the drug level in the blood and in the brain is not supported.
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CIRCANNUAL RHYTHM IN THE EFFICACY OF PSYCHOTROPIC DRUGS
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We recently reported that the phases of circadian rhythm in the efficacy of 8-OH-DPAT exhibit a 1-year variation. As stated above, the response to 8-OH-DPAT shows a circadian rhythm in rats. This rhythm was observed in every month in which an experiment was performed; the phase of the rhythm shifts regularly month after month, and the same approximate rhythm appears in the same month of different years. Furthermore, the width of monthly changes in rhythm is as large as 9 hours. Because the rhythm was observed in animals raised in a laboratory isolated from the natural environment, it was not thought to be due to variations caused by seasonal changes, such as temperature and photoperiodicity, but rather to some endogenous factors (43) (Figure 1 ). Discrepancies between studies in the phase of circadian rhythms in drug efficacy, even for an identical drug, may be partially explained by the presence of a circannual rhythm. There is no other season-controlled study than the one mentioned above.
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Fig. 1. Circadian rhythms in 8-OH-DPAT–induced forepaw treading and head weaving (5-HT syndrome), observed in five experiments performed at 3-month intervals. Values are the mean ± SD of eight animals. The black bar corresponds to the dark period. *p < .05, **p < .01, ***p < .001, ****p < .0001 (analysis of variance). Reproduced with permission from Springer-Verlag, from Nagayama H, Lu J-Q. Circadian and circannual rhythms in the function of central 5-HT1A receptors in laboratory rats. Psychopharmacology 1998;135:279–83.
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RHYTHMS IN THE EFFICACY OF PSYCHOTROPIC DRUGS AND THE NEUROTRANSMISSION SYSTEM
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Rhythm in the Intracerebral Neurotransmission System
Although the amount of drug that enters the brain is the same, the effects vary depending on the time of administration. This suggests the presence of a rhythm in drug susceptibility of the brain. The results of direct drug administration into the brain (10, 24) strongly support the hypothesis. This is also supported by rhythmic properties, which vary in relation to the dose, parameter measured, and brain region even for the same drug. It is difficult to explain these findings using pharmacokinetics. In addition, the parameters measured may have rhythms in efficacy with different phases because the phase of the drug susceptibility rhythm varies from region to region in the brain.
Rhythms have been reported for various neurotransmitters, receptors, enzymes, and the second messenger system in the brain. For this review, only the studies in which determinations were made in various regions other than the pineal body, at least six different times, were analyzed. Because the presence of a rhythm under constant conditions (44–46) and its disappearance after ablation of the suprachiasmatic nucleus (47) were demonstrated, the rhythms are considered to be endogenous, although there is one study with results that contradicts this evidence (48).
The presence of a circadian rhythm has been reported for neurotransmitters and their related substances, such as 5-HT (49–70), norepinephrine (51, 54, 57, 60–63, 66, 71–74), dopamine (19, 54, 62, 66, 72, 75–77), 5-HIAA (53, 55, 58, 65–69, 77–79), tryptophan, tyrosine, 5-hydroxytryptophan, 3-methoxy-4-hydroxyethyleneglycol, homovanillic acid, epinephrine, 3,4-dihydroxyphenylglycol, 3,4-dihydroxyphenylacetic acid, 3-methoxy-4-hydroxyphenylethyleneglycol, acetylcholine, GABA, and cholecystokinin. The rhythm phases were different among these substances. Also, the rhythm phases were different among various animal species (56, 57), strains (78), brain regions (60, 66, 69), and ages (62), even within a study. The rhythms also vary by discrete regions obtained by more detailed dissection, even within the same cortex (44). Most of these rhythms have a single peak. A bimodal rhythm is observed, however, for some substances.
A rhythm with a 24-hour period is observed for 5-HT, 
-adrenergic (45, 80–83), ß-adrenergic (45, 80–84), dopamine (81, 85, 86), GABA, benzodiazepine, imipramine, muscarinic, adenosine, and naloxone receptors. The tendencies of the discrepancies in the rhythm phases observed in these receptors are similar to those of neurotransmitters. These properties vary in complicated ways according to animal species (45, 86), brain region (83), age (87), and season (79, 80, 85, 88).
The enzyme activities related to neurotransmitters also have a circadian rhythm. Rhythm has been reported for the activities of tryptophan hydroxylase (69, 89–92), tyrosine hydroxylase, monoamine oxidase, tyrosine aminotransferase, dopamine-ß-hydroxylase, phenylethanolamine-N-methyltransferase, choline acetyltransferase, acetylcholinesterase, and glutamic acid decarboxylase. Although there are only a few of these reports, the results indicate that rhythmicity is different among different animal strains (90, 93), ages (62), and brain regions (62, 69).
The second messenger system also has a rhythm in cyclic adenosine monophosphate and cyclic guanidine monophosphate levels and in adenylate cyclase and phosphodiesterase activities. The presence of the rhythm and the phase are affected by animal strain (94) and brain region (44).
As described above, individual neurotransmitter systems have inherent rhythms. The main reasons for the differences in rhythm phase among studies may be that the phase depends on the species, strain, and age of animals and on brain regions. Even if these factors are taken into account, however, a discrepancy still remains. Seasonal changes in phase (79, 80, 85) may be a reason for this discrepancy, but season-controlled studies are rarely performed. Season control would greatly reduce the discrepancies. Another important issue is the method used to measure rhythms. Usually, a rhythm is not continuously measured over time in a single animal; instead, a group mean obtained from several animals is used to characterize the rhythm, which is measured only once in each animal at a given time point. Thus, it is desirable to establish a method by which the level of intracerebral substances in individual cerebral regions can be measured continuously for a long time in a single animal under freely moving conditions.
It is unlikely that these rhythms change without mutual dependency. It seems that the signals emitted from the suprachiasmatic nuclei are transmitted to each neurotransmitter system to produce a rhythm network that allows integral control of the brain as a whole through interactions among the respective rhythms. Some of these rhythms have amplitudes as large as several hundred percent. These results suggest that these rhythms must be regarded as one of the most important factors for investigation of various brain functions. In addition, studies of the mechanisms of the rhythm in drug efficacy can be used to investigate the causal mechanisms of drug action and brain function in general.
Rhythms of the 5-HT and Norepinephrine-Dopamine Systems in the Brain
The rhythm of the neurotransmission system in the brain might be affected by a large number of factors. To gain a general understanding of their operation, the tendencies of the 5-HT and norepinephrine-dopamine systems in the rat brain, which are closely related to the rhythm in the efficacy of psychotropic drugs, were analyzed. The number (frequencies) of peak times in the rhythms of substances in the above-mentioned studies are presented in Figure 2 .
Figure 2, A, shows the peak times of activity for tryptophan hydroxylase, 5-HT, and its metabolite, 5-HIAA. Tryptophan hydroxylase activity increases in the latter half of the dark period, resulting in enhanced 5-HT synthesis. Thus, the accumulation of 5-HT reaches a maximum level during the middle light period to the latter half of the light period, and the utilization of 5-HT is enhanced in the middle dark period, leading to an increase of 5-HIAA. An increase in the extracellular level of 5-HIAA during the dark period in rats has been observed using in vivo voltametry (79) and in vivo microdialysis (77). These findings are consistent with the findings of Hery et al. (95).
That the 5-HT releasers, tetrabenazine (40) and reserpine (96), are more effective during a dark period may reflect the activated release of 5-HT during the dark period. The effect of the 5-HT uptake blocker, clomipramine (7), is stronger at noon in humans. This may also be due to an increase in 5-HT release at noon (middle stage of activity), and, consequently, the uptake blocking effect becomes greater. Generally, drugs that have presynaptic effects seem to be more susceptible to the direct effects of their transmitter’s rhythm.
The waveform of the rhythm in the efficacy of 8-OH-DPAT is the mirror image of the waveform of the rhythm in the wet-dog-shake response to DOI. DOI is a selective agonist for the 5-HT2A and 5-HT2C receptors, and the wet-dog-shake response is a 5-HT2A receptor–mediated behavior that is not related to the 5-HT2C receptors. Because a rhythm in the effect of agonists is thought to be most greatly affected by the susceptibility rhythm of the relevant receptors, the 5-HT1A and 5-HT2A receptors are considered to have mirror-image waveforms in their susceptibility rhythm. Thus, it is thought that the rhythm of a neurotransmitter probably does not directly mediate the rhythm of its corresponding receptors.
The levels of norepinephrine and dopamine reach a peak during the middle dark period, followed by an increase in the numbers of - and ß-adrenergic receptors in the middle to terminal dark period (Figure 2, B). Many studies have demonstrated that the effects of amphetamine, an indirect dopamine agonist (5, 20, 21), reach a peak in the latter half of the dark period. In this period, when the level of the dopamine metabolite, homovanillic acid (not presented in the figure), reaches a peak, dopamine release might easily occur. The fact that amphetamine enhances dopamine release might be the reason that the rhythm in the efficacy of amphetamine reaches a peak in the latter half of the dark period.
Thus, even in the norepinephrine-dopamine system, presynaptically acting drugs may be affected by the rhythm of the relevant transmitters. This is not the case for postsynaptically acting drugs. The dopamine agonist, apomorphine, has a peak of the rhythm in efficacy in the light period in rats (31, 32, 41). Different antipsychotics have different peak rhythms. It is difficult to explain these facts from the above-mentioned dopamine rhythm. Thus, the study of rhythm of the dopamine receptor is necessary, but the reported phase of the dopamine receptor differs from study to study. This discrepancy is thought to be due mainly to the fact that agonists that are highly specific for individual receptor subtypes have not been used. It is necessary to clarify the waveform of rhythm for each receptor subtype and for each brain region.
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CLINICAL APPLICATION OF RHYTHMS IN DRUG EFFICACY
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The rhythms in drug efficacy found in animals for many drugs have also been confirmed in humans (1), and some psychotropic drugs have been confirmed to show such rhythms in animals and humans. On the basis of these findings, it is likely that psychotropic drugs may generally exhibit similar rhythms in humans.
What, then, can be expected when the results of animal experiments are applied to humans? We attempted to assess the clinical relevance in humans of our findings of the rhythm phase observed in rodents by administering a comparable clinical dose, taking into account that antiapomorphine effects correlate well with antipsychotic effects and that the pattern of daily activity in humans is opposite of that in rodents. As a result, it was speculated that chlorpromazine would be most effective in producing sedative and antipsychotic effects when administered at midnight and immediately after rising, respectively. For haloperidol, administration in the evening would be best for obtaining either a sedative or antipsychotic effect. That the phase of rhythm differs depending on the parameters measured suggests that the time of administration can be selected to optimally treat a target symptom or to minimize an adverse reaction. Furthermore, because different drugs have different phases of rhythm in efficacy even for the same symptom, this may further enhance the applicability of time of drug administration.
These suggestions, however, do not mean that once-a-day administration is always optimal. Also, in the case of divided administration, an uneven division corresponding with rhythms in efficacy and adverse reactions can be used instead of the commonly used even division. Whether administration should be made once daily at the time when drug susceptibility is maximal, or whether a large dose should be administered at the time of low susceptibility along with unevenly divided smaller doses at the time points of high susceptibility, should be studied for individual drugs.
Utilizing this phenomenon, we may be able to reduce the daily drug doses that are currently prescribed. Considering that psychotropic drugs are usually administered in large doses and over long periods of time and that the drugs show a variety of adverse reactions, the clinical significance of this phenomenon is potentially quite significant. The rhythmicity in efficacy was also observed in chronically treated animals (42), suggesting further clinical application.
Even if a rhythm in drug efficacy is present in humans, not only similarities but also differences in phase rhythm are likely to exist between animals and humans. Therefore, it is necessary to reconfirm these matters in humans, referring to results from animal experiments. Because it has been confirmed by animal experiments that individual drugs have different phases, the waveform of rhythm for individual drugs based on their clinical doses must be confirmed. The biological rhythms of individual patients, particularly shift workers, must also be taken into account. In addition, the time of administration is generally an important factor in clinical investigations.
Some adverse effects of psychotropic drugs have different consequences depending on the time of onset in relation to a patient’s particular lifestyle. For example, drowsiness due to psychotropic drugs is an adverse reaction disturbing daily life when it occurs during the day but may be considered beneficial when it occurs at night. This is certainly one important matter we confront with administration of antipsychotic drugs to patients. This matter, however, is independent of the importance of rhythms in drug efficacy and adverse reactions. For example, the same sedative effect described above may be a required drug effect all day long for some patients. In any case, this matter is independent of the main subject of this review; therefore, no further discussion is presented here.
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CONCLUSION
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There is a circadian rhythm in the efficacy of psychotropic drugs. This phenomenon has been studied in many animal species and confirmed in humans. Although there are various discrepancies among reports, such discrepancies will be considerably decreased by season-controlled administration studies. Some discrepancies may still remain unexplained but may be due to other methodological difficulties. In the research of rhythms, experimental animals should be raised under strict conditions. Room temperature and humidity must be kept constant, and only artificial illumination should be used to accurately control the time of illumination and complete darkness. In addition, noise from the environment must be muted, and the animal room should be cleaned at random time intervals under a dim red light. Only animals raised under such conditions for at least 3 to 4 weeks should be used for experiments. Illuminating conditions on drug administration during a dark period as well as conditions for observing the responses of animals after drug administration should also be controlled strictly. In some previous reports, some of these conditions were not described distinctly.
For wider clinical application of this phenomenon, it is necessary to identify the rhythm phases of each drug effect and the adverse reaction to a number of psychotropic drugs. Moreover, there are many other problems to overcome, such as whether once-a-day administration is desirable, whether unevenly divided administration is desirable, and, in the case of unevenly divided administration, the most desirable division. It is strongly suggested, however, that more effective treatment can be obtained by utilizing this phenomenon.
These rhythms seem to be endogenous circadian rhythms resulting from the rhythmicity in drug susceptibility of the brain, which is not dependent on drug pharmacokinetics. The rhythm is attributed to the rhythms in the neurotransmission system, such as neurotransmitters, receptors, and second messengers.
The causal mechanism of the rhythms in the efficacy of presynaptically acting drugs may be explained to some extent by the rhythm of the neurotransmitters, whereas that of postsynaptically acting drugs is difficult to explain on the same basis. It is necessary to elucidate the waveform of rhythm for each receptor subtype and for each brain region. It is also necessary to develop a technique capable of continuously measuring the rhythm of the neurotransmitter systems from individual animals over a long period of time.
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ACKNOWLEDGMENTS
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This research was supported by Grant-in-Aid for Scientific Research 09670998 from the Japanese Ministry of Education, Science, and Culture.
Received for publication June 5, 1998.
Revision received March 10, 1999.
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O. G. Cameron
Psychopharmacology
Psychosom Med,
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ABSTRACT
INTRODUCTION
), and tryptophan hydroxylase (
). B, Norepinephrine-dopamine system: norepinephrine (
),