Bipolar Disorders 2000: 2: 77–92Printed in Ireland. All rights reser6ed
I-Shin Shiaha,b and LakshmiN Yathama
a Division of Mood Disorders, Departmentof Psychiatry, University of BritishColumbia, Vancouver, British Columbia,Canada, b Department of Psychiatry,Tri-Service General Hospital, NationalDefense Medical Center, Taipei, Taiwan,ROC
Key words: anticonvulsants – bipolardisorder – 5-HT – lithium – mania –mood stabilizers – serotonin
Received 7 May 1999, revised andaccepted for publication 9 July 1999
Corresponding author: Lakshmi N Yatham,MBBS, FRCPC, MRC Psych (UK), Associ-ate Professor in Psychiatry and Director,Mood Disorders Clinical Research Unit, De-partment of Psychiatry, The University ofBritish Columbia, 2255 Wesbrook Mall,Vancouver, BC, V6T 2A1, Canada. Fax:+1 604 8227922; e-mail:[email protected]
Review
Serotonin in mania and in the mechanism ofaction of mood stabilizers: a review ofclinical studies
Shiah I-S, Yatham LN. Serotonin in mania and in the mechanism ofaction of mood stabilizers: a review of clinical studies.Bipolar Disord 2000: 2: 77–92. © Munksgaard, 2000
Objecti7es: Serotonin (5-hydroxytryptamine, 5-HT) was implicated inthe pathophysiology of manic-depressive illness as early as 1958. Al-though extensive evidence has accumulated since then to support 5-HT’s role in depression, relatively fewer studies examined its role inmania. The purpose of this paper was to review and summarize thecurrent state of knowledge on the role of 5-HT in mania and its treat-ment.
Methods: We systemically reviewed clinical studies of 1) 5-HT functionin mania and 2) 5-HT in the mechanism of action of mood stabilizers,including lithium and anticonvulsants.
Results: Review showed that cerebrospinal fluid, postmortem, platelet,neuroendocrine challenge, and tryptophan depletion studies providedsome evidence to support the hypothesis that a 5-HT deficit is involvedin mania and that enhancement of 5-HT neurotransmission exerts amood-stabilizing effect.
Conclusions: There is some evidence from clinical studies for the contri-bution of 5-HT in mania and in the mechanism of action of moodstabilizers. However, it is very likely that other neurotransmitters alsoplay important roles. Future directions for research include 1) in 6i6ostudy of 5-HT receptor subtypes using positron emission tomography,2) investigation of the interaction between 5-HT and other neurotrans-mitter systems, and 3) determination of the relationships between diag-nostic subtypes of mania and 5-HT function and otherneurotransmitter systems.
Serotonin (5-hydroxytryptamine, 5-HT) is an im-portant neurotransmitter within the central ner-vous system (CNS). The amount of 5-HT in theCNS is about 1–2% of that in the body (1). Be-cause this indoleamine transmitter cannot cross theblood–brain barrier, all the neuronal 5-HT is syn-thesized locally (1, 2). The synthesis of 5-HT in thebrain involves 1) uptake of the essential amino acidL-tryptophan, which is a primary substrate for thesynthesis, from plasma into serotonergic neurons,2) hydroxylation of L-tryptophan to 5-hydroxy-tryptophan (5-HTP) via the enzyme tryptophanhydroxylase, and 3) decarboxylation of 5-HTP to5-HT through the enzyme aromatic amino acid
decarboxylase (2). It appears that 5-HT can besynthesized in both cell bodies and nerve terminals(2). 5-HT synthesized in the cell body is trans-ported into the terminals of dendrites and axonsfor release. Following its release, 5-HT is eitherinactivated by re-uptake into serotonergic nerveterminals, or interacts with a complex system ofreceptors. Once back inside the serotonergic neu-ron, this neurotransmitter is either re-stored in thevesicles or metabolized by the enzyme monoamineoxidase (MAO) and then converted into an inac-tive metabolite, 5-hydroxyindoleacetic acid (5-HIAA). To date, based on pharmacological ormolecular properties, at least 14 types of 5-HT
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receptors have been identified in the mammalianbrain (3, 4). They are 5-HT1A, 5-HT1B, 5-HT1D,5-HT1E, 5-HT1F; 5-HT2A, 5-HT2B, 5-HT2C; 5-HT3,5-HT4; 5-HT5A, 5-HT5B, 5-HT6, and 5-HT7 recep-tors. Except for the 5-HT3 receptors, which areligand-gated ion channels, all 5-HT receptor sub-types belong to the superfamily of G-protein-cou-pled receptors (1, 5).
With regard to neuronal innervation, ascendingserotonergic fibers arise principally from two mid-brain nuclei, the dorsal raphe and the medianraphe, and project to virtually all forebrain re-gions, including thalamus, hypothalamus, caudate-putamen, hippocampus, and neocortex (6, 7). Thewidespread distribution of the serotonergic projec-tions may partially explain why alterations in 5-HTfunction in the brain would lead to modification ofa variety of physiological and behavioral re-sponses, such as sleep and wakefulness, food in-take, sexual activity, impulse control, learning andmemory (8, 9).
Given that 5-HT is involved in a variety ofphysiological and behavioral responses, it is notsurprising that disturbance in 5-HT function hasbeen implicated in the pathophysiology of manypsychiatric disorders, including mood disorders.5-HT was implicated in the pathophysiology ofmanic-depressive illness by Strom-Oslen and Weil-Malherbe as early as 1958 (10). However, Prangeet al. (11) were the first to formulate the permissivehypothesis of 5-HT function for bipolar disorder.They postulated that a deficit in central serotoner-gic neurotransmission permits the expression ofbipolar disorder, and that both the manic and thedepressive phases of bipolar disorder are character-ized by low central 5-HT function, but differ inhigh versus low central catecholaminergic (i.e.,norepinephrine (NE) and dopamine (DA)) neuro-transmission. This hypothesis was primarily basedon 1) the clinical observation that L-tryptophan,the precursor of 5-HT, was efficacious in the treat-ment of mania (11), 2) some earlier studies reveal-ing decreased levels of the 5-HT metabolite,5-HIAA, in cerebrospinal fluid (CSF) in both ma-nia and depression (12–14), and 3) the animalstudies showing that lithium enhanced brain 5-HTfunction (15–17). Although extensive evidence hasaccumulated since then to support a role for 5-HTin depression [(18–22) for review], relatively fewerstudies examined its role in mania. This undoubt-edly relates to the difficulty in recruiting drug-freemanic patients for research studies.
The purpose of this paper was to review andsummarize the current state of knowledge on therole of 5-HT in mania and its treatment. We sys-temically reviewed clinical studies of 1) 5-HT func-
tion in mania and 2) 5-HT in the mechanism ofaction of mood stabilizers, including lithium andanticonvulsants. We also discussed the limitationsof these studies and indicated future directions forresearch.
5-HT function in mania
Several approaches have been used to study 5-HTactivity in mania: 1) CSF studies, 2) postmortemstudies, 3) platelet studies, and 4) neuroendocrinechallenge studies.
Cerebrospinal fluid studies
CSF studies measured the levels of 5-HIAA, themajor metabolite of 5-HT, with the assumptionthat 5-HIAA levels provide an index of central5-HT activity (23, 24). Although half the concen-tration of lumbar 5-HIAA comes from the spinalcord (25, 26), the 5-HIAA levels in lumbar CSFmay still reflect brain functioning, since many 5-HT axons and nerve terminals in cord originate infunctionally important brain stem nuclei. Indeed ithas been shown that lumbar CSF 5-HIAA concen-trations do correlate with brain 5-HIAA in hu-mans (27).
Studies of CSF 5-HIAA in manic patients haveproduced variable and inconsistent results. Forexample, baseline CSF 5-HIAA levels in manicpatients, compared to ‘non-depressed’ controls,have been reported as decreased in four studies(12–14, 28), unchanged in nine studies (29–37),and increased in three studies (38–40). However,when baseline CSF 5-HIAA levels were comparedbetween manic and depressed patients, the resultsof previous studies were much more consistent.With the exception of one study (29), all otherstudies found that CSF 5-HIAA levels in manicswere not different from depressed patients (13, 14,28, 30–33, 36–38, 40, 41).
Administration of probenecid blocks the activetransport of 5-HIAA out of the CSF, leading toaccumulation of 5-HIAA levels in CSF (42, 43).This provides a more dynamic measure of centralserotonergic activity than the basal level of CSF5-HIAA (44–46). Of the four studies that exam-ined CSF 5-HIAA accumulation following admin-istration of probenecid in manics, depressives, andcontrols (30, 32, 38, 47), two reported that bothmanic and depressed patients have diminished CSF5-HIAA formation compared to controls (38, 47),and one reported that manic patients have signifi-cantly lower CSF 5-HIAA accumulation than de-pressives and controls (30). Furthermore, Goodwinet al. (32) found that manic and depressed patients
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have similar CSF 5-HIAA levels 18 h after admin-istration of probenecid. Although there were nocontrol group data available for their 18-h study,comparison with values obtained in the controlsover a 9-h period suggested that the rate of accu-mulation of 5-HIAA in both the manic and de-pressed patients may have been reduced (46).Taken together, the results of the probenecid-in-duced accumulation studies appeared to supportthat both mania and depression are associated witha reduction in central 5-HT function.
Postmortem studies
The only study that assessed 5-HT and 5-HIAAlevels in postmortem brains of subjects with awell-documented history of bipolar disorder re-ported significantly lower 5-HIAA levels and lower5-HT/5-HIAA ratios in frontal and parietal cortex,compared to postmortem brains from controls(48). The results of this study, therefore, provide asupport for regional decreases in central 5-HTactivity.
Platelet studies
Platelets share many properties with central 5-HTneurons, such as uptake, storage, and release of5-HT, 5-HT receptors and imipramine-bindingsites (49, 50). They are easily accessible for study,and therefore have been used as a peripheral modelfor 5-HT neurons to study 5-HT function in psy-chiatric patients.
Platelet 5-HT uptake. Meltzer et al. (51) examined5-HT uptake in 14 manic patients in comparison to20 healthy controls. They noted a tendency for adecrease in 5-HT uptake in four manic patientsand an increase in seven manic patients, but manicpatients as a group did not differ significantly fromhealthy controls. Similarly, Scott et al. (52) re-ported no difference in 5-HT uptake in eight manicpatients compared to 26 healthy controls. Meagheret al. (53) reported increased 5-HT uptake in 15manic patients compared to 19 healthy controls.However, manic patients as a group had a largevariation in their 5-HT uptake compared to thecontrol group in this study that could very well bedue to the effects of medication. Indeed, when fivedrug-free manic patients in this study were com-pared with controls, the 5-HT uptake was notdifferent between the two groups. Marazziti et al.(54), on the other hand, reported decreased 5-HTuptake in seven manics compared to 12 healthycontrols. Of the seven manics, only three weredrug-free, which confounds the interpretation ofresults.
Platelet imipramine-binding site. The imipramine-binding site that is present in both 5-HT neuronsand platelets appears to be closely linked to the5-HT active transport site. The binding affinity ofthis site to imipramine in platelets has been exam-ined to gain information about 5-HT neuron func-tion in manic patients. Of the four studies thatexamined imipramine binding in manic patients,two showed an increase (55, 56), while the othertwo showed no difference (57, 58) in binding inmanics compared to depressed patients. However,all four studies reported that binding was not dif-ferent in manics when compared to healthycontrols.
Taken together, the results of platelet studiesthat assessed 5-HT uptake or tritiated imipraminebinding did not show any consistent differencesbetween manic patients and controls. The dis-crepancy in findings between studies could be dueto methodological differences or problems, such aspatient heterogeneity, confounding effects of psy-chotropic medication, and sample sizes.
Other platelet 5-HT measures. In addition toplatelet 5-HT uptake and [3H]-imipramine binding,5-HT-induced platelet calcium mobilization, a pu-tative measure of 5-HT2 receptor sensitivity (59,60), has also been examined in patients with ma-nia. Okamoto et al. (61) reported that there is anincrease in the rapid peak and prolonged plateauphase in platelet intracellular Ca2+ mobilization inten untreated acute manic patients compared to 14matched healthy subjects and ten euthymic bipolarpatients treated mainly with lithium. As for therapid peak, a similar result was also obtained inplatelets of patients with bipolar depression (62).This may suggest an increase in the sensitivity of5-HT2 receptors in both mania and bipolar depres-sion. In support of this hypothesis, a recent ex 6i6ostudy (63) showed that administration of 5-HT ledto a significant elevation in platelet intracellularcalcium levels in patients in both the manic anddepressive phases of bipolar disorder, compared tonormal controls and bipolar euthymic patients. Incontrast, a recent study, using [125I]-ketanserin asthe radioligand, reported that platelet 5-HT2 recep-tor-binding sites in 29 drug-free male manic pa-tients were not different from those in 29 malehealthy controls (64). Furthermore, another probefor assessing 5-HT2 receptor sensitivity, theadenosine diphosphate (ADP)-augmented 5-HT-induced platelet aggregation response, was re-ported to be significantly lower in both manic anddepressed patients compared to normal controls,and it was reversed following clinical recovery (65).The discrepancy between the studies that examined
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platelet 5-HT2 receptor-mediated activity couldbe due to the differences in patient populationsand/or to the nature of the means of measuringplatelet 5-HT2 receptor activity.
Neuroendocrine challenge studies
The neuroendocrine challenge paradigm offers auseful means of assessing central (hypothalamic)5-HT function. This approach is based on theobservation that 5-HT exhibits an excitatory in-fluence on the release of cortisol, adrenocorti-cotropic hormone (ACTH), prolactin, and possi-bly growth hormone (GH) [(66, 67) for review],and the assumption that the extent of release ofhormones following a challenge with the 5-HTagonist provides an index of the responsivity ofthe 5-HT system (68). Depending upon the probeemployed, it is possible to assess the ‘net’ central5-HT activity or the sensitivity of various 5-HTreceptor subtypes (68).
This paradigm has been used extensively to as-sess 5-HT function in depression [(69–71) for re-view] and other psychiatric disorders [(72–74) forreview]. There are a total of six neuroendocrinechallenge studies to date that examined the roleof 5-HT in mania by using different serotonergicprobes. Studies that examined prolactin responsesto serotonergic probes in manic patients haveyielded conflicting results. Yatham (75, 76) re-ported no significant differences in prolactin re-sponses to buspirone or D,L-fenfluramine betweenmanic patients and matched healthy controls. Incontrast, Thakore et al. (77) demonstratedblunted prolactin response to D-fenfluramine, amore selective 5-HT probe, in manic patients incomparison to healthy subjects. The discrepanciesin the prolactin responses between studies arelikely to be due to difference in drug selectivity.It has been suggested that buspirone and D,L-fenfluramine possess additional dopamine effects,whereas D-fenfluramine has more specific 5-HTeffects with stimulation of 5-HT release and inhi-bition of its reuptake (78). Since D-fenfluramine-induced prolactin release is considered to reflect‘net’ 5-HT activity (79), the finding of Thakore etal. (77) would suggest that ‘net’ 5-HT activity isdecreased in mania, presumably due to low 5-HTavailability in central 5-HT synapses. This wouldbe expected to lead to enhanced postsynaptic 5-HT receptor sensitivity (80).
In keeping with this hypothesis, we, in a recentstudy using a selective 5-HT1A agonist ipsapirone(81), found that manic patients have enhanced
ACTH and cortisol responses compared to con-trols (82). Given that ACTH and cortisol re-sponses elicited by 5-HT1A receptor agonists havebeen shown to be mediated by postsynaptic 5-HT1A receptors (83–85), our findings would sug-gest an increase in postsynaptic 5-HT1A receptorsensitivity in manic patients. Likewise, cortisolresponses to other 5-HT challenges, such as5-hydroxytryptophan (5-HTP) (80) and D,L-fenfluramine (76), have also been reported to beenhanced in manic patients in comparison tohealthy controls, although the difference in corti-sol responses between the two groups did notreach significance in the latter study.
In addition to prolactin and cortisol responses,GH release to sumatriptan, a putative 5-HT1D re-ceptor agonist, has also been investigated inmanic patients recently (86). In contrast to theresults of the study of 5-HT1A receptor sensitivityin mania (82), this study did not find any signifi-cant difference in the GH response to sumatrip-tan between manic patients and normal controls.This might suggest that 5-HT1D receptor sensitiv-ity is not altered in mania. However, since suma-triptan penetrates the CNS to only a limitedextent (87), future studies using selective 5-HT1D
probes with better blood–brain barrier perme-ability are warranted to explore further the roleof 5-HT1D receptors in mania.
Taken together, the neuroendocrine challengestudies suggest that central presynaptic 5-HT ac-tivity is decreased and postsynaptic 5-HT recep-tor sensitivity is increased in mania. However,they provide information about hypothalamic 5-HT activity only, and not about 5-HT activity inlimbic or other cortical areas that may be morerelevant to the pathophysiology of mania.
5-HT in the mechanism of action of moodstabilizersEffects of lithium on 5-HT function
There have been several excellent review articlesindicating that lithium’s antidepressant effects arerelated to its enhancement of 5-HT function inthe central nervous system (19, 20, 88–91).Therefore, we did not include those studies in-volving depressed patients and only focused onthe studies that examined lithium’s effect on 5-HT activity in manics, healthy controls, or eu-thymic bipolar patients. Four major paradigmshave been utilized: 1) CSF studies, 2) plateletstudies, 3) neuroendocrine challenge studies, and4) tryptophan depletion studies.
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Table 1. Summary of clinical studies of serotonin (5-HT) function in mania
Studies Mania versus
Non-depressed controls Depression
Cerebrospinal fluid (CSF) studies¡ (12)6, (13)18, (14)3, (28)10Baseline CSF 5-HIAA levell (29)4, (30)8, (31)6, (32)17, (33)42, (34)11, l (13)18, (14)3, (28)10, (30)8, (31)6, (32)17,(35)14, (36)13, (37)11 (33)42, (36)13, (37)11, (38)19, (40)5, (41)7
(38)19, (39)4, (40)5 (29)4
Probenecid induced accumulation ¡ (30)8, (38)19, (47)5 l (32)17 ¡ (30)8
Postmortem studiesPostmortem brain 5-HIAA level ¡a(48)9
Platelet studiesPlatelet 5-HT uptake ¡ (54)7 l (51)14, (52)8, (53)15
Platelet [3H]-imipramine l (55)15, (56)16, (57)10, (58)15 l (57)10, (58)15 (55)15, (56)16
5-HT-induced platelet calcium (61)10
immobilizationl (63)21 (63)21Platelet intracellular Ca++ response
to 5-HTl (64)29Platelet [125I]-ketaserin binding
l (65)6¡ (65)6ADP augmented 5-HT inducedplatelet aggregation
Neuroendocrine challenge studiesl (75)11Buspirone induced PRL response
D,L-fenfluramine induced PRL l (76)10
responseD-fenfluarmine induced PRL response ¡ (77)9
D,L-fenfluramine induced COR l (76)10
response5-HTP induced COR response (80)16 l (80)16
(81)6Ipsapirone induced ACTH and CORresponsesSumatriptan induced GH response l (86)8
References are indicated in parentheses. Numbers of subjects for studies are indicated by italic superscripts.5-HIAA=5-hydroxyindoleacetic acid; ADP=adenosine diphosphate; ACTH=adrenocorticotropic hormone; COR=cortisol; GH=growth hormone; 5-HTP=5-hydroxytryptophan; PRL=prolactin. = increased responsiveness; ¡=decreased responsiveness; l=no change; multiple symbols indicate mixed results.a Postmortem brain 5-HIAA level decreased in frontal and parietal cortex in subjects with a history of bipolar affective disorder.
effects. Sjostrom and Ross (33) failed to utilize awithin-subject design and many of their patientsreceived neuroleptics.
However, larger studies have generally shownthat lithium increases CSF 5-HIAA levels in manicpatients (20). Fyro et al. (93) reported a significantincrease in CSF 5-HIAA levels in 13 manic orhypomanic patients after 12 days treatment withlithium compared to before treatment. Bowers andHeninger (94) reported a similar effect after amean of 27 days of lithium in 23 mixed affectivedisorder patients. Berrettini et al. (95) showed thateight lithium-treated euthymic bipolar patients hadsignificantly higher CSF 5-HIAA levels than theydid drug-free after at least 2 weeks of lithiumdiscontinuation. Swann et al. (96) found that tenmanic patients had higher CSF 5-HIAA levelsafter 18 days of lithium than before treatment, butthe difference did not reach significance.
CSF studies
Mendels (92) first reported that lithium signifi-cantly increased CSF 5-HIAA levels in two manicpatients, and suggested that lithium’s antimaniceffect may be due to its enhancing effect on 5-HTneurotransmission, thus supporting the permissivehypothesis of bipolar disorder. In a subsequentstudy, Wilk et al. (31) also showed that successfultreatment with lithium in two manic patients led toa sharp increase in CSF 5-HIAA levels. The twoinitial studies are limited by a small sample size.Likewise, three other earlier studies (14, 30, 33)with negative findings are also difficult to interpretbecause of small sample sizes or their methodologyand study design. The study of Bowers et al. (30)included only four manic patients. Mendels et al.(14) examined changes in CSF 5-HIAA levels fromthe perspective of clinical state rather than drug
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Platelet/blood studies
Platelet 5-HT uptake. There is conflicting evidencewith regard to the effects of short-term lithiumtherapy on platelet 5-HT uptake. For example,Meltzer et al. (97) reported that lithium treatmentfor 2–3 weeks led to a significant decrease inplatelet 5-HT uptake in 14 drug-free manic pa-tients. Poirier et al. (98) also showed a significantdecrease in platelet 5-HT uptake in seven healthysubjects after 20 days of lithium administration.However, Murphy et al. (99) reported that 1 weekof lithium treatment led to a significant increase inplatelet 5-HT uptake in nine mixed affective disor-der patients. Scott et al. (52) reported no signifi-cant change in platelet 5-HT uptake after lithiumtreatment for 5 days or 3 weeks in seven healthysubjects, or for 5 days, 3 weeks, or 3 months in asmall group of mixed affective patients. In con-trast, studies of the effect of long-term lithiumtreatment on platelet 5-HT uptake have shownmore consistent results. Meltzer et al. (97) mea-sured platelet 5-HT uptake in seven manic patientsbefore and after at least 12 months of lithiumtreatment, and found that lithium treatment of atleast 1-year duration was associated with a signifi-cant increase in the number of platelet uptake sites.Likewise, Born et al. (100) reported that bipolarpatients treated with lithium for at least 3 monthshad significantly greater platelet 5-HT uptake com-pared to those not on lithium or matched healthycontrols. Coppen et al. (101) showed that euthymicbipolar patients receiving lithium for 6 weeks orfor 1 year had greater platelet 5-HT uptake com-pared to remitted drug-free depressed patients. Inkeeping with these findings, Goodnick et al. (102)observed that discontinuation of chronic lithiumtreatment for a mean of 4.4 years in 11 euthymicbipolar patients led to a decrease in platelet 5-HTuptake compared to on-lithium baseline.
Platelet imipramine-binding site. With regard to theeffect of lithium on platelet [3H]-imipramine bind-ing, Baron et al. (103) found a decrease in maximalbinding (Bmax) in platelet [3H]-imipramine bindingin 33 euthymic bipolar patients chronically treatedwith lithium for periods ranging from 3 to 15years, compared to normal controls. They sug-gested that the density of [3H]-imipramine-bindingsites in platelets is a trait marker for bipolar illness.In keeping with this, Wood et al. (104) reported adecrease in platelet [3H]-imipramine binding inseven drug-free euthymic bipolar patients com-pared to 17 healthy controls; however, this was notthe case in 16 lithium-treated euthymic bipolarpatients. Moreover, two other studies also did not
find any significant difference in Bmax [3H]-imipramine binding between drug-free euthymicbipolar patients and normal controls (105, 106).Similarly, Goodnick et al. (102) reported thatplatelet [3H]-imipramine binding in seven euthymiclithium-treated bipolar patients was not altered bylithium discontinuation. Glue et al. (107) reportedthat 20 days of lithium treatment had no signifi-cant effect on platelet imipramine binding in eightnormal healthy subjects. Poirier et al. (98) alsoshowed no significant change in platelet [3H]-imipramine binding in seven healthy subjects after20 days of lithium administration. In summary,lithium treatment does not appear to alter theplatelet imipramine-binding site. To our knowl-edge, there is no study that measured plateletimipramine binding in drug-free acute manic pa-tients before and after monotherapy with lithium.
Other platelet/blood 5-HT measures. Several otherplatelet/blood 5-HT activities have also been usedto examine the role of 5-HT in the mechanism ofaction of lithium. Wood et al. (108) reported asignificant increase in 5-HT-induced platelet aggre-gation response in 24 patients who had beentreated with long-term lithium prophylaxis for amean of 5.5 years, compared to 22 drug-free de-pressed patients and 23 normal controls. Based ontheir finding, the authors suggest a supersensitivityin 5-HT2 receptor function following lithium treat-ment. However, another two putative 5-HT2 recep-tor measures, platelet binding sites for lysergic acid(LSD) and 5-HT-induced calcium mobilization inplatelets, were not altered following lithium treat-ment (107, 109). Glue et al. (107) reported that 20days of lithium treatment had no significant effecton platelet LSD-binding sites in eight healthy sub-jects. Kusumi et al. (109) reported no significanteffect of 4 weeks of lithium administration (600mg/day) on 5-HT-induced calcium mobilization inthe platelets of seven healthy subjects. Addition-ally, two studies reported no significant effect oflithium treatment on platelet 5-HT content inhealthy subjects (98, 107). Likewise, Artigas et al.(110) reported no significant difference in wholeblood 5-HT or plasma total tryptophan level be-tween 22 patients treated chronically with lithium,14 healthy controls, and 11 patients treated chron-ically with antipsychotic drugs. However, theyfound that plasma 5-HIAA and plasma-free 5-HTwere significantly increased in lithium-treated pa-tients compared to the other two groups (110).Their findings therefore provide some support tothe enhancing effect of lithium on 5-HT in theperiphery.
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Table 2. Summary of clinical studies of 5-HT in the mechanism of action of lithium
Studies Lithium (Li)
Mania Healthy controls Euthymic bipolar patients
Cerebrospinal fluid (CSF) studies (94)23, (95)8Baseline CSF 5-HIAA level (31)2, (92)2, (93)13
l (14)3, (30)4, (33)12, (96)10
Platelet studiesPlatelet 5-HT uptake (short term effect of Li) ¡ (97)14 l (52)7 ¡ (99)7 l (52)a (99)9, (101)7
Platelet 5-HT uptake (long term effect of Li) (97)7 l (52)a (100)10, (101)7
Platelet [3H]-imipramine l (107)8 l (104)16, (105)9, (106)12
¡ (103)33
(108)24Platelet 5-HT-induced aggregation responsePlatelet LSD binding l (107)8
Platelet 5-HT induced Ca++ mobilization l (109)7
Platelet 5-HT content l (98)7, (107)8
Whole blood 5-HT and plasma total tryp- l (110)22
tophanPlasma 5-HIAA and free 5-HT (110)22
Neuroendocrine challenge studiesl (121)8, (151)15D,L-fenfluramine induced PRL response
l (120)8D-fenfluramine induced PRL response (107)8I.V. tryptophan induced PRL response
Buspirone induced PRL response l (75)6
l (118)11 (117)8Clomipramine induced PRL response (122)11, (151)15D,L-fenfluramine induced COR response
Clomipramine induced COR/ACTH responses l (118)11, (117)8
5-HTP induced COR response (111)7
l (119)10Gepirone induced hormonal responsesl (107)8I.V. tryptophan induced GH response
Tryptophan depletion studies l (133)10, (135)4 M (134)7
References are indicated in parentheses. Numbers of subjects for studies are indicated by italic superscripts.a The number of study subjects was not provided by this study.M=manic symptoms relapsed following tryptophan depletion procedure; LSD=Lysergic acid; I.V.= intravenous.
Neuroendocrine challenge studies
Many neuroendocrine challenge studies have ex-amined the effects of lithium on 5-HT function indepressed patients (111–116) and healthy controls(90, 107, 117–120). Some (20, 90, 107, 111, 113,114, 117), but not all (116, 118–120), studiesshowed enhancement of 5-HT-mediated hormonalresponse following lithium treatment. However,there are only two studies that examined 5-HTfunction in manic patients before and after lithiumtreatment. Meltzer et al. (111) reported that amean of 23.8 days of lithium treatment alone led toan increase in cortisol response to 5-HTP in sevenmanic patients, supporting the hypothesis that in-creasing serotonergic activity may have an anti-manic effect. Yatham (75) measured prolactinresponse to buspirone in six drug-free manic pa-tients before and after 3 weeks of lithium treatmentalone and found no treatment effect of lithium onthe 5-HT1A receptor-mediated prolactin response.Similarly, Walsh et al. (119) also showed no signifi-
cant effect of lithium administration for 2 weekson the hormonal responses to gepirone, a moreselective 5-HT1A receptor agonist, in ten healthysubjects. In the two studies that measured pro-lactin (121) or cortisol response (122) tofenfluramine in euthymic bipolar patients receivinglithium, cortisol response was enhanced, while pro-lactin release was unaltered compared to controls.
In summary, lithium appears to enhance thecortisol response to 5-HT precursor or 5-HT re-leaser, but does not seem to affect the prolactinresponse to 5-HT releaser or 5-HT1A receptor ago-nists in bipolar patients.
Tryptophan depletion studies
Administration of an oral tryptophan-free mixture,containing large amounts of other amino acids,induces hepatic protein synthesis and leads torapid depletion of plasma tryptophan by nearly80% within 5 h (26, 123–125). This degree oftryptophan depletion reduces brain 5-HT to ap-
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proximately 20% of normal levels in animals (126).In humans, the tryptophan depletion techniqueleads to lower CSF tryptophan levels (127) and asignificant reduction in 5-HT synthesis (128). Thisparadigm has been used widely to study behavioraleffects of depletion of 5-HT synthesis in variouspsychiatric disorders, including major depression[(129–132) for review].
This paradigm has also been used to study theeffects of lithium on 5-HT function in euthymicbipolar patients. Benkelfat et al. (133) reportedthat a total of ten lithium-treated manic patientsthat had been stable and euthymic for more than ayear did not relapse following the ingestion of atryptophan depletion mixture. In contrast, Cap-piello et al. (134) showed that two out of sevenmanic patients who had recently been treated withlithium and had been in remission for less than amonth had a symptomatic relapse following anamino acid drink. This may suggest that mainte-nance of clinical improvement of manic symptomsin some recently lithium-remitted, but not in long-term stable, bipolar patients depends on the short-term availability of tryptophan in the brain.However, Cassidy et al. (135) were unable to repli-cate such a finding in four recently manic patientssuccessfully treated with lithium. Further tryp-tophan depletion studies with a larger number ofpatients are warranted to understand the role of5-HT in the antimanic effects of lithium in bipolarpatients.
Effects of anticonvulsants on 5-HT function
In addition to lithium, anticonvulsants such asdivalproex sodium (DVP) [(136, 137) for review]and carbamazepine [(138) for review] have beenshown to be effective in the treatment and prophy-laxis of mania. More recently, several new anticon-vulsants, such as lamotrigine, gabapentin, andtopiramate, have also been reported to have someefficacy in manic patients [(139) for review]. Since a5-HT deficit is implicated in mania and lithium’santimanic effect may be related to its enhancingeffect on 5-HT neurotransmission, one may expectthat the efficacy of these anticonvulsants in manicillness may also be associated with their effects on5-HT neurotransmission. Indeed, there has beensome evidence from clinical studies to support this.
Divalproex sodium
Maes et al. (140) measured plasma cortisol re-sponse to L-5-HTP in ten drug-free manic patientsbefore and after valproate treatment for 3 weeks.They found that administration of L-5-HTP pro-
duced an increase in cortisol responses both beforeand after valproate treatment; however, the L-5-HTP-induced cortisol response was significantlyhigher after treatment with valproate than beforetreatment. Their findings suggest that chronictreatment with valproate may enhance central 5-HT function in manic patients, and appear to beconsistent with the hypothesis that increasing 5-HTfunction plays a role in the antimanic effects ofvalproate. In addition, two other studies have alsoshown that valproate treatment leads to an in-crease in central 5-HT activity in humans. Fahn(141) reported that treatment with valproate in-creased CSF levels of 5-HIAA in a patient withpostanoxic intentional myoclonus. We recently re-ported that a 1-week treatment with DVP signifi-cantly attenuated the hypothermic response toipsapirone, a 5-HT1A receptor agonist, in tenhealthy human males (142). This suggests thatDVP enhances 5-HT neurotransmission by causinga subsensitivity of presynaptic 5-HT1A autorecep-tors, because the hypothermic response to 5-HT1A
receptor agonists has been suggested to be medi-ated by presynaptic 5-HT1A autoreceptors (143–145), although a mixed pre- and postsynapticactivation has also been suggested for mediation ofhypothermia in rats (146). In contrast to the posi-tive results of the above studies, Kusumi et al.(109) reported no in 6itro effect of DVP (100 mM)on basal calcium or 5-HT-induced intracellularcalcium mobilization in the platelets of sevenhealthy subjects.
Carbamazepine
To our knowledge, there is no study to date thatexamined the effects of carbamazepine on 5-HTactivity in manic patients. However, some humanstudies have shown evidence for an increase in5-HT function during carbamazepine treatment.For example, Elphick et al. (147) studied plasmaprolactin response to intravenous administrationof tryptophan in seven healthy human males be-fore and after a 10-day course of carbamazepine.They found that after the carbamazepine treat-ment, the prolactin response to tryptophan wassignificantly enhanced compared to before treat-ment. Moreover, carbamazepine treatment was re-ported to increase plasma total and freetryptophan in epileptic patients (148), which couldlead to an increase in brain 5-HT function (149). Incontrast, Post et al. (150) found no significanteffect of carbamazepine on CSF levels of 5-HIAAin affectively ill patients. Kusumi et al. (109) re-ported no in 6itro effect of carbamazepine (10 mM)for 1 or 4 h on basal calcium or 5-HT-inducedintracellular calcium mobilization in the platelets
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of seven healthy subjects. More recently, Mannel etal. (151) administered D,L-fenfluramine challengetests to 30 mixed affective disorder patients after amean period of 9.2 months of prophylactic treat-ment with either lithium or carbamazepine. Of the30 patients, 15 were treated with lithium and theother 15 received carbamazepine. The authorsfound that the cortisol response to D,L-fenfluarminewas significantly increased in lithium-treated pa-tients compared to those receiving carbamazepine,whereas there was no significant difference in theprolactin response to D,L-fenfluramine between thetwo groups. Their findings are in keeping with theenhancing effect of lithium, but not carbamazepine,on 5-HT function. However, the interpretation oftheir data was limited by a lack of placebo control,heterogeneity of diagnostic groups, and some pa-tients taking neuroleptics within 72 h before D,L-fenfluramine challenge testing.
New anticonvulsants: lamotrigine, gabapentin, topiramate
Lamotrigine is a new anticonvulsant, which hasbeen approved for use as an adjunct drug in thetreatment of refractory partial seizure with orwithout generalized tonic/clonic seizures (152). Asreviewed by Calabrese et al. (153), a series of clinicalreports involving bipolar patients suggest that thismedication is perhaps a mood stabilizer like lithium,with antimanic and antidepressant properties. Al-though evidence suggests that the antiepileptic ac-tion of lamotrigine may be related to its inhibitionof voltage-sensitive sodium channels and suppres-sion of the subsequent release of glutamate (154), themechanism of action underlying its efficacy in mooddisorders remains unknown. To date, two studiesexamined the effects of lamotrigine on 5-HT func-tion in humans. Southam et al. (155) reported thatlamotrigine treatment led to a concentration-depen-dent inhibition of 5-HT uptake in both humanplatelets and rat brain synaptosomes, raising thepossibility that an alteration in 5-HT function maycontribute to the efficacy of lamotrigine in bipolarillness. In contrast, another neuroendocrine chal-lenge study did not find any significant effect of1-week lamotrigine administration (100 mg/day) on5-HT1A
receptor-mediated hypothermic and cortisol re-sponses in ten healthy human males (156). Morestudies are clearly warranted to further explore therole of 5-HT function in the mechanism of action oflamotrigine.
Another new anticonvulsant that showed efficacyin the treatment of mood disorders is gabapentin(157–162). Several mechanisms have been proposed
to explain its pharmacology, such as 1) competingwith the amino acids leucine, isoleucine, valine, andphenylalanine for transport, 2) increasing the con-centration and the rate of synthesis of g-aminobu-tyric acid (GABA) in the brain, 3) interacting withan auxiliary subunit of voltage-gated Ca2+ chan-nels, 4) reducing the release of several monoamineneurotransmitters, and 5) inhibiting voltage-acti-vated Na+ channels (163). Two clinical studiesdemonstrated that gabapentin significantly in-creased whole blood 5-HT levels and CSF 5-HIAAlevels in healthy human subjects and epileptic pa-tients, respectively, suggesting that gabapentin mayalter 5-HT activity in humans (164, 165). To ourknowledge, there is no other study that examined theeffects of gabapentin on 5-HT function in patientswith mood disorders or healthy humans.
The third novel anticonvulsant that has beensuggested to have some benefit in the treatment ofbipolar illness is topiramate (166). Evidence frompreclinical and clinical studies suggests that theantiepileptic mechanisms of topiramate may involve1) blockade of voltage-sensitive sodium channels, 2)an enhancement of GABA activity, and 3) antago-nism of kainate to activate the kainate/a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA) subtype of glutamate receptors (167, 168).Whether the above pharmacological properties con-tribute to the possible effect of topiramate in thetreatment of mood disorders and whether topira-mate also affects central 5-HT neurotransmissionremains unknown. More studies are needed toclarify these issues.
Discussion
As reviewed above, previous studies in the literaturehave provided some evidence to support a role for5-HT in mania and in the mechanism of action ofmood stabilizers (please see Tables 1–3 for sum-mary). However, the results of CSF and plateletstudies in mania are inconsistent, and these studiescannot answer the question of whether there is aregional decrease in brain 5-HT activity. Such apossibility appears to be supported by the post-mortem study (48) that showed a decrease in 5-HIAA levels and 5-HT/5-HIAA ratios in frontaland parietal cortical regions in postmortem brainsof subjects with bipolar disorder. This study, how-ever, could tell us whether decreased 5-HT in corti-cal regions was due to manic state or depressivestate, as details of the mental state around the timeof death for the subjects were not provided. Asreviewed earlier, the results of neuroendocrine
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Table 3. Summary of clinical studies of 5-HT in the mechanism of action of anticonvulsants
AnticonvulsantsStudies
DVP CBZ Lamotrigine Gabapentin Topiramate
Cerebrospinal fluid (CSF) studies (141)1 l (150)aBaseline CSF 5-HIAA level (165)5
Platelet/blood studiesPlatelet 5-HT uptake ¡ (155)a
l (109)7 l (109)7Platelet 5-HT-induced intracellular Ca2+ mobilizationPlasma total and free tryptophan (148)20
(164)6Whole blood 5-HT level
Neuroendocrine challenge studiesD,L-fenfluramine induced PRL and COR responses l (151)15
(147)7I.V. tryptophan induced PRL response (140)105-HTP induced COR response¡ (142)10 l (156)10Ipsapirone induced hypothermic response responsesl (142)10 l (156)10Ipsapirone induced ACTH and/or COR responses
References are indicated in parentheses. Numbers of subjects for studies are indicated by italic superscripts.aThe number of study subjects was not provided by this study.DVP=divalproex sodium; CBZ=carbamazepine.
challenge studies in manic patients suggest a de-crease in presynaptic 5-HT activity and an increasein postsynaptic 5-HT receptor function in this con-dition. They, however, provide the information on5-HT activity in the hypothalamic region only, andnot in other brain regions. Therefore, further stud-ies are clearly needed to assess 5-HT function inmanic patients in various other brain regions, toassess the 5-HT role in mania, and verify the 5-HThypothesis for this condition.
With the development of the positron emissiontomography (PET) technique and suitable radioli-gands, it is now possible to in 6i6o examine distinct5-HT receptor subtypes in different brain regionsin humans. For example, suitable radioligandshave been developed for quantitative determina-tion of the 5-HT2 (169) and 5-HT1A (170, 171)receptors in humans. There have been several PETstudies that examined 5-HT receptors in patientswith various psychiatric disorders (172–179), in-cluding major depression (176–179). But, this hasnot been done in manic patients to date. Suchreceptor imaging studies will likely enhance ourunderstanding of the role of 5-HT in mania and itstreatment.
Although in this review, we focused on the con-tribution of 5-HT in the pathophysiology of maniaand in the mechanisms of action of mood stabiliz-ers, it is very likely that other neurotransmittersalso play important roles. As mentioned in theintroduction, the permissive hypothesis of bipolardisorder postulates that mania is characterized bylow 5-HT and high NE and DA function, whereasdepression is characterized by low 5-HT, NE, andDA function. There has been some evidence in the
literature to support the hypothesis of excess cate-cholamine (NE and DA) function in mania [(180)for review]. Additionally, low acetylcholine (Ach)[(181) for review] and low GABA [(182, 183) forreview] activities have also been hypothesized tocontribute to the etiology of mania. Furthermore,there is a significant body of anatomical, biochem-ical, and electrophysiological data from animalstudies that demonstrate complex interaction be-tween the 5-HT and other neurotransmitter sys-tems [(184, 185) for review]. It would be plausibleto hypothesize that the interrelationship between5-HT and these other neurotransmitter systems isalso important to the etiology of mania, and thatsuccessful treatment in mania may alter the activityof these neurotransmitter systems and/or changetheir interaction, rather than affect 5-HT activityonly. Further studies of simultaneous measurementof activity of different neurotransmitter systems inmanic patients before and after treatment withmood stabilizers are needed to verify this.
Another issue that is related to the interaction of5-HT and other neurotransmitters, and needs to beaddressed in future studies, is diagnostic subtypes.Acute mania can be subdivided into classic puremania, mania with mood-congruent or mood-in-congruent psychotic features, and mixed state(186). It is possible that patients with differentsubtypes of mania may have alterations in differentneurotransmitter activity and/or interaction. Forexample, Swann et al. (96) found that femalemixed manic patients had higher values for CSF5-HIAA and homovanillic acid (HVA) than puremanics. Similarly, in a subsequent study by thesame group (41), patients with mixed mania had
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higher urinary excretion of NE and higher CSF3-methoxy-4-hydroxyphenylglycol (MHPG) levels,compared to patients with pure mania. Their find-ings suggest that mixed manic patients may differfrom pure manics in the biochemical basis for theirsymptoms. Future biological studies delineatingspecific subtypes of mania will extend our currentunderstanding of pathophysiology and ultimatelylead to better treatment strategies for differentsubtypes of mania.
In conclusion, clinical studies from platelet,CSF, neuroendocrine challenge, postmortem, andtryptophan depletion have provided some evidenceto support the hypothesis that a 5-HT deficit isinvolved in mania, and that enhancement of 5-HTneurotransmission exerts a mood-stabilizing effect;however, alterations in the functioning of otherneurotransmitters such as NE, DA, Ach, andGABA, and their interaction with 5-HT, also likelycontribute. Future directions for research into therole of 5-HT in mania and in the mechanisms ofaction of mood stabilizers should include 1) in 6i6ostudies of 5-HT receptor subtypes using the PETtechnique, 2) investigation of the interactions of5-HT and other neurotransmitter systems, 3) deter-mination of the relationships of diagnostic sub-types of mania and 5-HT function and otherneurotransmitter systems.
AcknowledgementsThis work was supported in part by funding from theMedical Research Council of Canada to Lakshmi N.Yatham.
References
1. Cooper JR, Bloom FE, Roth RH. Serotonin (5-hydrox-ytryptamine) and histamine. In: Cooper JR, Bloom FE,Roth RH, eds. The Biochemical Basis of Neuropharmacol-ogy, 7th edn. New York: Oxford University Press, 1996;352–409.
2. Marsden CA. The neuropharmacology of serotonin in thecentral nervous system. In: Feighner JP, Boyer WF, eds.Selective Serotonin Re-Uptake Inhibitors, vol. vol. 5, 2ndedn. New York: Wiley, 1996; 1–33.
3. Hoyer D, Martin GR. Classification and nomenclature of5-HT receptors: a comment on current issues. Behav BrainRes 1996; 73: 263–268.
4. Hoyer D, Martin GR. 5-HT receptor classification andnomenclature: towards a harmonization with the humangenome. Neuropharmacology 1997; 36: 419–428.
5. Kroeze WK, Roth BL. The molecular biology of serotoninreceptors: therapeutic implications for the interface ofmood and psychosis. Biol Psychiatry 1998; 44: 1128–1142.
6. Steinbusch HWM. Distribution of serotonin-immunoreac-tivity in the central nervous system of the rat-cell bodiesand terminal. Neuroscience 1981; 6: 557–618.
7. Tork I. Anatomy of the serotonergic system. Ann NY AcadSci 1990; 600: 9–35.
8. Jacobs BL, Fornal CA. Serotonin and behavior: a generalhypothesis. In: Bloom FE, Kupfer DJ, eds. Psychopharma-cology: The Fourth Generation of Progress. New York:Raven Press, 1995; 461–469.
9. Smith KA, Cowen PJ. Serotonin and depression. In: HonigA, van Praag HM, eds. Depression: Neurobiological,Psychopathological and Therapeutic Advances. NewYork: Wiley, 1997; 129–146.
10. Strom-Oslen R, Weil-Malherbe H. Humoral changes inmanic depressive psychosis with particular reference to theexcretion of catecholamine in urine. J Ment Sci 1958; 104:696–704.
11. Prange AJ, Wilson IC, Lynn CW, Alltop LB, StikeleatherRA, Raleigh RN. L-Tryptophan in mania: contribution toa permissive hypothesis of affective disorder. Arch GenPsychiatry 1974; 30: 56–62.
12. Dencker SJ, Malm U, Roos BE, Werdinius B. Acidmonoamine metabolites of cerebrospinal fluid in mentaldepression and mania. J Neurochem 1966; 13: 1545–1548.
13. Coppen A, Prange AJJ, Whybrow PC, Noguera R. Abnor-mality of indoleamines in affective disorders. Arch GenPsychiatry 1972; 26: 474–478.
14. Mendels J, Frazer A, Fitzgerald RG, Ramsey TA, StokesJW. Biogenic amine metabolites in the cerebrospinal fluidof depressed and manic patients. Science 1972; 175: 1380–1382.
15. Sheard MH, Aghajanian GK. Neuronally activatedmetabolism of brain serotonin: effect of lithium. Life Sci1970; 9: 285–290.
16. Tagliamonte A, Tagliamonte P, Perez-Cruet J, Stern S,Gessa GL. Effects of psychotropic drugs on tryptophanconcentration in the rat brain. J Pharmacol Exp Ther 1971;177: 475–480.
17. Knapp S, Mandell AJ. Short- and long-term administra-tion of lithium: effects on the brain’s serotonergic biosyn-thetic systems. Science 1973; 180: 645–647.
18. van Praag HM. Depression, suicide, and serotoninmetabolism in the brain. In: Post RM, Ballenger JC, eds.Neurobiology of Mood Disorders. Baltimore: Williamsand Wilkins, 1984; 601–618.
19. Meltzer HY, Lowy MT. The serotonin hypothesis ofdepression. In: Meltzer HY, ed. Psychopharmacology: TheThird Generation of Progress. New York: Raven Press,1987; 513–526.
20. Price LH, Charney DS, Delgado PL, Heninger GR.Lithium and serotonin function: implications for the sero-tonin hypothesis of depression. Psychopharmacology 1990;100: 3–12.
21. Malone K, Mann JJ. Serotonin and major depression. In:Mann JJ, Kupfer DJ, eds. Biology of Depressive Disorders,Part A: A Systems Perspective. New York: Plenum Press,1993; 29–49.
22. Maes M, Meltzer HY. The serotonin hypothesis of majordepression. In: Bloom FE, Kupfer DJ, eds. Psychopharma-cology: The Fourth Generation of Progress. New York:Raven Press, 1994; 933–944.
23. Williams WA, Shoaf SE, Hommer D, Rawlings R, Lin-noila M. Effects of acute tryptophan depletion on plasmaand cerebrospinal fluid tryptophan and 5-hydroxyin-doleacetic acid in normal volunteers. J Neurochem 1999;72: 1641–1647.
24. Moir ATB, Ashcroft GW, Crawford TBB, Eccleston D,Guildberg HC. Cerebral metabolites in cerebrospinal fluidas a biochemical approach to brain. Brain 1970; 93:357–367.
25. Banki CM, Molnar G. Cerebrospinal fluid 5-hydroxyindo-lacetic acid as an index of central serotonergic processes.Psychiatry Res 1981; 5: 23–32.
87
Shiah and Yatham
26. Young SN, Gauthier S. Effect of tryptophan administra-tion on tryptophan, 5-hydroxyindolacetic acid and in-doleacetic acid in human lumbar and cisternalcerebrospinal fluid. J Neurol Neurosurg Psychiatry 1981;44: 323–327.
27. Stanley M, Traskman-Bendz L, Dorovini-Zis K. Correla-tions between aminergic metabolites simultaneously ob-tained from human CSF and brain. Life Sci 1985; 37:1279–1286.
28. Banki CM. Correlation between CSF metabolites andpsychomotor activity in affective disorders. J Neurochem1977; 28: 255–257.
29. Ashcroft GW, Crawford TBB, Eccleston D, SharmanDF, MacDougall FJ, Stanton JB, Binns JK. 5-Hydrox-yindole compounds in the cerebrospinal fluid of patientswith psychiatric or neurological diseases. Lancet 1966; 2:1049–1052.
30. Bowers MB, Heninger JGR, Gerbode G. Cerebrospinalfluid 5-hydroxyindoleacetic acid and homovanillic acid inpsychiatric patients. Int J Neuropharmacol 1969; 8: 255–262.
31. Wilk S, Shopsin B, Gershon S, Suhl M. Cerebrospinalfluid levels of MHPG in affective disorders. Nature 1972;235: 440–441.
32. Goodwin FK, Post RM, Dunner DL, Gordon EK. CSFamine metabolites in affective illness: the probenecid tech-nique. Am J Psychiatry 1973; 130: 73–79.
33. Sjostrom R, Roos B-E. 5-Hydroxyindolacetic acid andhomovanillic acid in cerebrospinal fluid in manic-depres-sive psychosis. Eur J Clin Pharmacol 1972; 4: 170–176.
34. Aschroft GW, Dow RC, Yates CM, Pullar IA. Signifi-cance of lumbar CSF metabolite measurements in affec-tive illness. In: Tuomisto J, Paasonen M, eds. CNS andBehavioral Pharmacology. Helsinski, Finland: Universityof Helsinki, 1976; 277–284.
35. Swann AC, Secunda S, Davis JM, Robins E, Hanin I,Koslow SH, Maas J. CSF monoamine metabolites inmania. Am J Psychiatry 1983; 140: 396–400.
36. Gerner RH, Fairbanks L, Anderson GM, Young JG,Scheinin M, Linnoila M, Hare TA, Shaywitz BA, CohenDJ. CSF neurochemistry in depressed, manic, andschizophrenic patients compared with that of normalcontrols. Am J Psychiatry 1984; 141: 1533–1540.
37. Ashcroft GW, Glen AIM. Mood and neuronal fluctua-tions: a modified amine hypotheses for the etiology ofaffective illness. Adv Biochem Psychopharmacol 1974; 11:335–339.
38. Ross BE, Sjostrom R. 5-Hydroxyindoleacetic acid (andhomovanillic acid) levels in the cerebrospinal fluid afterprobenecid application in patients with manic-depressivepsychosis. Pharmacol Clin 1969; 1: 153–155.
39. Vestergaard P, Sorensen T, Hoppe E, Rafaelsen OJ,Yates CM, Nicolaou N. Biogenic amine metabolites incerebrospinal fluid of patients with affective disorders.Acta Psychiatr Scand 1978; 58: 88–96.
40. Koslow SH, Maas JW, Bowden CL, Davis JM, Hanin I,Javaid J. CSF and urinary biogenic amines and metabo-lites in depression and mania: a controlled univariateanalysis. Arch Gen Psychiatry 1983; 40: 999–1010.
41. Swann AC, Stokes PE, Secunda SK, Maas JW, BowdenCL, Berman N, Koslow SH. Depressive mania versusagitated depression: biogenic amine and hypothalamic-pi-tuitary adrenocortical function. Biol Psychiatry 1994; 35:803–813.
42. Guldberg HC, Ashcroft GW, Crawford TB. Concentra-tions of 5-hydroxyindolylacetic acid and homovanillicacid in the cerebrospinal fluid of the dog before andduring treatment with probenecid. Life Sci 1966; 5: 1571–1575.
43. Olsson R, Roos BE. Concentrations of 5-hydroxyin-doleacetic acid and homovanillic acid in the cerebrospinalfluid after treatment with probenecid in patients withParkinson’s disease. Nature 1968; 219: 502–503.
44. van Praag HM, Korf J, Puite J. 5-Hydroxyindoleaceticacid levels in the cerebrospinal fluid of depressive patientstreated with probenecid. Nature 1970; 225: 1259–1260.
45. Post RM, Goodwin FK. Approaches to brain amines inpsychiatric patients: a reevaluation of cerebrospinal fluidstudies. In: Iversen LL, Iversen SD, Snyder SH, eds.Handbook of Psychopharmacology: Biology of Moodand Antianxiety Drugs, vol. vol. 13. New York: PlenumPress, 1973; 147–185.
46. Mendels J, Frazer A. Reduced central serotonergic activ-ity in mania: implications for the relationship betweendepression and mania. Br J Psychiatry 1975; 126: 241–248.
47. Sjostrom R. 5-Hydroxyindole acetic acid and homovanil-lic acid in cerebrospinal fluid in manic-depressive psycho-sis and the effect of probenecid treatment. Eur J ClinPharmacol 1973; 6: 75–80.
48. Young LT, Warsh JJ, Kish SJ, Shannak K, HornykeiwiczO. Reduced brain 5-HT and elevated NE turnover andmetabolites in bipolar affective disorder. Biol Psychiatry1994; 35: 121–127.
49. Stahl SM. The human platelet. Arch Gen Psychiatry1977; 34: 509–516.
50. Stahl SM. Platelets as pharmacological models for thereceptors and biochemistry of monoaminergic neurons.In: Longenecker GL, ed. The Platelets: Physiology andPharmacology. New York: Academic Press, 1985; 307–340.
51. Meltzer HY, Arora RC, Baber R. Serotonin uptake inblood platelets of psychiatric patients. Arch Gen Psychi-atry 1981; 38: 1322–1326.
52. Scott M, Reading HW, Louden JB. Studies on humanblood platelets in affective disorders. Psychopharmacol-ogy 1979; 60: 131–135.
53. Meagher JB, O’Halloran A, Carney PA. Changes inplatelet 5-HT uptake in mania. J Affect Disord 1990; 19:191–196.
54. Marazziti D, Lenzi A, Galli L, San Martino S, CassanoGB. Decreased platelet serotonin uptake in bipolar Ipatients. Int Clin Psychopharmacol 1991; 6: 25–30.
55. Lewis DA, McChesney C. Tritiated imipramine bindingto platelets in manic subjects. J Affect Disord 1985; 9:207–211.
56. Ellis PM, Mellsop GW, Beeston R, Cooke RR. Platelettritiated imipramine binding in patients suffering frommania. J Affect Disord 1991; 22: 105–110.
57. Muscettola G, Di Lauro A, Giannini CP. Platelet 3H-imipramine binding in bipolar patients. Psychiatry Res1986; 18: 343–353.
58. Marazziti D, Lenzi A, Cassano GB. Serotonergic dys-function in bipolar disorder. Pharmacopsychiatry 1991;24: 164–167.
59. Kusumi I, Koyama T, Yamashita I. Effects of variousfactors on serotonin-induced Ca2+ response in humanplatelets. Life Sci 1991; 48: 999–1010.
60. Kagaya A, Mikuni M, Kusumi I, Yamamoto H, Taka-hashi K. Serotonin-induced acute desensitization ofserotonin2 receptors in human platelets via a mechanism
88
Serotonin, mania, and mood stabilizers
involving protein kinase. J Pharmacol Exp Ther 1990;255: 305–311.
61. Okamoto Y, Kagaya A, Shinno H, Motohashi N, Ya-mawaki S. Serotonin-induced platelet calcium mobiliza-tion is enhanced in mania. Life Sci 1994; 56: 327–332.
62. Dubovsky SL, Murphy J, Christiano J, Lee C. The cal-cium second messenger system in bipolar disorder: datasupporting new research directions. J NeuropsychiatryClin Neurosci 1992; 4: 3–14.
63. Berk M, Bodemer W, Van Oudenhove T, Butkow N. Theplatelet intracellular calcium response to serotonin is aug-mented in bipolar manic and depressed patients. HumPsychopharmacol 1995; 10: 189–193.
64. Velayudhan A, Sunitha TA, Balachander S, Reddy JYC,Khanna S. A study of platelet serotonin receptor inmania. Biol Psychiatry 1999; 45: 1059–1062.
65. McAdams C, Leonard BE. Changes in platelet aggrega-tory responses to collagen and 5-hydroxytryptamine indepressed, schizophrenic and manic patients. Int ClinPsychopharmacol 1992; 7: 81–85.
66. Tuomisto J, Mannisto P. Neurotransmitter regulation ofanterior pituitary hormones. Pharmacol Rev 1985; 37:251–332.
67. Yatham LN, Steiner M. Serotonin as a neuroendocrinemodulator. J Serotonin Res 1994; 1: 7–19.
68. Yatham LN, Steiner M. Neuroendocrine probes of sero-tonergic function: a critical review. Life Sci 1993; 53:447–463.
69. Delgado PL, Charney DS. Neuroendocrine challengetests in affective disorders: implications for future patho-physiological investigations. In: Horton R, Katona C,eds. Biological Aspects of Affective Disorders. NewYork: Academic Press, 1991; 145–190.
70. Stahl SM. Neuroendocrine markers of serotonin respon-sivity in depression. Prog Neuro-Psychopharmacol BiolPsychiat 1992; 16: 655–659.
71. Cowen PJ. Pharmacological challenge tests and brainserotonin function in depression and during SSRI treat-ment. In: Briley M, Montgomery S, eds. AntidepressantTherapy: At the Dawn of the Third Millennium. London:Martin Dunitz, 1998; 175–189.
72. Coccaro EF, Murphy DL. Serotonin in Major PsychiatricDisorders. Washington, DC: American Psychiatric Press,1990.
73. Sandler M, Coppen A, Harnett S. 5-Hydroxytryptaminein Psychiatry. New York: Oxford University Press, 1991.
74. Newman ME, Shapira B, Lerer B. Evaluation of centralserotonergic function in affective and related disorders bythe fenfluramine challenge test: a critical review. Int JNeuropsychopharmacol 1998; 1: 49–69.
75. Yatham LN. Buspirone induced prolactin release in ma-nia. Biol Psychiatry 1994; 35: 553–556.
76. Yatham LN. Prolactin and cortisol responses tofenfluramine challenge in mania. Biol Psychiatry 1996; 39:285–288.
77. Thakore JH, O’Keane V, Dinan TG. D-fenfluramine-in-duced prolactin responses in mania: evidence for sero-tonergic subsensitivity. Am J Psychiatry 1996; 153:1460–1463.
78. van Praag HM, Lemus C, Kahn R. Hormonal probes ofcentral serotonergic activity: do they really exist? BiolPsychiatry 1986; 22: 86–98.
79. Quattrone A, Tedeschi G, Aguglia U, Scopacasa F, Di-renzo GF, Annunziato L. Prolactin secretion in man: auseful tool to evaluate the activity of drugs on central5-hydroxytryptaminergic neurons. Studies withfenfluramine. Br J Clin Pharmacol 1983; 16: 471–475.
80. Meltzer HY, Umberkoman-Wita B, Robertson A, TricouBJ, Lowy M, Perline R. Effects of 5-hydroxytryptophanon serum cortisol levels in major affective disorders. I.Enhanced responses in depression and mania. Arch GenPsychiatry 1984; 41: 366–374.
81. Lesch KP, Rupprecht R, Poten B, Muller U, Sohnle K,Fritze J, Schulte HM. Endocrine responses to 5-hydrox-ytryptamine-1A receptor activation by ipsapirone in hu-mans. Biol Psychiatry 1989; 26: 203–205.
82. Yatham LN, Shiah IS, Lam RW, Tam EM, Zis AP.Hypothermic, ACTH, and cortisol responses to ip-sapirone in patients with mania and healthy subjects. JAffect Disord 1999; 54: 295–301.
83. Bagdy G, Makara GB. Hypothalamic paraventricularnucleus lesions differentially affect serotonin-1A (5-HT1A)and 5-HT2 receptor agonist-induced oxytoxin, prolactinand corticosterone responses. Endocrinology 1994; 134:1127–1131.
84. Gilber F, Brazell C, Tricklebank MD, Stahl SM. Activa-tion of the 5-HT1A subtype increases rat ACTH concen-tration. Eur J Pharmacol 1988; 147: 431–439.
85. Koenig JI, Gudelsky GA, Meltzer HY. Stimulation ofcorticosterone and beta-endophin secretion in the rat byselective 5-HT receptor subtype activation. Eur J Phar-macol 1987; 137: 1–8.
86. Yatham LN, Zis AP, Lam RW, Tam E, Shiah IS. Suma-triptan-induced growth hormone release in patients withmajor depression, mania, and normal controls. Neuropsy-chopharmacology 1997; 17: 258–263.
87. Dallas FA. The kinetics of 14C GR43175 in the rat anddog. Cephalagia 1989; 9 (Suppl): 53–56.
88. Bunney WE, Garland-Bunney BL. Mechanisms of actionof lithium in affective illness: basic and clinical implica-tions. In: Meltzer HY, ed. Psychopharmacology: TheThird Generation of Progress. New York: Raven Press,1987; 553–565.
89. Wood AJ, Goodwin GM. A review of the biochemicaland neuropharmacological actions of lithium. PsycholMed 1987; 17: 579–600.
90. Cowen PJ, Cohen PR, McCance SL, Friston KJ. 5-HTneuroendocrine responses during psychotropic drug treat-ment: an investigation of the effects of lithium. J NeurosciMethods 1990; 34: 201–205.
91. Lenox RH, Manji HK. Lithium. In: Schatzberg AF,Nemeroff CB, eds. The American Psychiatric Press Text-book of Psychopharmacology. Washington, DC: Ameri-can Psychiatric Press, 1995; 303–349.
92. Mendels J. Relationship between depression and mania.Lancet 1971; i: 342.
93. Fyro B, Patterson V, Sedvall G. The effect of lithiumtreatment on manic symptoms and levels of monoaminemetabolites in cerebrospinal fluid of manic depressivepatients. Psychopharmacologia 1975; 44: 99–103.
94. Bowers MB, Heninger GR. Clinical effects and cere-brospinal fluid acid monoamine metabolites. CommunPsychopharm 1977; 1: 135–145.
95. Berrettini WH, Nurnberger JI, Scheinin JM, Seppala T,Linnoila M, Narrow W, Simmons-Alling S, Gershon ES.Cerebrospinal fluid and plasma monoamines and theirmetabolites in euthymic bipolar patients. Biol Psychiatry1985; 20: 257–269.
96. Swann AC, Koslow SH, Katz MM, Maas JW, Javaid J,Secunda S, Robins E. Lithium carbonate treatment ofmania: cerebrospinal fluid and urinary monoaminemetabolites and treatment outcome. Arch Gen Psychiatry1987; 44: 345–354.
89
Shiah and Yatham
97. Meltzer HY, Arora RC, Goodnick PJ. Effects of lithiumcarbonate on serotonin uptake in blood platelets of pa-tients with affective disorders. J Affect Disord 1983; 5:215–221.
98. Poirier MF, Galzin AM, Pimoule C, Schoemaker H, LeQuan Bui KH, Meyer P, Gay C, Loo H, Langer SZ.Short-term lithium administration to healthy volunteersproduces long-lasting pronounced changes in plateletserotonin uptake but not imipramine binding. Psy-chopharmacology 1988; 94: 521–526.
99. Murphy DL, Colburn RW, Davis JM, Bunney WEJ.Stimulation by lithium on monoamine uptake in humanplatelets. Life Sci 1969; 8: 1187–1194.
100. Born GVR, Grignani G, Martin K. Long-term effect oflithium on the uptake of 5-hydroxytryptamine by humanplatelets. Br J Clin Pharmacol 1980; 9: 321–325.
101. Coppen AJ, Swade C, Wood K. Lithium restores abnor-mal platelet 5-HT transport in patients with affectivedisorders. Br J Psychiatry 1980; 136: 235–238.
102. Goodnick PJ, Arora RC, Jackman H, Meltzer HY. Neu-rochemical changes during discontinuation of lithiumprophylaxis. II. Alterations in platelet serotonin function.Biol Psychiatry 1984; 19: 891–898.
103. Baron M, Barkai A, Gruen R, Peselow E, Fieve RR,Quitkin F. Platelet [3H]imipramine binding in affectivedisorders: trait versus state characteristics. Am J Psychi-atry 1986; 143: 711–716.
104. Wood PL, Suranyi-Cadotte B, Schwartz G, Nair NPV.Platelet 3H-imipramine binding and red blood cell cholinein affective disorders: indications of heterogeneous patho-genesis. Biol Psychiatry 1983; 18: 715–719.
105. Mellerup ET, Plenge P, Rosenberg R. 3H-Imipraminebinding sites in platelets from psychiatric patients. Psychi-atry Res 1982; 7: 221–227.
106. Berrettini WH, Nurnberger JI, Post RM, Gershon ES.Platelet 3H-imipramine binding in euthymic bipolar pa-tients. Psychiatry Res 1982; 7: 215–220.
107. Glue PW, Cowen PJ, Nutt DJ, Kolakowska T, Grahame-Smith DG. The effect of lithium on 5-HT-mediated neu-roendocrine responses and platelet 5-HT receptors.Psychopharmacologia 1986; 90: 398–402.
108. Wood K, Swade C, Abou-Saleh MT, Coppen A. Appar-ent supersensitivity of platelet 5-HT receptors in lithium-treated patients. J Affect Disord 1985; 8: 69–72.
109. Kusumi I, Koyama T, Yamashita I. Effect of moodstabilizing agents on agonist-induced calcium mobiliza-tion in human platelets. J Psychiatr Neurosci 1994; 19:222–225.
110. Artigas F, Sarrias MJ, Martinez E, Gelpi E, Alvarez E,Udina C. Increased plasma free serotonin but unchangedplatelet serotonin in bipolar patients treated chronicallywith lithium. Psychopharmacology 1989; 99: 328–332.
111. Meltzer HY, Lowy M, Robertson A, Goodnick P, PerlineR. Effect of 5-hydroxytryptophan on serum cortisol levelsin major affective disorders. III. Effect of antidepressantsand lithium carbonate. Arch Gen Psychiatry 1984; 41:391–397.
112. Price LH, Charney DS, Delgado PL, Heninger GR.Lithium treatment and serotonin function: neuroen-docrine and behavioral responses to intravenous tryp-tophan in affective disorder. Arch Gen Psychiatry 1989;46: 13–19.
113. Cowen PJ, McCance SL, Cohen PR, Julier DL. Lithiumincreases 5-HT-mediated neuroendocrine responses in tri-cyclic resistant depression. Psychopharmacology 1989; 99:230–232.
114. Cowen PJ, McCance SL, Ware CJ, Cohen PR, CalmersJS, Julier DL. Lithium in tricyclic resistant depression:correlation of increased brain 5-HT function with clinicaloutcome. Br J Psychiatry 1991; 159: 341–346.
115. McCance-Katz E, Price LH, Charney DS, Heninger GR.Serotonergic function during lithium augmentation ofrefractory depression. Psychopharmacology 1992; 108:93–97.
116. Shapira B, Yagmur MJ, Gropp C, Newman M, Lerer B.Effect of clomipramine and lithium on fenfluramine-in-duced hormone release in major depression. Biol Psychi-atry 1992; 31: 975–983.
117. McCance SL, Cohen PR, Cowen PJ. Lithium increases5-HT-mediated prolactin release. Psychopharmacology1989; 99: 276–281.
118. Manji HK, Hsiao JK, Risby ED, Oliver J, Rudorfer MV,Potter WZ. The mechanisms of action of lithium. I.Effects on serotonergic and noradrenergic systems in nor-mal subjects. Arch Gen Psychiatry 1991; 48: 505–512.
119. Walsh AE, Ware CJ, Cowen PJ. Lithium and 5-HT1Areceptor sensitivity: a neuroendocrine study in healthyvolunteers. Psychopharmacology 1991; 105: 568–572.
120. Power AC, Dorkins CE, Cowen PJ. Effect of lithium onthe prolactin response to D-fenfluramine in healthy sub-jects. Biol Psychiatry 1993; 33: 801–805.
121. Muhlbauer HD. The influence of fenfluramine stimula-tion on prolactin plasma levels in lithium long-term-treated manic-depressive patients and healthy subjects.Pharmacopsychiatry 1984; 17: 191–193.
122. Muhlbauer HD, Muller-Oerlinghausen B. Fenfluraminestimulation of serum cortisol in patients with major affec-tive disorders and healthy controls: further evidence for acentral serotonergic action of lithium in man. J NeuralTransm 1985; 61: 81–94.
123. Gessa GL, Biggio G, Fadda F, Lorsini GU, TagliamonteA. Effect of oral administration of tryptophan-free aminoacid mixtures on serum tryptophan, brain tryptophan andserotonin metabolism. J Neurochem 1974; 22: 869–870.
124. Young SN, Smith SE, Pihl RO, Finn P. Tryptophandepletion causes a rapid lowering of mood in normalmales. Psychopharmacology 1985; 87: 173–177.
125. Young SN, Ervin FR, Pihl RO, Finn P. Biochemicalaspects of tryptophan depletion in primates. Psychophar-macology 1989; 98: 508–511.
126. Moja EA, Cipolla P, Castoda D, Tofanetti O. Dose-re-sponsive decrease in plasma tryptophan and in braintryptophan and serotonin after tryptophan-free aminoacid mixtures in rats. Life Sci 1989; 44: 971–976.
127. Carpenter LL, Anderson GM, Pelton GH, Gudin JA,Kirwin PS, Price LH, Heninger GR, McDougle CJ. Tryp-tophan depletion during continuous CSF sampling inhealthy human subjects. Neuropsychopharmacology1998; 19: 26–35.
128. Nishizawa S, Benkelfat C, Young SN, Leyton M,Mzengeza S, de Montigny C, Blier P, Diksic M. Differ-ences between males and females in rates of serotoninsynthesis in human brain. Proc Natl Acad Sci USA 1998;94: 5308–5313.
129. Delgado PL, Charney DS, Price LH, Aghajanian GK,Landis H, Heninger GR. Serotonin function and themechanism of antidepressant action: reversal of antide-pressant induced remission by rapid depletion of plasmatryptophan. Arch Gen Psychiatry 1990; 47: 411–418.
130. Delgado PL, Price LH, Miller HL, Salomon RM, LicinioJ, Krystal JH, Heninger GR. Rapid serotonin depletionas a provocative challenge test for patients with majordepression: relevance to antidepressant action and the
90
Serotonin, mania, and mood stabilizers
neurobiology of depression. Psychopharmacol Bull 1991;27: 321–330.
131. Reilly JG, McTavish SF, Young AH. Rapid depletion ofplasma tryptophan: a review of studies and experimentalmethodology. J Psychopharmacol 1997; 11: 381–392.
132. Delgado PL, Moreno FA, Potter R, Gelenberg AJ. Nore-pinephrine and serotonin in antidepressant action: evi-dence from neurotransmitter depletion studies. In: BrileyM, Montgomery S, eds. Antidepressant Therapy: At theDawn of the Third Millennium. London: Martin Duntiz,1998; 141–161.
133. Benkelfat C, Seletti B, Palmour RM, Hillel J, EllenbogenM, Young S. Tryptophan depletion in stable lithiumtreated patients with bipolar disorder in remission. ArchGen Psychiatry 1995; 52: 154–155.
134. Cappiello A, Sernyak MJ, Malison RT, Christopher JM,Heninger GR, Price LH. Effects of acute tryptophandepletion in lithium remitted manic patients: a pilotstudy. Biol Psychiatry 1997; 42: 1076–1078.
135. Cassidy F, Murry E, Carroll BJ. Tryptophan depletion inrecently manic patients treated with lithium. Biol Psychi-atry 1998; 43: 230–232.
136. McElroy SL, Keck PE, Pope HG, Hudson JI. Valproatein the treatment of bipolar disorder: literature review andclinical guidelines. J Clin Psychopharmacol 1992; 12:42S–52S.
137. Calabrese JR, Woyshville MJ, Rapport DJ. Clinical effi-cacy of valproate. In: Joffe RT, Calabrese JR, eds. Anti-convulsants in Mood Disorders. New York: MarcelDekker, 1994; 131–146.
138. Martin LS, Joffe RT, Bebchuk JM. Clinical efficacy ofcarbamazepine. In: Joffe RT, Calabrese JR, eds. Anticon-vulsants in Mood Disorders. New York: Marcel Dekker,1994; 111–130.
139. Post RM, Frye MA, Denicoff KD, Leverich GS, Kim-brell T, Dunn RT. Beyond lithium in the treatment ofbipolar illness. Neuropsychopharmacology 1998; 19:206–219.
140. Maes M, Calabrese J, Jayathilake K, Meltzer HY. Effectsof subchronic treatment with valproate on L-5-HTP-in-duced cortisol responses in mania: evidence for increasedcentral serotonergic neurotransmission. Psychiatr Res1997; 71: 67–76.
141. Fahn S. Post-anoxic myoclonus movement with valproicacid. New Engl J Med 1978; 319: 313–314.
142. Shiah IS, Yatham LN, Lam RW, Zis AP. Effects ofdivalproex sodium on 5-HT1A receptor function inhealthy human males: hypothermic, hormonal, and be-havioral responses to ipsapirone. Neuropsychopharma-cology 1997; 17: 382–390.
143. Goodwin GM, DeSouza RJ, Green AR. The pharmacol-ogy of the hypothermic response in mice to 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT): a model ofpresynaptic 5-HT1A function. Neuropharmacology 1985;24: 1187–1194.
144. Martin KF, Phillips I, Hearson M, Prow MP, Heal DJ.Characterization of 8-OH-DPAT-induced hypothermia inmice as a 5-HT1A autoreceptor response and its evalua-tion as a model to selectively identify antidepressants. BrJ Pharmacol 1992; 107: 15–21.
145. Bill A, Knight M, Forster EA, Fletcher A. Direct evi-dence for an important species difference in the mecha-nism of 8-OH-DPAT-induced hypothermia. Br JPharmacol 1991; 103: 1857–1864.
146. Glaser T, De Vry J. Neurobiology of 5-HT1A receptors.In: Stahl SM, Gastpar M, Keppel HJM, Traber J, eds.
Serotonin 1A Receptors in Depression and Anxiety. NewYork: Raven Press, 1992; 35–53.
147. Elphick M, Yang J-D, Cowen PJ. Effects of carba-mazepine on dopamine- and serotonin-mediated neuroen-docrine responses. Arch Gen Psychiatry 1990; 47:135–140.
148. Pratt JA, Jenner P, Johnson AL, Shorvon SD, ReynoldsEH. Anticonvulsant drugs alter plasma tryptophan con-centrations in epileptic patients: implications for anti-epileptic action and mental function. J Neurol NeurosurgPsychiatr 1984; 47: 1131–1133.
149. Fernstrom JD. Role of precursor availability in controlon monoamine synthesis in brain. Physiol Rev 1983; 63:484–546.
150. Post RM, Ballenger JC, Uhde TW, Bunney WE. Efficacyof carbamazepine in manic-depressive illness: implicationsfor underlying mechanisms. In: Post RM, Ballenger JC,eds. Neurobiology of Mood Disorders. Baltimore:Williams and Wilkins, 1984; 777–816.
151. Mannel M, Muller-Oerlinghausen B, Czernik A, Sauer H.5-HT brain function in affective disorder: D,L-fenfluramine-induced hormone release and clinical out-come in long-term lithium/carbamazepine prophylaxis. JAffect Disord 1997; 46: 101–113.
152. Messenheimer JA. Lamotrigine. Epilepsia 1995; 36 (2(Suppl)): S87–S95.
153. Calabrese JR, Rapport DJ, Shelton MD, Kimmel SE.Clinical studies on the use of lamotrigine in bipolar disor-der. Neuropsychobiology 1998; 38: 185–191.
154. Gilman JT. Lamotrigine: an antiepileptic agent for thetreatment of partial seizure. Ann Pharmacother 1995; 29:144–151.
155. Southam E, Kirkby D, Higgins GA, Hagan RM. Lamot-rigine inhibits monoamine uptake in vitro and modulates5-hydroxytryptamine uptake in rats. Eur J Pharmacol1998; 358: 19–24.
156. Shiah IS, Yatham LN, Lam RW, Zis AP. Effects oflamotrigine on the 5-HT1A receptor function in healthyhuman males. J Affect Disord 1998; 49: 157–162.
157. Young LT, Robb JC, Patelis-Siotis I, MacDonald C,Joffe RT. Acute treatment of bipolar depression withgabapentin. Biol Psychiatry 1997; 42: 851–853.
158. Schaffer CB, Schaffer LC. Gabapentin in the treatment ofbipolar disorder. Am J Psychiatry 1997; 154: 291–292.
159. Ryback RS, Brodsky L, Munasifi F. Gabapentin in bipo-lar disorder. J Neuropsychiatry Clin Neurosci 1997; 9:301.
160. McElroy SL, Soutullo CA, Keck PE, Kmetz GF. A pilottrial of adjunctive gabapentin in the treatment of bipolardisorder. Ann Clin Psychiatry 1997; 9: 99.
161. Erfurth A, Kammereer C, Grunze H, Normann C,Walden J. An open label study of gabapentin in thetreatment of acute mania. J Psychiatr Res 1998; 32:261–264.
162. Knoll J, Stegman K, Suppes T. Clinical experience usinggabapentin adjunctively in patients with a history ofmania or hypomania. J Affect Disord 1998; 49: 229–233.
163. Taylor CP, Gee NS, Su T-Z, Kocsis JD, Welty DF,Brown JP, Dooley DJ, Boden P, Singh L. A summary ofmechanistic hypotheses of gabapentin pharmacology.Epilepsy Res 1998; 29: 233–249.
164. Rao ML, Clarenbach P, Vahlensieck M, Kraetzschmar S.Gabapentin augments whole blood serotonin in healthyyoung men. J Neural Transm 1988; 73: 129–134.
165. Ben-Menachem E, Persson LI, Hedner T. Selected CSFbiochemistry and gabapentin concentrations in the CSFand plasma in patients with partial seizures after a singleoral dose of gabapentin. Epilepsy Res 1992; 11: 45–49.
91
Shiah and Yatham
166. Marcotte D. Use of topiramate, a new anti-epileptic as amood stabilizer. J Affect Disord 1998; 50: 245–251.
167. Rosenfeld WE. Topiramate: a review of preclinical, phar-macokinetic, and clinical data. Clin Ther 1997; 19: 1294–1308.
168. Perucca E. A pharmacological and clinical review ontopiramate, a new antiepileptic drug. Pharmacol Res1997; 35: 241–256.
169. Nyberg S, Nordstrom A-L, Halldin C, Farde L. Positronemission tomography studies of 5-HT2-receptors. In:Kane JM, Moller H-J, Awouters F, eds. Serotonin inAntipsychotic Treatment. New York: Marcel Dekker,1996; 181–193.
170. Farde L, Ito H, Swahn CG, Pike VW, Halldin C. Quanti-tative analyses of carbonyl-carbon-11-WAY-100635 bind-ing to central 5-hydroxytryptamine-1A receptors in man.J Nucl Med 1998; 39: 1965–1971.
171. Ito H, Halldin C, Farde L. Localization of 5-HT1A recep-tors in the living human brain using [carbonyl-11C]WAY-100635: PET with anatomic standardization technique. JNucl Med 1999; 40: 102–109.
172. Lewis R, Kapur S, Jones C, Dasilva J, Brown GM,Wilson AA, Houle S, Zipursky RB. Serotonin 5-HT2
receptors in schizophrenia: a PET study using[18F]setoperone in neuroleptic-naive patients and normalsubjects. Am J Psychiatry 1999; 156: 72–78.
173. Mayberg HS, Robinson RG, Wong DF, Parikh R,Bolduc P, Starkstein SE, Price T, Dannals RF, Links JM,Wilson AA. PET imaging of cortical S2 serotonin recep-tors after stroke: lateralized changes and relationship todepression. Am J Psychiatry 1988; 145: 937–943.
174. Blin J, Baron JC, Dubois B, Crouzel C, Fiorelli M,Attar-Levy D, Pillon B, Fournier D, Vidailhet M, AgidY. Loss of brain 5-HT2 receptors in Alzheimer’s disease:in 6i6o assessment with positron emission tomographyand [18F]setoperone. Brain 1993; 116: 497–510.
175. Wang GJ, Volkow ND, Logan J, Fowler JS, Schlyer D,MacGregor RR, Hitzemann RJ, Gjedde A, Wolf AP.Serotonin 5-HT2 receptor availability in chronic cocaineabusers. Life Sci 1995; 56: 299–303.
176. Biver F, Wikler D, Lotstra F, Damhaut P, Goldman S,Mendlewicz J. Serotonin 5-HT2 receptor imaging in ma-jor depression: focal changes in orbito-insular cortex. Br JPsychiatry 1997; 171: 444–448.
177. Massou JM, Trichard C, Attar-Levy D, Feline A, Cor-ruble E, Beaufils B, Martinot JL. Frontal 5-HT2A recep-tors studied in depressive patients during chronictreatment by selective serotonin reuptake inhibitors. Psy-chopharmacology 1997; 133: 99–101.
178. Yatham LN, Liddle PF, Dennie J, Shiah IS, Adam MJ,Lane C, Lam RW, Ruth TJ. Decrease in brain serotonin2 receptor binding in patients with major depressionfollowing desipramine treatment: a positron emission to-mography study with fluorine 18-labeled setoperone.Arch Gen Psychiatry 1999; 56: 705–711.
179. Attar-Levy D, Martinot JL, Blin J, Dao-Castellana MH,Crouzel C, Mazoyer B, Poirier MF, Bourdel MC, Ay-mard N, Syrota A, Feline A. The cortical serotonin2receptors studied with positron-emission tomography and[18F]-setoperone during depressive illness and antidepres-sant treatment with clomipramine. Biol Psychiatry 1999;15: 180–186.
180. Buki VMV, Goodnick PJ. Catecholamines. In: GoodnickPJ, ed. Mania: Clinical and Research Perspectives. Wash-ington, DC: American Psychiatric Press, 1998; 119–134.
181. Janowsky DS, Overstreet DH. Acetylcholine. In: Good-nick PJ, ed. Mania: Clinical and Research Perspectives.Washington, DC: American Psychiatric Press, 1998; 119–134.
182. Petty F, Kramer GL, Davis LL. Gamma-aminobutyricacid. In: Goodnick PJ, ed. Mania: Clinical and ResearchPerspectives. Washington, DC: American PsychiatricPress, 1998; 157–169.
183. Shiah IS, Yatham LN. GABA function in mood disor-ders: an update and critical review. Life Sci 1998; 63:1289–1303.
184. Tassin J-P, Darracq L, Blanc G, Trovero F. Integratingthe monoamine systems. In: Briley M, Montgomery S,eds. Antidepressant Therapy: At the Dawn of the ThirdMillennium. London: Martin Duntiz, 1998; 1–18.
185. Khan AU. Interaction among neurotransmitters. In:Khan AU, ed. Neurochemistry of Schizophrenia and De-pression. Clovis: AJ Publisher, 1998; 277–298.
186. Kusumakar V, Yatham LN, Haslam DRS, Parikh SV,Matte R, Silverstone PH, Sharma V. Treatment of mania,mixed state, and rapid cycling. Can J Psychiatry 1997; 42(2 (Suppl)): 79S–86S.
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