BRITISH JOURNAL OF PSYCHIATRY $2001), 178, 448^453

Effects of rapid tryptophan depletion on brain informed consent for participation in the study.study.

5-HT5-HT22 receptors: a PET study Positron emission tomography LAKSHMI N. YATHAM, PETER F. LIDDLE, I-SHIN SHIAH, RAYMOND W. LAM, scanning and RTD protocol MICHAEL J. ADAM, ATHANASIOS P. ZIS and THOMAS J. RUTH All study subjects had a high-resolution magnetic resonance imaging scan of the head to exclude cerebral pathology and facilitate localisation of brain regions in PET images. The 1818F-setoperone was pre- pared by a modified method of Crouzel etet Background TheThemechanismby mechanismby which Rapid tryptophan depletion RTD) alal 1988), as described by Adam et aletal rapid tryptophan depletion RTD) paradigm induces a transient relapse of 1997). Each subject was scanned on two depressive symptoms in approximately separate days 5 h after the ingestion of paradigminduces depressive relapse 50% of patients with recently remitted amino acid mixtures. The scanning on one in recentlyremittedrecently remitted patients with depression treated with selective serotonin day was preceded by the ingestion of a depression is unknown. reuptake inhibitors SSRIs) but not in nutritionally balanced mixture 15 amino those treated with norepinephrine reuptake acids and 2.3 g of LL-tryptophan; control ses- Aims Todetermine the effects of RTD inhibitors NRIs) Delgado et aletal, 1999).,1999). sion) and on the other day by the ingestion

on brain 5-HT22 receptors using positron The RTD does not induce any mood changes of a tryptophan-deficient amino acid mix- emission tomography PET) and 1818 F-F- consistently in healthy volunteers Lam et aletal,, ture 15 amino acid drink that contained labelled setoperone. 2000). The RTD probably decreases brain all the other amino acids but no trypto- 5-hydroxytryptamine 5-HT) levels in all phan; RTD session). The composition of MethodMethod Ten healthy women groups, but only 50% of SSRI-treated the amino acid mixture was the same as underwenttwo PETscans.Each scan was patients experience depressive relapse; that used by Delgado et aletal 1999). The amino hence, a decrease in brain 5-HT alone acid mixture was flavoured with chocolate done 5 h after the ingestion of either a cannot account for a depressive relapse. It syrup and the unpleasant ingredients were balanced or a tryptophan-deficient amino is, however, conceivable that a decrease in given in a capsule form. The administration acid mixture, and the two test sessions brain 5-HT levels could induce changes in of the amino acid mixture was done in a were separated by atleast 5 days. another component of the 5-HT system, randomised, counterbalanced protocol, such as the 5-HT22 receptors that determine with two test days separated by at least 5 ResultsResults The RTD decreased plasma whether or not a subject experiences days.days. free tryptophan levels significantly but it depressive symptoms. In this study, we Subjects presented to the Mood assessed the effects of RTD on brain 5-HT Disorders Clinical Research Unit at 7 a.m. had no significantsignificanteffects effects on mood. 22 receptors in healthy women using positron At 7.15 a.m., an intravenous cannula was Subjects showed a significantdecrease in emission tomography PET) and 1818F-labelledF-labelled inserted and a blood sample was drawn for 1818 brain 5-HT5-HTbrain 22 receptor binding in various setoperone  F-setoperone). free tryptophan levels. Behavioural ratings corticalregions following the RTD session. were completed prior to and 5 h after the ingestion of amino acid mixtures. Ratings Conclusions When taken with the METHOD included a 20-item Hamilton Rating Scale evidence that antidepressanttreatmentis for Depression HRSD) consisting of the Subjects 29-item HRSD Williams et aletal, 1991) mod- associated with a decrease in brain 5-HT 22 This study was approved by the University ified to exclude the nine items that could receptors, these findings suggestthat a of British Columbia human ethics commit- not be rated within the same day, such as decrease in 5-HT22 binding following RTD tee. Subjects for the study were recruited sleep, eating because patients were fasting), might be an adaptive response that through advertisements. They were evalu- weight and diurnal variation. We also provides protection againstagainstdepressive depressive ated by a structured clinical interview for administered the Profile of Mood States DSM±IV, non-patient version SCID±NP; POMS; McNair et aletal, 1988) to detect sub- symptoms. SpitzerSpitzer et aletal, 1992). Because reduction in clinical mood changes. After subjects Declaration of interest None. the rate of 5-HT synthesis is greater in ingested the amino acid mixture, they stayed women following RTD Nishizawa et aletal,, in a room for the next 5 h. During this period, 1998), we recruited ten women with no subjects were allowed to read magazines. life-time history of psychiatric diagnosis Approximately 5 h later, they had a second and no family history of psychiatric dis- blood sample drawn for free tryptophan orders in the first-degree relatives for parti- levels. Following this, the subjects were cipation in the study. Subjects' ages ranged escorted to the PET suite. from 21 to 47 years, with a mean s.d.) of Blood samples were centrifuged 30.3 7.87) years. All subjects were physi- immediately for 30 min and an ultrafiltrate cally healthy, drug free and gave written of plasma was obtained by additional

448448

Downloaded from https://www.cambridge.org/core. 30 Sep 2021 at 15:27:25, subject to the Cambridge Core terms of use. RAPID TRYPTOPHAN DEPLETION

centrifuge 2000 gg) at room temperature for to and dissociation from non-specific bind- cortex and cerebellum did not vary sig-

30 min through a cellulose ultrafiltration ing sites. The ratio Bmax=Kd is known as the nificantly between the RTD and control membrane system Amicon Co., Beverley, specific binding potential. Because the time sessions. Furthermore, it should be noted MA, USA) for assay of plasma free trypto- course ofcourseof 1818F-setoperone accumulation in that the quantity that is determined for phan levels. The ultrafiltrate samples were cerebellum is not affected by saturating each subject is not the change in binding

frozen atfrozenat 77707088C and later assayed using doses of the 5-HT22 blocker ketanserin Blin potential itself, but is f 2cbÁ Bmax=Kd†.. high-performance liquid chromatography et aletal, 1990), it is reasonable to assume that None the less, under the assumption that with fluorometric detection Anderson etet specific binding in the cerebellum is negligi- non-specific binding is not affected by alal, 1981).,1981). ble. However, recently, Petit-Tabou et aletal tryptophan depletion, this quantity can be Subjects had a transmission scan done 1999) have shown that the non-specific regarded as a measure of change in binding to correct PET images for attenuation. binding is lower in cortex than that in potential.potential. Following this, subjects were given 148± cerebellum in humans. Under circum- Statistical Parametric Mapping SPM96) 259 MBq of 1818F-setoperone intravenously. stances where non-specific binding in software Friston et aletal, 1991, 1995) was The radioactivity in the brain was mea- cerebellum differs from that in cortex, the used to align PET images, co-register them sured with the PET camera system ECAT ratio of binding in cortex to that in cere- to magnetic resonance images and trans- 953B/31 CTI/Siemens, Knoxville, TN, bellum is given by: form the magnetic resonance images and USA). The spatial resolution of images is PET images) into the standard coordinate about 5 mm. We performed 15 frame frame used for templates in SPM96. Then Cx=Cb ˆ f 2cb‰ Bmax=Kd†‡ k5=k6†cx ‡ 1Š 1818 dynamicdynamicemissionemission scans on each subject 2† anan F-setoperone binding image was for a total of 110 min. The numbers and created by dividing each pixel in the RTD

durations of the frames were as follows: wherewhere f 2cb is the value of f 2derived using and control session realigned normalised 55662 min 10 min), 4665 min 20 min), cerebellar values for the transfer co- mean images by that image's average cere- 446610 min 40 min) and 26620 min20min bellar value. A mean activity value from efficientsefficients k5 andand k6, whereas,whereas k5=k6†cx isis 40 min). The subjects underwent the same evaluated using cortical values for k5 andand two large regions of interest one on the protocol 5±7 days later, so that by the end k6.. Assuming that non-specific binding is right and one on the left) drawn on three of the second test session the subjects had not affected by tryptophan depletion, the contiguous cerebellar slices was used as 1818F-setoperone scans preceded by an RTD change inchangein Cx=Cb between the baseline that image's average cerebellar value. The session and control test sessions. At the and depleted sessions is given by: binding images were smoothed by applying end of each test session, subjects were a 12-mm full width at half-maximum assessed clinically. None had any sub- FWHM) isotropic Gaussian filter to Á Cx=Cb†ˆf 2cbÁ Bmax=Kd† 3† stantial changes in mood. improve the signal-to-noise ratio.

wherewhere Á Bmax=Kd† is the change in specific binding potential. Data analysis An alternative approach would be to Statistical analysis A multipurpose imaging tool Pietrzyk etet employ a change in the ratio of regional to Statistical parametric mapping SPM96) alal, 1994) was used to draw regions in mean global cortical setoperone concentra- software was used to determine the change frontal, temporal and parietal cortex and tion to obtain a value that is proportional in cortex/cerebellum ratio hereafter referred

cerebellum. When time±activity curves to the change in local binding potential to as the 5-HT22 binding potential: 5-HT22BP)BP) were plotted, they showed that the cortex/ between conditions see Yatham et aletal,, between the RTD and control sessions. The cerebellum ratio was constant between 70 1999, for details). This method has the grey matter threshold was determined using and 110 min, indicating the occurrence of advantage of circumventing the uncertainty a multipurpose imaging tool Pietrzyk et aletal,, pseudo-equilibrium during this time period surrounding the differences in non-specific 1994) and was set at 1.3 times the mean for the tracer. Hence, the PET data binding between cortex and cerebellum. global cerebral image intensity, to exclude obtained during this period were used for This method, however, is only valid provided non-grey matter voxels in the analysis. For comparing the differences in binding that the mean global binding potential does each voxel, the ZZ value corresponding to

between the RTD and control sessions. not vary substantially between conditions. thethe tt statistic for the difference in 5-HT22BPBP If it is assumed that there is no specific Our data suggestthat the mean s.d.) global between the RTD and control sessions was binding potential was significantly lower in computed. We also computed the ZZ valuevalue binding to 5-HT22 receptors in the cere- bellum and, furthermore, that non-specific the RTD session 1.56965 0.38850)) than for each voxel for the difference in 5-HT22BPBP binding is the same in cerebellum as in in the control session 1.64726 0.35139)) between the first and second scans for each cortex, the ratio of binding in cortex CxCx)) PP550.01) and hence this method cannot be subject to examine the order of scanning to cerebellum CbCb) is given by: used to compare the differences in binding effects. In estimating the significance of between the sessions. change in individual voxels, the method We therefore employed the method developed by Worsley 1994) as implemen- Cx=Cb ˆ f 2 Bmax=Kd†‡1 1† based on the ratio of cortical to cerebellar ted in SPM was used to correct for multiple

wherewhere Bmax is the total number of receptors, binding to derive a measure of change in comparisons, taking into account the corre-

Kd is the equilibrium dissociation rate con- 5-HT5-HT22 receptor binding potential for each lation between voxels. In addition, we also stant of the ligand±receptor complex and voxel from the measured change in cortex/ computed the significance of change in f 2 ˆ 1=‰1 ‡ k5=k6†Š, where,where kk5 and5and kk66 cerebellum ratio employing Equation 3)), clusters of contiguous voxels exceeding a are the transfer coefficients for association assuming that the non-specific binding in threshold of Z ˆ 2:33,, as implemented in

449449

Downloaded from https://www.cambridge.org/core. 30 Sep 2021 at 15:27:25, subject to the Cambridge Core terms of use. YATHAYATHAM M E T AL

SPM96 based on the method of Poline et aletal 1997).1997). Behavioural and plasma free trypto- phan data were analysed using paired and unpairedunpaired tt-tests and repeated-measures analysis of variance ANOVA) with time and session as intrasubject factors. Data are presented as mean s.d.) and all tests were two-tailed, with significance set at PP550.05. All analyses were performed on a personal computer using the Statistical Package for Social Science SPSS) software, version 7.5 SPSS, 1996).

RESULTSRESULTS Effects of RTD on plasma free tryptophan levels and mood Fig. 11Fig. Mean s.d.) plasma free tryptophan levels during rapid tryptophan depletion RTD) and control Figure 1 shows the plasma free tryptophan sessions in ten healthy subjects. levels during the RTD and control sessions. Baseline mean s.d.) plasma free tryptophan levels did not differ significantly between control 0.86 0.07) mmg/ml) and RTD 0.95 0.09)0.09) mmg/ml) sessions ttˆ770.72, d.f.d.f.0.72, ˆ18,18, PPˆ0.47). As expected, the RTD session sig- nificantly reduced plasma free tryptophan levels to 0.27 0.19) mmg/ml, 71.5% decrease) ttˆ7.76, d.f.d.f.7.76, ˆ9,9, PP550.0001), whereas in the control session there was a significant increase in plasma free tryptophan levels to 2.76 1.16) mmg/ml;g/ml; ttˆ775.51, d.f.5.51,d.f.ˆ9,9, PP550.0001). Moreover, repeated-measures ANOVA showed a significant session66 time interaction effect FFˆ46.2, d.f.46.2,d.f.ˆ1, 9,1,9, PP550.0001), indicating that RTD led to a significant reduction in the plasma free tryptophan level when compared with the control session. With regard to behavioural rating, none of our study subjects became depressed during either session, as shown by no significant changes in the HRSD and POMSratings not shown; data available from L.N.Y. upon request).

Effects of RTD on brain 5-HT22 receptors

The 5-HTThe5-HT22BP was decreased significantly following the RTD session compared with Fig. 22Fig. Statistical parametric maps of tt values displayed as maximum intensity projections on the sagittal the control session. Analysis with SPM upper left), left), transverse transverse lower lower left) left) and and coronal coronal upper upper right) right) renderings renderings of of the the brain. brain.These These projections projections show show showed an extensive cluster of voxels regions of decreased 1818F-setoperone binding following an RTD session.Voxels for which ZZ exceeds 2.33 are embracing frontal, temporal, parietal and occipital cortical regions Fig. 2). The shown in shades of grey range 2.33^ 4.67).

reduction in 5-HT22BP in this cluster was highly significant even after correcting for multiple comparisons PP550.0001) Table 1). The cluster included 28 106 voxels and was 7.9% for the entire cluster. There were The location and ZZ value for change in

this corresponds to about 39% of the 134 voxels within this cluster that satisfied 5-HT5-HT22BP at local maxima where ZZ exceededexceeded volume of grey matter that was in the field the criteria for significance for individual 4.00 4.00PP550.025 after correction for multiple

of view. The mean reduction in 5-HT22BPBP voxels.voxels. comparisons) are given in Table 1. The areas

450

Downloaded from https://www.cambridge.org/core. 30 Sep 2021 at 15:27:25, subject to the Cambridge Core terms of use. RAPID TRYPTOPHAN DEPLETION

Ta b l e 11Tab Cluster size, PP andand ZZ values, and coordinates with PP and ZZ values, for brain regions with significant Several studies in recent years have decreases inindecreases 1818F-setoperone binding in ten healthy subjects following a rapid tryptophan depletion depletion RTD) RTD) session session suggested that the in vivoinvivo measurement of neurotransmitter receptors is affected by changes in the levels of endogenous neuro- Cluster Voxels transmitter. This has been demonstrated

SizeSize ZZ value CorrectedCorrected ZZ valueCorrected Coordinates Brain region very elegantly in the case of D22 receptorsreceptors PP valuevalue PP valuevalue by manipulating endogenous dopamine xyx yzz levels Breier et aletal, 1997; Laruelle et aletal,, 1997). These studies have shown that 28106281064.67 0.000 4.67 0.004 775656 7738 772222Left fusiform gyrus increasing the synaptic dopamine concen- 4.514.510.008 7738 7720204Leftinsula 4 Left insula tration with amphetamine or methyl- 4.504.50 0.0080.008 775656 773014 Left superior temporal gyrus phenidate reduces, whereas decreasing the 4.180.029 77242456 10 Left superior frontal gyrus synaptic dopamine concentration with dopamine synthesis inhibitor aa-methyl--methyl-pp-- tyrosine AMPT) increases, the striatal

DD22 receptor binding as measured with 1111C-raclopride Breier et aletal, 1997) or 123123I-iodobenzamide IBZM) Laruelle etet alal, 1997). It is, therefore, conceivable that the changes in endogenous 5-HT levels

could affect the estimates of 5-HT22 receptorreceptor binding with PET. However, RTD is expected to decrease rather than increase brain 5-HT levels. This should leave a

greater number of 5-HT22 receptors unoccu- pied. In such a situation, one would expect

to see an increase in 5-HT22BP as measured withwith 1818F-setoperone. Because we found a

decrease in 5-HT22BP, this is unlikely to be due to a confounding effect of a decrease in brain 5-HT levels.

Is the decrease in 5-HT5 -HT22BP due to a change in 5-HT22 receptor affinity or density? The methods used in this study provide a

semi-quantitative estimate of 5-HT22BP butBPbut do not permit an independent deter-

mination of Bmax density) or Kd affinity).affinity). Therefore, we cannot tell whether the Fig. 33Fig. Sagittal renderings of the brain showing areas of significant decreases in 18F-setoperone binding decrease in 5-HT BP observed in the study indicated by arrows 1, left superior temporal gyrus; gyrus; 2, 2, left left fusiform fusiform gyrus; gyrus; 3, 3, left left insula; insula; 4, 4, left left superior superior frontal frontal 22 subjects following RTD was due to a gyrus; 5, left superior frontal gyrus) in ten healthy subjects following an RTD session. decrease in Bmax or an increase in Kd.. However, most Peroutka & Snyder, that showed the most significant decrease inin humans using PET and 1818F-setoperone. 1980; Kellar & Stockmeier, 1986; Paul etet

5-HT5-HT22BP included the left fusiform gyrus, Our findings indicated that RTD led to a alal, 1988; Mason et aletal, 1993; Klimek et aletal,,

left insula, left superior temporal gyrus significant widespread reduction in 5-HT22BPBP 1994; Hensler & Truett, 1998), although and left superior frontal gyrus Table 1 in various cortical regions bilaterally. The not all Blackshear & Sanders-Bush,

and Fig. 3). reduction in 5-HT22BP was particularly pro- 1982), studies that examined the acute or

There was no difference in 5-HT22BPBP minent in the left fusiform gyrus, left insula, chronic effects of antidepressants or between first and second scans, indicating left superior temporal gyrus and left superior electroconvulsive shock on various 5-HT that scanning order had no systematic effect frontal gyrus. receptors in rats reported an alteration in

on 5-HTon5-HT22BP.BP. A potential source of artefactual result Bmax and notandnot Kd; this would suggest that must be considered before ascribing the pharmacological or somatic interventions

decrease in 5-HT22BP to a true decrease in commonly lead to changes in Bmax andand

DISCUSSION 5-HT5-HT22 receptor density. The estimates of notnot Kd. Hence, the decrease in 5-HT22BPBP

5-HT5-HT22BP might have been confounded by observed in our study subjects is more This is the first study to measure the effects changes in endogenous 5-HT levels that likely to be due to a decrease in Bmax thanthan

of RTD on brain 5-HT22 receptors in living would have occurred following RTD. to an increase in Kd..

451

Downloaded from https://www.cambridge.org/core. 30 Sep 2021 at 15:27:25, subject to the Cambridge Core terms of use. YATHAYATHAM M E T AL

Could 5-HT22 receptorsreceptors Could a change in 5-HT22 receptorreceptor orbitofrontal cortex and thalamus in those down-regulate rapidly? density determine whether or not patients who relapsed following tryptophan Another issue that needs to be considered a subject experiences depressive depletion but not in those who did not symptoms following RTD? relapse Bremner et aletal, 1997). This would before ascribing the decrease in 5-HT22BPBP support the argument that some SSRI- to a decrease in Bmax and hence to a decrease Our finding of no mood changes in healthy treated patients may be able to mount a in 5-HTin5-HT22 receptor density is whether recep- tor density could change within a 6±7 h time volunteers following RTD is consistent compensatory mechanism to prevent the period following an intervention. Indeed, with the findings of previous studies in relapse of depressive symptoms. This hy- healthy volunteers see Lam et aletal, 2000,,2000, pothesis, however, needs to be tested in animal studies have shown that 5-HT22 recep-recep- for a review). Could a decrease in 5-HT patients with recently remitted depression tor density was significantly reduced 48 h 22 after a single dose of mianserin Blackshear receptor density in our subjects following before any firm conclusions can be drawn. & Sanders-Bush, 1982; Hensler & Truett, RTD explain the lack of mood changes? A 1998). Similarly, rats that received injections number of animal studies have indeed ACKNOWLEDGEMENTS of 5-HTof5-HT agonist DOM 4-methyl-2,5- shown that most, but not all, antidepressant 22 medications down-regulate 5-HT receptorsreceptors dimethoxyphenylisopropylamine) every 8 h 22 This study was supported by grants from the Medi- cal Research Council of Canada and the Canadian showed a significant decrease in 5-HT Peroutka & Snyder, 1980; Blackshear & 22 Psychiatric Research Foundation to L.N.Y. receptors in frontal cortex following the Sanders-Bush, 1982; Cross & Horton, second injection Leysen & Pauwels, 1990). 1988; Paul et aletal, 1988; Hrdina & Vu, Other studies have shown that treatment 1993; Klimek et aletal, 1994). Furthermore, REFERENCES with imipramine, amitriptyline and desipra- we have shown recently in a PET study that patients with depression show a significant Adam, M. J., Lu, S., Jivan, S., et aletal $19 9 7)7)$19 SimplifiedSimplified mine for 2±7 days also led to a reduction in purification and synthesis of F-18 setoperone. Journal ofofJournal decrease in brain 5-HT receptors following 5-HT5-HT receptor density Paul et aletal, 1988;,1988; 22 Labeled Compounds and Radiopharmaceuticals,, 40,258. 22 treatment with desipramine Yatham et aletal,, MasonMason et aletal, 1993). A single dose of fluox- Anderson, G. M.,Young, J. G., Cohen, D. J., et aletal 1999). Taken together, these observations $19 81) Liquid-chromatographic determination of etine decreases 5-HT1A1A receptor density may indicate that reduced 5-HT receptorreceptor serotonin and tryptophan in whole blood and plasma. within a 24-h period Klimek et aletal, 1994),,1994), 22 Clinical Chemistry,, 2727, 775^776.,775^776. therefore it is feasible that RTD could lead density may be potentially a critical event to a rapid reduction in 5-HT receptorreceptor in the prevention and relief of depressive Blackshear, M. A. & Sanders-Bush, E.$19 $1982) 82) 22 symptoms.symptoms. Serotonin receptor sensitivity after acute and chronic density.density. treatment with mianserin. Journal of Pharmacology and If this were true, only those subjects that Experimental Therapeutics,, 221,,303^308. 303^308. fail to down-regulate their brain 5-HT 22 Blin, J., Sette, G., Fiorelli, M., et aletal $1990)$19 9 0) AmethodAmethod receptors following RTD or those that do for the in vivo investigation of the serotonergic 5-HT22 not have down-regulated 5-HT22 receptorsreceptors receptors in the human cerebral cortex using positron Should tryptophan depletion cause should show a transient relapse of depres- emission tomography and 1818F-labeled setoperone. Journal of Neurochemistry,, 5454,1744^1754. an up-regulation rather than a sive symptoms. Animal studies have shown down-regulation of 5-HT22 that desipramine an NRI) consistently Breier, A., Su, T, P., Saunders, R., et aletal $19 9 7) receptors? Schizophrenia is associated with elevated amphetamine- down-regulates 5-HT22 receptors Peroutka induced synaptic dopamine concentrations: evidence In general, neurotransmitter receptors up- & Snyder, 1980; Goodnough & Baker, from a novel positron emission tomography method. regulate following depletion of a neuro- 1994), whereas SSRIs such as fluoxetine Proceedings of the National Academy of Sciences USA,, 9494,, transmitter or administration of an do not appear to have consistent effects 2569^2574. Bremner, J. D., Innis, R. B., Salomon, R. M., et aletal antagonist, and down-regulate following on 5-HTon5-HT22 receptors Peroutka & Snyder, the administration of an agonist. However, 1980; Hrdina & Vu, 1993). The fact that $19 9 7) Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion- it is well known that the regulation of brain patients treated with NRIs do not relapse induced depressive relapse. Archives of General PsychiatryPsychiatry,, 5454, 364^374.,364^374. 5-HT5-HT22 receptors does not follow the classi- following RTD is in keeping with this cal receptor regulation model because both hypothesis because these patients already Butler, P.D.,P. D., Pranzatelli, M. R. & Barkai, A. I. $19 9 0) Regional central serotonin-2receptor 5-HT5-HT22 agonists as well as antagonists would have down-regulated 5-HT22 recep-recep- consistently down-regulate 5-HT receptorsreceptors tors. This hypothesis would predict that binding and phosphoinositide turnover in rats with 22 5,7-dihydroxytryptamine lesions. Brain Research Bulletin,, Leysen, 1990). Also, some animal studies patients treated with SSRIs would be vul- 2424,125^129. have shown that experimentally induced nerable to RTD-induced depression because Cross, J. A. & Horton, R.W.$19 $1988) 8 8) Effects of chronic 5-HT neuronal lesions that deplete 5-HT they would not be expected to have down- oral administration of the antidepressants, desmethylimipramine and zimelidine on rat cortical cause either no change Butler et aletal, 1990),1990) regulated 5-HT22 receptors. However, only GABAGABA binding sites: a comparison with 5 -HT binding or a decrease in brain 5-HT receptorsreceptors 50% of SSRI-treated patients relapse BB 22 22 site changes. British Journal of Pharmacology,, 9393,331^336., 331^336. LeysenLeysen et aletal, 1982). These studies indicate following RTD; possibly these are the that the regulation of 5-HT receptors is patients that cannot down-regulate their Crouzel, C.,Venet, M., Irie,T., et aletal $19 8 8) Labelling ofofLabelling 22 a serotonergic ligand with 1818 F:F: 18F-setoperone. Journal ofofJournal peculiar and cannot be predicted based on 5-HT5-HT22 receptors to prevent relapse of symp- Labeled Compounds and Radiopharmaceuticals,, 25,, the classic receptor regulation model. Thus, toms. There are no PET studies to date 403^414.403^414.

the finding of a decrease in 5-HT22BPBP that measured the effects of RTD on brain Delgado, P.L., Miller,Miller,H. H. L., Salomon, R. M., et aletal

following RTD is consistent with what is 5-HT5-HT22 receptors in patients with depression. $1999)$1999) Tryptophan-depletion challenge in depressed known about the regulation of this receptor However, a recent PET study that examined patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism and with the findings of previous animal brain glucose metabolism reported a of antidepressant action. Biological Psychiatry,, 4646,, studies.studies. decrease in the middle frontal gyrus, 212^220.212^2 20.

452

Downloaded from https://www.cambridge.org/core. 30 Sep 2021 at 15:27:25, subject to the Cambridge Core terms of use. RAPID TRYPTOPHAN DEPLETION

Friston,Friston,K.J.,Frith,C.D.,Liddle,P.F., K. J., Frith, C. D., Liddle, P. F., et aletal $19 91) Comparing function PET) images: the assessment of significant change. Journal of Cerebral Blood Flow and CLINICAL IMPLICATIONS MetabolismMetabolism,, 1111, 690^699.

&& __ ,,Holmes,A.P.,Worsley,K.J., Holmes, A. P., Worsley, K. J., et aletal $19 95) A decrease in brain 5-HT22 receptors may be critical in determining whether or not Statistical parametric maps in functional imaging: a subjects experience depressive depressive symptoms symptoms following following tryptophan tryptophan depletion. depletion. general linear approach. Human Brain Mapping,, 22,, 189^210. && Brain 5-HT5-HTBrain 22 receptors may be an important target for an antidepressant effect. Goodnough, D. B. & Baker,G. B.$19 $1994) 94)

55-Hydroxytryptamine -Hydroxytryptamine 22 and beta-adrenergic receptor && A decrease in brain 5-HT levels alone may not cause depressive symptoms. regulation in rat brain following chronic treatment with desipramine and fluoxetine alone and in combination. LIMITATIONS Journal of Neurochemistry,, 6262, 2262^2268.

Hensler, J. G. & Truett, K. A.$19 $1998) 9 8) Effect of chronic && Because this study did not use kinetic modelling, it is not possible to tell whether serotonin-2receptor agonist or antagonist administration on serotonin-1A receptor sensitivity. the decrease in setoperone binding observed in subjects was due to changes in Neuropsychopharmacology,, 19, 354^364.,354^364. receptor density or affinity. Hrdina,P.D.&Vu,T.B.$1993)Hrdina,P.D.&Vu,T.B.$19 93) Chronic fluoxetine && Because none of the subjects experienced depressive symptoms, the the study study does does treatment upregulates 5-HTuptake sites and 5-HT22 receptors in rat brain: an autoradiographic study. not answer the question of whether or not the response of 5-HT22 receptors to rapid Synapse,, 1414,,324^331. 324^331. tryptophan depletion depletion differs differs between between those those who who become become depressed depressed and and those those who who Kellar, K. J. & Stockmeier,C. A.$19 $1986) 8 6) Effects ofofEffects do not.donot. electroconvulsive shock and serotonin axon lesions on beta-adrenergic and serotonin-2receptors in rat brain. && We interpret the observed changes in 5-HT receptors as a possible Annals of the New York Academy of Sciences,, 462462,,76^90. 76^90. 22 compensatory process that protects against depression, but this study cannot tell us Klimek,V., Zak-Knapik, J. & Mackowiak, M.$19 $1994) 94) Effect of repeated treatment with fluoxetine and whether 5-HT22 receptors play a a role role in in the the pathophysiology pathophysiology of of major major depression. depression.

citalopram, 5-HTuptake5-HT uptake inhibitors, on 5-HT1A1A andand 5-HT5-HT22 receptors in the rat brain.Journal of Psychiatry and Neuroscience,, 19, 63^67.,63^67.

Lam, R.W., Bowering, T. A., Tam,Tam,E. E. M., et aletal $2000) Effects of rapid tryptophan depletion in patients with seasonal affective disorder in natural summer remission. LAKSHMI N. YATHAM, MBBS, Division of Mood Disorders, The University of British Columbia; PETER F. Psychological Medicine,, 3030, 79^87.,79^87. LIDDLE, MBBS, Division of Schizophrenia, The University of British Columbia; I-SHIN SHIAH, PhD, Department Laruelle, M., D'Souza, C. D., Baldwin, R. M., et aletal of Psychiatry,Tri-Service General Hospital, National Defense Medical Centre,Taipei,Taiwan; RAYMOND W. LAM, MD, Division of Mood Disorders, The University of British Columbia; MICHAEL J. ADAM, PhD, TRIUMF $19 9 7) Imaging DDImaging 22 receptor occupancy by endogenous dopamine in humans. Neuropsychopharmacology,, 17,, Positron EmissionTomography Programme, The University of British Columbia; ATHANASIOS P. ZIS, MD, 162^174. Division of Mood Disorders, The University of British Columbia; THOMAS J. RUTH, PhD,TRIUMFPhD, TRIUMF Positron EmissionTomography Programme,TheProgramme, The University of British Columbia,Vancouver,BC,CanadaColumbia,Vancouver,BC, Canada Leysen, J. E.$19 $1990) 9 0) Gaps and peculiarities in 5-HT2A2A receptor studies. Neuropsychopharmacology,, 33, 361^369.,361^369. CorrespCorrespondence:ondence: Lakshmi N.Yatham, AssociateAssociate Professor of PsychPsychiatry,Directoriatry,Director of Mood Disorders __ ,,Geerts,R.,Gommeren,W., Geerts, R., Gommeren,W., et aletal $19 82)82)$19 Regional distribution of serotonin-2-receptor binding sites in the Clinical Research Unit,The University of British Columbia, 2255 Wesbrook Mall,Vancouver,BC,Canada brain and effects of neuronal lesions. Archives of V6T 2A1.Tel:1 604 822 0562; Fax: 1 604 822 7922; e-mail: yatham @@unixg.ubc.ca International Pharmacodynamics,, 256,301^305., 301^305. First received 23 June June 2000, final finalrevision1November revision 1November 2000, 2000, accepted accepted 2 2 November November 2000) 2000) __ & Pauwels, P.P.J. J.$19 $1990) 9 0) 5-HT5-HT2A2A receptors, roles, and regulation. Annals of the New York Academy of Sciences,, 600, 183^191.,183^191.

Mason, G. A.,Walker,C. H. & Little, K.Y.$19 $1993) 93) Peroutka,S.J.&Snyder,S.H.$1980)Peroutka, S. J. & Snyder, S. H. $19 8 0) Long-term SPSSSPSS$1996)$19 9 6) SPSS for Windows .Version 7.5).Chicago,IL: Effects of concurrent subchronic treatments with antidepressant treatment decreases spiroperidol- SPSS. desmethylimipramine and propranolol on beta- labeled serotonin receptor binding. Science,, 210210, 88^90.,88^90. adrenergic and serotonin 22 receptors in rat brain. Psychopharmacology,, 110,110^114. Petit-Tabou,M.-C., Landeau, B., Barre, L., et aletal Williams, J. B.W.,B. W., Link, M. & Rosenthal,Rosenthal, N. E.$19 $1991) 91) $1999)$19 9 9) Parametric PET imaging of 5HT receptor McNair,D.M.,Lorr,D.&Droppelman,L.F.$1988)McNair,D.M.,Lorr,D.&Droppelman,L.F.$19 8 8) 2A2A Structured Interview Guide for the Hamilton Depression distribution with 1818F-setoperone in the normal human Manual for the Profile of Mood States.SanDiego,CA: Rating Scale, Seasonal Affective Disorders Version neocortex. Journal of Nuclear Medicine,, 4040,25^32. EducationTesting Services. .SIGH^SAD). New York: New York Psychiatric Institute. Pietrzyk,U., Herholz, K., Fink, G., et aletal $19 94) AnAn Nishizawa, S., Benkelfat, C.,Young, S. N., et aletal interactive technique for three-dimensional image $19 9 8) Differences between males and females in rates Worsley, KK. . J.$19 94)9 4 ) Local maxima and the expected registration: validation for PET, SPECT, MRI, and CT of serotonin synthesis in human brain. Proceedings of the Euler characteristic of excursion sets of Chi22,, FF andand tt brain studies. Journal of Nuclear Medicine,, 3535, 2011^2018. National Academy of Sciences USA,, 9494, 5308^5313. fields.fields. Advanced Applied Probability,, 2626,13^42. Poline, J. B.,Worsley, K. J., Evans, A. C., et aletal $19 9 7)7)$19 Paul, I. A., Duncan, G. E., Powell, K. R., et aletal $19 8 8)8)$19 Combining spatial extent and peak intensity to test for Regionally specific neural adaptation of beta adrenergic Yatham, L. N., Liddle, P.P.F., F., Dennie, J., et aletal $19$1999) 9 9) activations in functional imaging. Neuroimage,, 55, 83^96. and 5-hydroxytrytpamine22 receptors after Decrease in brain serotonin 2receptor binding in antidepressant administration in the forced swim test Spitzer, R. L., Williams, J. B. W., Gibbon, M., et aletal patients with major depression following desipramine and after chronic antidepressant drug treatment. JournalJournal $19 92) Structured Clinical Interview for DSM ^ III ^ R, treatment: a positron emission tomography study with of Pharmacology and Experimental Therapeutics,, 246246,, Nonpatient Edition.Washington, DC: American fluorine 18-labeled setoperone. Archives of General 956^962.956^962. Psychiatric Association. PsychiatryPsychiatry,, 5656, 705^711.,705^711.

453

Downloaded from https://www.cambridge.org/core. 30 Sep 2021 at 15:27:25, subject to the Cambridge Core terms of use.