Am J Psychiatry 1 41 : I 0, October 1984 1159

Regular Articles

Pretreatment Neurotransmitter Metabolite Levels andResponse to Tricyclic Antidepressant Drugs

James W. Maas, M.D., Stephen H. Koslow, Ph.D., Martin M. Katz, Ph.D.,Charles L. Bowden, M.D., Robert L. Gibbons, Ph.D., Peter E. Stokes, M.D.,

Eli Robins, M.D., and John M. Davis, M.D.

Relationships between pretreatment

neurotransmitter metabolite levels and response to

imipramine and amitriptyline were studied in I 04

depressed patients. Normal values for urinary

norepinephrine and low values for urinary MHPG

were associated with greater incidence of drugresponse in bipolar, but not unipolar, patients. For

unipolar, but not bipolar, patients low CSF 5-HIAAand high urinary metanephrine values were

associated with a greater incidence of drug response.These data indicate that the pretreatment functional

state of catecholamine and serotonin systems isassociated with type of response to drug treatment.

The authors present hypotheses about the association

of alterations in serotonin and norepinephrine

systems and definable subtypes of depression.

(AmJ Psychiatry 141:1159-1171, 1984)

Received Nov. 23, 1982; revised March 14, 1983; accepted June

14, 1983. From the National Institute of Mental Health-Clinical

Research Branch Collaborative Program on the Psychobiology of

Depression-Biological Studies. Address reprint requests to Dr.

Maas, Department of Psychiatry, the University of Texas Health

Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio,

TX 78284.Completed with the cooperation and participation of the Collaho-

rative Program investigators: S.H. Koslow (project director), S.

Secunda (deputy project director), MM. Katz (senior investigator),

I. Hanin (consultant), B. Harris-Larkin (protocol monitor) (NIMH);

J.W. Maas (chairman) (University of Texas Health Science Center at

San Antonio); D.E. Redmond, Jr., A. Swann (Yale University School

of Medicine); J.M. Davis, R. Casper, S. Chang, D. Garver, J. Javaid

(Illinois State Psychiatric Institute); J. Mendels, D. Brunswick, A.

Frazer, A. Ramsey, S. Stern (Philadelphia VA Medical Center); P. E.

Stokes, J. Kocsis (Cornell University Medical College); E. Robins

(Washington University School of Medicine, St. Louis); J. Croughan

(Washington University School of Medicine and Jewish Hospital, St.

Louis); C. Bowden, R. Shulman (University of Texas Health Science

Center at San Antonio).

Supported by grants MH-38034, MH-26975, MH-26977, MH-

26979, MH-26978, MH-31921, and MH-36232 from NIMH.

E arlier studies (1, 2) have suggested that depressivestates are associated with disorders in brain nor-

epinephrine or serotonin (5-hydroxytryptamine, or 5-HT) metabolism and/or disposition. In the explorationof these hypotheses results emerged which indicated

that there are relationships between pretreatment neu-rotransmitter metabolites and the subsequent responseto treatment with tricyclic antidepressants. For exam-ple, it has been reported that a low pretreatment levelof urinary 3-methoxy-4-hydroxyphenylglycol

(MHPG), which may reflect norepinephrine metabo-lism by the human brain (3), is associated with asubsequent favorable response to imipramine and oth-

er antidepressant drugs, whereas a high level is associ-ated with an unfavorable response (4-9). Also, some(5, 6, 10) investigators have found that high or normal

pretreatment levels of urinary MHPG predict a favor-able response to amitriptyline, but other studies (7, 1 1,12) have not shown this association. Relationshipsbetween CSF indoleamine metabolites and nortripty-line response have also been reported (13). On thebasis of these observations it was suggested that thereis a biological subtype of depression which is charac-terized by a low pretreatment urinary MHPG level anda particular sensitivity to treatment with imipramine.Further, since imipramine and its metabolic productdesmethylimipramine have multiple effects on norad-renergic neurons (14) and because MHPG is a major

metabolite of the neurotransmitter norepinephrine,Maas (15) hypothesized that patients with the biologi-

cal subtype of depression characterized by a low

MHPG level and imipramine responsivity have a func-tional disorder in noradrenergic systems. Also, given

the initial reports (5, 6, 10) which indicated thatpatients with high or normal MHPG values respondedparticularly well to amitriptyline, a drug that blocksreuptake of 5-HT but not of norepinephrine, Maas(15) hypothesized that the subgroup of depressedpatients who have normal to high MHPG levels and

NEUROTRANSMI1TER METABOLITE LEVELS AND ANTIDEPRESSANTS

1160 Am J Psychiatry 141:10, October 1984

respond to amitriptyline have a disorder in serotoner-gic systems. These hypotheses, which suggest that

there are two separable groups of depressed patients,one with a disorder in noradrenergic systems and theother with a dysfunction in serotonergic systems, haveimportant implications for improving the treatment ofdepressed patients and for understanding the patho-physiology of depressive states. For these reasons, theinvestigation of relationships between multiple mea-sures of neurotransmitter metabolites obtained fromthe same patient during the pretreatment period andthe subsequent response to treatment with imipramine

or amitriptyline has been one of the major foci of theNIMH collaborative study of the psychobiology ofdepression (16, 17).

In this paper we present data dealing with relation-ships between pretreatment, or baseline, values of CSFMHPG, CSF 5-hydroxyindoleacetic acid (5-HIAA),

and CSF homovanillic acid (HVA) and the subsequentresponse of depressed patients to treatment with imip-ramine or amitriptyline. These three compounds arethe major metabolites in brain of the neurotransmittersnorepinephrine, 5-HT, and dopamine, respectively. Wealso present data relevant to pretreatment urine levels

of the catecholamines norepinephrine and epinephrineand their metabolites normetanephrine, metanephrine,

vanillylmandelic acid (VMA), and MHPG and thesubsequent response of these patients to imipramine oramitriptyline.

METHOD

The methods employed in the NIMH collaborative

study of the biology of the depressive disorders havebeen given in detail in a paper by Secunda et al. (17),but for clarity we will note here issues relevant to thisreport.

All patients met the Research Diagnostic Criteria(RDC) (18) for a major depressive disorder of eitherthe bipolar or unipolar type as well as the inclusion

and exclusion criteria for primary affective disorder(19). Explicit inclusion and exclusion criteria are de-tailed in the paper by Secunda et al. (17). In this paperwe use the term “depressed patients” to mean unipolarand bipolar patients.

The data presented in this paper were obtained from

104 depressed patients who completed a baseline of 2weeks of placebo administration and a period of drug

treatment with either amitriptyline or imipramine.Secunda et al. (17) have given details of the pretreat-ment and drug treatment protocols. We assigned 125patients to a particular drug on a random basis (17),64 to amitriptyline and 61 to imipramine. However,nine patients did not complete the amitriptyline treat-ment protocol and 12 did not complete the imipramine

protocol; thus, 55 patients received amitriptyline and49 received imipramine. The reasons for not complet-ing the protocols were similar for the two drugs. Of the

21 patients who were dropped from the two protocols,

13 were removed before the end of 2 weeks of drug

treatment and 7 before the end of 3 weeks. None ofthese patients remained in the protocols long enoughto be classified by type of response.

Twenty-six unipolar and 23 bipolar depressed pa-tients were treated with imipramine and completed theprotocol. Thirty-eight unipolar and 17 bipolar patients

completed the amitriptyline protocol. The low numberof bipolar depressed patients who received amitrip-

tyline and for whom biochemical data were availablepresented special problems in the analysis of the data,which will be noted later in this paper.

The drugs were administered double blind, and thedose and schedule were fixed. The dose was raised to250 mg/day by day 7 of treatment. Some patients(approximately 15%) were unable to tolerate thisdose, and it was decreased.

The research protocol required that an evaluation ofresponse be made after 4 weeks of drug treatment. Atthat time patients were categorized as being responders(essentially recovered) or nonresponders (essentiallyunrecovered or with minimal or no change) or werecategorized as having indeterminate responses. Thisindeterminate group was heterogeneous, i.e., con-tamed both patients who had only a modest therapeu-tic response to drug treatment and patients who, witha longer period of treatment, might have eventuallymet the criteria for recovery or nonrecovery. Given thisheterogeneity, these indeterminate patients were ex-cluded from the data analysis in this paper and in apreliminary report (7). (Although not reported, statis-tical analyses including these indeterminate subjectswere performed, and the results were essentially the

same as those obtained for only the recovered andnonrecovered groups).

Classification as a responder or nonresponder wasbased on changes in several general indices of theseverity of the depressive state, i.e., the Hamilton scale,the Video Interview Behavior and Symptom Scale(VIBES) Improvement Scale (global), the VIBES Gener-al Severity Scale (number 327) (20 and an unpublishedpaper by M. M. Katz et al.), and the Schedule forAffective Disorders and Schizophrenia-Change, GlobalAssessment Scale (SADS-C GAS).

A patient was classified as a responder if 1) on day29 of treatment the Hamilton score was 10 or lowerand two or more of the following were true: a) theHamilton score had dropped 40% or more from thebaseline period, b) the global VIBES score was 3 orless, c) the VIBES severity score was 3 or less, and d)the SADS-C GAS score was 61 or higher or if 2) on day29 the Hamilton score was between 1 1 and 15 and twoor more of the following were true: a) the Hamiltonscore had dropped 40% or more from the baselineperiod, b) the global VIBES score was 2 or lower, c) theVIBES severity score was 2 or lower, and d) the SADS-

C GAS score was 70 or higher. A patient was classifiedas a nonresponder if on day 29 his or her Hamiltonscore was 16 or higher and three of the following were

true: a) the Hamilton score had dropped 25% or less

MAAS, KOSLOW, KATZ, ET AL

Am J Psychiatry I 41 : 1 0, October 1984 1161

from the baseline period, b) the global VIBES scorehad changed less than 1 point and was equal to orhigher than 4, c) the VIBES severity score had changedless than 1 point and was 4 or higher, and d) the SADS-

C GAS score was SO or lower.The neurotransmitter metabolites we assayed were

MHPG, VMA, normetanephrine, metanephrine, 5-

HIAA, and HVA. The catecholamines assayed werenorepinephrine and epinephrine. The norepinephrine,

epinephrine, normetanephrine, metaneph rine, andVMA were assayed from 24-hour urine specimens andHVA and S-HIAA from specimens of lumbar CSE

MHPG was assayed from both urine and CSF speci-mens. Levels of the CSF metabolites were determined

by selected ion monitoring (gas chromatography-mass

spectrometry), urinary MHPG and VMA by gas-liquidchromatography, and norepinephrine, epineph rine,

normetaneph rine, and metaneph rine by spectrophoto-

fluorimetry. Details of collection periods, collectionmethods, and analytic techniques are given in thepaper by Secunda et al. (17); a brief description

follows.Four consecutive 24-hour urine samples were ob-

tamed during study days 7-10. Samples from days 9and 10 were used for assays unless they were notacceptable, in which case samples from day 7 or 8 were

used. The urine samples were refrigerated during theentire 24-hour collection period. Completeness of sam-pie collection was determined by comparison of vol-

ume and creatinine with normative data, corrected forbody mass and examined for consistency across days.Acceptable samples were divided into aliquots (blindreplicates) and frozen at -70#{176}C until assayed.

Lumbar puncture was performed between 8:00 and9:00 a.m. on day 1 1 after the patient had been withoutfood for 8 hours and had received bed rest and whilethe subject was in a sitting position. The 20-ml samplesof CSF were kept on ice, mixed, and divided intoaliquots (blind replicates). Sodium metabisulfite andappropriate internal standards were added, and the

samples were frozen at -70#{176}C until analyzed.All analyses of each substance were done on coded

replicate samples, blind to the analytical center. Assayson a particular substance were analyzed in a single

laboratory regardless of the center of origin.The values for the CSF metabolites are expressed as

picomoles per milliliter, and the values for the urinarycatecholamines and metabolites are given as micro-grams per 24 hours. Owing to sample loss, failures incollection, and technical problems every chemical val-ue was not available for every patient.

The patients were classified as having low or highamounts of the neurotransmitter metabolite on thebasis of a median split; i.e., if the subject’s metabolitelevel was lower than that of the median for the entire

group of depressed patients, that subject was classifiedas having a low value, and if the metabolite level washigher than the median value the patient was classified

as having a high value. Only the values from depressedpatients were used to obtain the median scores; this

initial designation as high or low refers only to the

patient’s placement relative to other depressed patients

and not to healthy subjects. The actual median valuesused to make the splits are shown in table 1.

As in other studies (13, 21-27), our female patientshad statistically significantly higher CSF levels of 5-

HIAA and HVA than did the male subjects (28). It hasalso been found (28) that in our study sample the

depressed male patients had significantly higheramounts of metanephrine than the depressed femalesubjects. Given these findings, the median values takenfor classifying levels as high or low differed betweenmen and women for CSF S-HIAA and HVA andurinary metanephrine (see table 1).

We next compared these “low” and “high” groupvalues with those obtained from a group of age- and

sex-matched healthy control subjects who were also apart of this collaborative study (28). When this was

done it was found that for urinary normetanephrineand MHPG and CSF MHPG the “low” and “high”groups had mean values which were significantly

lower or higher than those of the control subjects. Incontrast, for epinephrine, norepinephrine, metaneph-rine, and VMA the “low” groups of patients were not

significantly different from the normal control sub-jects, whereas the “high” group had significantly high-

er values than did the normal subjects. For this reason,in this paper the urinary normetanephrine and MHPGand CSF MHPG patient groups are referred to as

“low” or “high” and the epinephrine, norepinephrine,metanephrine, and VMA groups are referred to as“normal” or “high,” respectively. This is done so thereader may relate the patient values to the values ofhealthy subjects. For CSF 5-HIAA both men andwomen in the “high” group of patients had group

mean values that were significantly higher than thoseof normal subjects, whereas the “low” group classifi-cation vis-#{224}-vis controls was confounded by a gendereffect; the “low” group value for depressed men wassignificantly lower than that of control subjects, but nosignificant difference between the “low” group ofdepressed women and female control subjects was

found. In this paper, for clarity of presentation the

depressive groups are referred to as having “low” or“high” S-HIAA values.

We also examined relationships between antidepres-

sant drug levels, treatment response, and pretreatmentneurotransmitter values. Concentrations of imipra-mine and amitriptyline and their metabolites desmeth-ylimipramine and nortriptyline were determined inboth plasma and CSE The plasma measures wereobtained during week 4 of drug treatment and the CSFmeasures after 3 weeks of treatment. The levels ofdrugs and their demethylated products were deter-mined with gas chromatography-mass spectrometry.

In addition to the values for the parent and demethyl-

ated drugs, we calculated the sum of the two and theratio of the demethylated to the parent compound. Adetailed description of the protocol is given in thepaper by Secunda et al. (17).

NEUROTRANSMITTER METABOLITE LEVEI.S AND ANTII)EPRESSANTS

1162 Am J Psychiatry 141:10, October 1984

TABLE 1. Mean and Median Pretreatment Values of Catechol-amines and Neurotransmitter Metabolites of Depressed Patients

Value

Measure N Median Mean SE

CSF (pmol/ml)

MHPG 99 47.5 47.6 1.14

HVAWomen 43 215.0 209.0 11.8

Men 49 177.7 178.2 8.5

5-HIAAWomen 43 132.6 129.7 5.1

Men 49 101.1 104.6 4.2

Urine (�i.g/24 hours)VMA 112 3220 3560 203.3

Normetanephrine 1 17 232.5 279.2 15.8

MHPG 1l4 1949.5 2128.5 100.0

Metanephrine

Women 55 111.5 121.9 7.5Men 65 146.8 148.8 8.0

Norepinephrine 91 35.3 39.7 2.5

Epinephrine 88 20.6 22.2 1.4

RESULTS

The numbers of subjects classified as responders,indeterminate responders, or nonresponders to imipra-mine or amitriptyline are shown in table 2. As expect-ed from previous literature (29), there were no signifi-cant differences between the two drugs in their overalltherapeutic effectiveness as antidepressant agents.From table 2 it may also be noted that there were 13

and 12 depressed patients who had indeterminateresponses to amitriptyline and imipramine, respective-ly. For reasons noted in the Method section thesesubjects are not included in subsequent analyses andare shown in table 2 only to provide the number ofindeterminate responders in each of the drug groups.In evaluating results presented in the remainder of thispaper note that when the indeterminate groups areremoved the ratio of responders to nonresponders forthe total sample and for each drug is approximately2:1, and, conversely, the ratio of nonresponders toresponders for both drugs is approximately 1 :2. Theactual numbers of patients from whom biochemical

data were available are less than those shown in table 2because of such factors as sample loss and technical

errors.A comparison of the baseline values for catechol-

amine and neurotransmitter metabolites for the pa-

tients who subsequently completed the amitriptylineand imipramine treatment protocols indicated thatexcept for CSF MHPG there were no significantdifferences in the pretreatment biochemical values ofthe two drug groups. Pretreatment mean (±SE) CSFMHPG was modestly but significantly lower in theimipramine group (44.5±2.0 pmol/ml, N=42) than inthe amitriptyline group (50.4± 1.7 pmol/ml, N=43)(t=2.27, p=.O3). These data indicate that subsequentdifferences in response to imipramine and amitrip-tyline associated with pretreatment metabolite values

TABLE 2. Response of Depressed Patients to Amitriptyline orImipraminea

N umber of Patients

Amitriptyline

Outcome Group or Imipramine Amitriptyline Imipramine

Responder 52 28 24

Indeterminate 25 13 12

Nonresponder 27 14 13

Total 104 55 49

aNo significant difference in response to the two drugs was found.

were not artifacts of differences in baseline metabolitevalues for the two drug groups.

The median and mean values of the chemical varia-

bles are given in table 1. In some cases the median andmean values are quite close, whereas for others this isnot so. This divergence of the mean and median valuesis consistent with an earlier report (28) from theNIMH collaborative study in which it was noted thatfor some metabolites the distributions were skewed

and nonnormal.

Pretreatment Variables and Response to

Amitriptyline or Imipramine

As may be seen from table 3, there were significantrelationships between urinary norepinephrine andMHPG values and the type of subsequent response ofthe bipolar depressed patients to amitriptyline or imip-ramine. A normal urinary norepinephrine or a lowMHPG level was associated with a favorable responseand a high value with a lack of response. In assessingthese results, and those presented later in the paper,one should remember (see table 2) that without abiochemical predictor the ratio of responders to nonre-sponders is approximately 2:1, whereas in the normalnorepinephrine and low urinary MHPG bipolar pa-

tient groups the ratio is approximately 7:1. Converse-ly, for bipolar patients with high urinary norepineph-rine or MHPG values the ratio of responders to

nonresponders is 1 : 1 or less, rather than the expected2:1.

There were also significant relationships betweenpretreatment urinary norepinephrine and VMA andthe type of response in the total patient group, butthese effects appear to be due principally, if not totally,to the bipolar patient group.

Given these relationships between values for norepi-nephrine and MHPG and the type of treatment re-sponse for the bipolar patients, we selected the bipolarpatients who had low or high values for both variables,

i.e., low norepinephrine and low MHPG or highnorepinephrine and high MHPG, and looked at theirresponse types. Of the 1 1 “low-low” patients 10 wereresponders, and of the four “high-high” patients threewere nonresponders (p.O3, Fisher’s exact test).

Table 4 shows relationships between urinary meta-nephrine and CSF 5-HIAA and the type of response todrug treatment. These results are different from those

MAAS, KOSLOW, KATZ, ET AL

Am J Psychiatry 141:10, October 1984 1163

TABLE 3. Relationships Between Placement as Low, Normal, or High on Pretreatment Urinary Norepinephrine, MHPG, or VMA andSubsequent Type of Response to Amitriptyline or Imipramine in Depressed Patients

Measurea

All Depres sed Patients Bipolar Depr essed Patients Unipolar Dep ressed Patients

N

Respond-

ers

Nonre-

sponders pb N

Respond-

ers

Nonre-

sponders pb NRespond-

ersNonre-

sponders pb

Norepineph-

rine 54 .026 22 .025 32 .389

Normal 25 6 14 2 11 4

High 12 11 2 4 10 7

MHPG 68 .232 30 .025 38 .671

Low 25 10 13 2 12 8

High 19 14 7 8 12 6

VMA 69 .049 32 .080 37 .290Normal 29 8 14 3 15 5

High 18 14 8 7 10 7

�For any given compound, subjects’ levels were classified as normal, low, or high with procedures described in the Method section of the text.

h1f the number of subjects was 40 or higher, the chi-square statistic was used; if the number was lower than 40 and the probability in any cell was less than 5, Fish-

er’s exact test was used,

TABLE 4. Relationships Between Placement as Low, Normal, or High on Pretreatment Urinary Metanephrine and CSF 5-HIAA andSubsequent Type of Response to Amitriptyline or Imipramine in Depressed Patients

All Depres sed Patients Bipolar Depr essed Patients

Nonre-sponders pb

Unipolar Dep ressed Patients

Measurea NRespond-

ers

Nonre-

sponders pt NRespond-

ers NRespond-

ersNonre-

sponders pb

Metaneph-

rine 73 .006 32 .335 41 .003

Normal 22 19 12 7 10 12

High 27 S 10 3 17 2

S-HIAA 62 .075 28 .396 34 .078Low 24 8 11 4 13 4

High 16 14 8 5 8 9

‘For any given compound, subjects’ levels were classified as normal, low, or high with procedures described in the Method section of the text.

b1f the number of subjects was 40 or higher, the chi-square statistic was used; if the number was lower than 40 and the probability in any cell was less than S, Fish-

er’s exact test was used.

for urinary norepinephrine and MHPG in that the

pretreatment variables are related to outcome in theunipolar, but not the bipolar, group of patients. Fur-

ther, in the case of metanephrine high, not low,pretreatment values are associated with a favorabletreatment response. The relationship between CSF 5-HIAA and treatment response represents a trend(p=.O78), since it is not significant at the usuallyaccepted probability level of 0S. It is shown, however,

because this relationship between CSF 5-HIAA andresponse type consistently emerged with different typesof analyses as well as when the patient sample wasfurther subdivided (q.v.).

Next, we examined the unipolar patients who hadhigh metanephrine and low CSF S-HIAA (the “high-low” group) and those who had low metanephrine andhigh CSF S-HIAA (the “low-high” group) and corn-pared them in terms of response type. Ten unipolarpatients were “high-low” and of these nine wereresponders, whereas six of the nine “low-high” sub-

jects were nonresponders (p=.Ol7, Fisher’s exact test).No significant relationships between treatment re-

sponse type and CSF HVA or urinary epinephrine ornormetanephrine were found for the total group ofdepressive subjects or when the unipolar and bipolargroups were examined separately.

The analyses described thus far were performed with

nonparametric methods. In addition, however, wecompared pretreatment values for the amines andmetabolites in the recovered and nonrecovered patientgroups treated with amitriptyline or imipramine usingthe usual (parametric) statistical technique of analysis

of covariance. This method was used because in somecases there were significant effects due to age, sex, anddiagnosis (28) that needed to be separated from theoutcome condition. These analyses were performedwith each metabolite for the total group of depressedpatients and for the unipolar and bipolar groupsseparately. For the metabolites for which there weresignificant differences in pretreatment values betweenthe subsequent responder and nonresponder groups,

the mean (±SE) values are given in table S. In general,the results with parametric analyses of covarianceagree with those obtained with the nonparametricmethods (compare tables 3, 4, and 5). For example, forthe bipolar patients the following pretreatment amineor metabolite values were significantly lower in thepatients who subsequently responded than in thosewho remained unrecovered: urinary MHPG (p=.O34),normetanephrine (p=.O46), VMA (p=.OSS), and nor-epinephrine (p=.OS9) and CSF MHPG (p=.O3). Giventhis last finding for CSF MHPG from the analysis of

NEUROTRANSMI1TER METABOLITE LEVELS AND ANTIDEPRESSANTS

1164 Am J Psychiatry 1 41 : 1 0, October 1984

TABLE 5. Pretreatment Values for Amines and Metabolites in Depressed Patients Who Recovered or Remained Unrecovered After TreatmentWith Amitriptyline or Imipramine

Group and Measure

Responders Nonresponders

N Mean SE N Mean SE pa

Bipolar depressed patients

CSF MHPG (pmol/mI) 20 41.6 2.1 10 53.2 3.1 .030

Urinary values (p.g/24 hours)

MHPG 20 1856.0 191.2 10 2970.9 490.0 .034Normetanephrine 22 204.4 33.9 10 364.4 72.5 .046

VMA 22 3407.7 523.9 10 4916.0 766.6 .055

Norepinephrine 16 25.0 4.3 6 39.7 3.1 .059

Unipolar depressed patients

CSF S-HIAA (pmol/ml) 21 117.8 8.9 13 126.8 6.6 .076

Urinary metanephrine (ji.g/24 hours) 27 143.2 8.9 14 110.6 11.4 .009

All depressed patients

CSF MHPG (pmol/ml) 42 45.2 1.64 24 51.9 2.2 .034

Urinary values (p.g/24 hours)

Metanephrine 49 139.6 7.7 24 113.1 8.8 .029

Normetanephrine 48 250.4 22.2 24 336.8 41.2 .035

�Since for many of the metabolites there were significant effects due to age, sex, or diagnosis (28), the significance of the differences due to the outcome group per sewas determined with analyses of covariance. The p value therefore refers to the significant differences between outcome groups after age, sex, and diagnosticrelationships were taken into account. There were no significant differences between the responders and nonresponders for the metabolites or amines not shown.

covariance, it is interesting that with the nonparamet-nc Fisher’s exact test there was a trend for CSF MHPG

to be lower in the responding bipolar patients(p=.O77). For the unipolar patients there was a trend

for the CSF 5-HIAA value to be lower in the respond-ers than in the nonresponders (p=.O76). The pretreat-ment metanephrine value was also significantly higher(p=.OO9) in the unipolar responders than in the nonre-sponders.

In summary, the results of both parametric andnonparametric analyses indicate that bipolar patientswho have normal or low pretreatment values of nor-epinephrine, urinary MHPG, CSF MHPG, and per-haps VMA and normetanephrine are more likely torespond favorably to treatment with imipramine oramitriptyline than are patients who have high values ofthese metabolites. These relationships are not foundwith unipolar patients. Conversely, unipolar patientswho have high pretreatment levels of metanephrineand low levels of CSF 5-HIAA are more likely to havea favorable response to imipramine or amitriptyline.These latter relationships are not found with bipolarpatients.

Pretreatment Variables and Response to Imipramine

Using the Fisher exact test for the total group ofdepressed patients treated with imipramine, we founda significant relationship between CSF S-HIAA and thetype of response to imipramine (N=32, p=.O4O). Asbefore, a low value was associated with a high mci-dence of response and a high value with a low mci-dence of response.

When the imipramine-treated group was dividedinto bipolar and unipolar types of depression and theFisher exact test was performed, the bipolar, but not

the unipolar, patients had significant relationships inthe expected directions between response type and

pretreatment levels of both urinary MHPG and norepi-nephrine. For example, of the bipolar patients 12 hadlow pretreatment urinary MHPG values and of these10 subsequently recovered, whereas seven subjects hadhigh MHPG values and of these five did not recover(N=19, p=.O29, Fisher’s exact test). For norepineph-rine, 10 patients had normal pretreatment values andof these eight recovered, whereas four of the five

patients with high norepinephrine values were nonre-

sponders (N= 15, p=.O47). There was also a trend forthis pattern to be found in the CSF MHPG values ofthe bipolar patients; i.e., of the 12 patients with low

CSF MHPG 10 responded, and four of the sevenpatients with high levels were nonresponders (N= 19,p=.O9S). These relationships were not seen with the

unipolar patients.Given these relationships between pretreatment un-

nary norepinephnine and MHPG in bipolar patients

treated with imipramine, it was interesting to examinethe response to imipramine of bipolar patients whohad high or low levels of both urinary norepinephnineand MHPG. Only 12 patients filled these require-ments, but of the nine “low-low” patients 8 wereclassified as responders, and all of the three patientsclassified as “high-high” were nonresponders (Fisher’sexact test, p=.Ol8).

Relationships between metanephrine and the type ofresponse to imipnamine were seen in the unipolar, butnot the bipolar, group. For metanephnine, seven unipo-lar patients were classified as having high levels and allof these were responders, whereas of the seven patientswith normal levels four were nonnespondens (N= 14,p=.035, Fisher’s exact test). No statistically significantrelationships were found with nonparametric analysesbetween other metabolites and imipramine treatmentresponse for the total group or for the unipolar and

bipolar groups separately.In addition to these nonparametric analyses, we

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Am J Psychiatry 141:10, October 1984 1165

compared pretreatment mean values in the recoveredand nonrecovered patient groups using usual paramet-nc statistical techniques. Because in some cases signifi-cant differences occurred as a function of sex, age, and

diagnosis, analyses of covariance were used to separatethese variables from differences due to outcome per Se.These analyses were performed with each metabolite

for all depressed patients treated with imipramine and

for the unipolar and bipolar groups separately. Thesignificant differences found between the pretreatmentvalues of the imipramine responder and nonrespondergroups were as follows. Among the bipolar patientsthe responders had significantly lower pretreatmentvalues of urinary MHPG (p=.O39), VMA (p.O1S),and norepinephrine (p= .002) than the nonresponders.Among the unipolar patients the responders had asignificantly lower CSF S-HIAA value than the nonre-sponders (p=.OO6). Given this finding for CSF S-HIAAwith the analysis of covariance, it is interesting thatwhen the CSF 5-HIAA values were examined with amedian split and the Fisher exact test, there was astrong trend (N=14, p=.O63) for a low CSF S-HIAAvalue to be associated with a favorable response toimipramine. For example, of the eight unipolar pa-tients classified as having low CSF S-HIAA valuesseven were responders and of the six classified as high

four were nonresponders. Using analyses of covariancewe found no other significant differences as a function

of outcome.In summary, the findings in the group treated with

imipramine are similar to those in the larger combined

amitriptyline and imipramine groups; i.e., 1) pretreat-

ment urinary norepinephrine and MHPG, and perhapsVMA and CSF MHPG, were associated with response

type and this result was seen only with the bipolar

patients; and 2) pretreatment metanephrine and CSF5-HIAA values were associated with response type butthis result was seen only with the unipolar patients.

Pretreatment Variables and Response to

Amitriptyline

For both VMA and metanephrine, we found signifi-cant relationships between pretreatment values andtype of response to amitriptyline in the total group of

patients. For example, of the 15 responders 13 had lowVMA values, whereas of the 20 nonresponders 1 1 hadhigh values (N=37, p.O49, Fisher’s exact test). Formetanephrine, of the 26 responders 15 had highvalues, and of the 13 nonresponders 10 had normalvalues (N=39, p=.O43, Fisher’s exact test).

When the amitriptyline group was divided intounipolar and bipolar subgroups it was found that with

the unipolar group for metanephrine, of the 12 pa-tients with high values 10 were responders and of the

15 patients with normal values eight were nonre-sponders (N=27, p=.OS8, Fisher’s exact test). Thus,the noted relationship between metanephrine and re-

sponse type for the total group appears to be principal-ly due to the unipolar patients. This is consistent with

the relationship found with the combined imipramineand amitriptyline treatment groups and the imipra-

mine group alone.No significant relationships between any of the

other amines or metabolites and response to amitrip-tyline were found for the total group or for theunipolar and bipolar groups examined separately.

The pretreatment mean metabolite values in therecovered and nonrecovered amitriptyline treatment

group were also examined with the parametric analysisof covariance, whereby the effects of sex and age wereremoved. No significant differences for any of theneurotransmitter metabolite values were found.

In evaluating these results with amitriptyline, how-ever, it should be noted that by chance the randomassignment of patients to drug groups resulted in arelatively small number of bipolar patients receivingamitriptyline (17 bipolar and 38 unipolar patientswere in the amitriptyline group). This type of assign-ment and the fact that all biochemical assays were notavailable for all patients meant that a relatively limitednumber of biochemical values was available for thebipolar subjects treated with amitriptyline. Conse-quently, the statistical analyses that could be done with

response type and metabolites in the bipolar groupwere limited by the very small sample size. Conversely,

however, the larger proportion of unipolar patientsalso gives greater strength to both the positive andnegative results found with this group. For example,

the failure to find a relationship between CSF S-HIAAand outcome with amitriptyline treatment for eitherthe total group or the unipolar group alone is particu-larly interesting given theoretical expectations and thefact that a significant relationship was found in theimipramine-treated group.

Pretreatment Variables, Response, and Tricyclic

Levels

It is possible that the demonstrated relationshipsbetween low or high pretreatment neurotransmittermetabolite levels and type of subsequent drug responsemight be related to the level of the antidepressant drugin CSF or plasma; i.e., it could be that a givenpretreatment neurotransmitter metabolite value is as-

sociated with drug response because the pretreatmentmetabolite value, by means of some unknown mecha-nism, is associated with the subsequent CSF or plasma

tricyclic concentration in the responder and nonre-sponder groups. To test this possibility, we classifiedpatients as 1 ) responders with high neurotransmittermetabolite levels, 2) nonresponders with high metabo-

lite levels, 3) responders with low metabolite levels,and 4) nonresponders with low metabolite levels. Foreach of these four groups we calculated means and a

measure of variance for the following: plasma imipra-mine level, plasma desmethylimipramine level, ratio ofplasma imipramine to desmethylimipramine, and total

level of imipramine plus desmethylimipramine. Wealso calculated these four drug measures for the CSF

NEUROTRANSMITTER METABOLITE LEVELS AND ANTIDEPRESSANTS

1166 Am J Psychiatry 1 4 1 : I 0, October 1984

values of the patients treated with imipramine. Similar-ly, these measures were calculated for the patients whoreceived amitriptyline. We then performed analyses ofvariance for all amines and neurotransmitter metabo-lites to determine if there were significant differences

between the four groups in any of the noted CSF or

plasma drug indices. We found no significant differ-ences in any of the plasma or CSF drug indices withinany of the metabolite level response groups.

DISCUSSION

In this paper we have explored the relationshipsbetween the type of therapeutic responses to imipra-

mine and amitriptyline and pretreatment biochemicalvariables. In general the biochemical variables mea-sured may be seen as markers for the functioning ofdifferent types of systems, i.e., the sympathetic nervoussystem (urinary norepinephrine, normetanephrine,VMA, and MHPG), the adrenal medulla (urinary epi-

nephrine, metanephrine, VMA, and MHPG), and CNSserotonergic, noradrenergic, and dopaminergic neurons(CSF S-HIAA, MHPG, and HVA, respectively).

The results that emerged consistently were as fol-lows. Normal pretreatment values of urinary norepi-

nephrine and low urinary MHPG values were associat-ed with a greater incidence, and high values with alesser incidence, of drug response in bipolar, but notunipolar, patients. These results were found with the

use of either parametric or nonparametric statisticaltechniques. We also found, with bipolar patients only,similar results for other measures of noradrenergicfunction, viz., CSF MHPG, urinary VMA, and urinarynormetanephrine. (In the case of these last threemetabolites, relationships between pretreatment valuesand the type of response were detected only as trendswith the use of nonparametric analyses [p<.l, >.0S]

but with the use of more sensitive parametric tech-niques the differences were significant [p<.OS�). In theaggregate these data strongly suggest that in bipolarpatients the functional state of noradrenergic neurons,as assessed by values of urinary norepinephrine,MHPG, VMA, and normetanephrine and CSF MHPG,is associated with the responsivity to drug treatment.

In contrast, a different group of markers was foundto be associated with the therapeutic response to drugs

in the unipolar patients; i.e., in this clinical subtypemarkers for adrenal medulla and CNS serotonergic

neuron function (metanephrine and CSF S-HIAA, re-spectively) were related to treatment outcome. Thesemetabolites were not related to treatment response in

the bipolar patients. Further, in the case of metaneph-rine the relationships to response type were in theopposite direction from those that were previously

found; i.e., high values of metanephrine were associat-ed with a greater incidence of response. This wasfound with the total group of unipolar patients andwhen either of the two drug groups was consideredseparately.

The grouping of patients on the basis of biochemicalmarkers and drug responsiveness is generally consist-ent with earlier findings and hypotheses (15, 24) aboutthe probable existence of biochemically and pharma-cologically separable types of depression, with onetype having a disorder in noradrenergic systems andthe other in serotonergic systems. However, the resultsfrom this collaborative study also provide importantnew information and considerably broaden the origi-nal conceptualization. In addition, there are severalpoints of disagreement between our results and thoseof some earlier reports. We will next discuss the areasof confirmation and expansion as well as disagree-ment.

In earlier studies (4-8) the principal focus was on

urinary MHPG as a marker for responsiveness toimipramine because of the possibility that MHPGprovides an index of CNS noradrenergic function (3).Although the results of this study confirm the earlierreports of relationships between urinary MHPG andimipramine response, they also indicate that norepi-

nephrine itself, as well as other norepinephrine metab-olites, can serve as a marker of response to treatmentwith imipramine and perhaps amitriptyline. These

findings of relationships between antidepressant drugresponse and norepinephrine and its metabolites as a

group, rather than a single metabolite, suggest that onemay be defining a disorder in the functioning of thenoradrenergic neurons of the sympathetic and centralnervous systems and that the functional state of thesenoradrenergic systems determines the type of drugresponse. It also seems possible that by combining

measures of catecholamines and metabolites clearerrelationships between pretreatment biochemical valuesand the type of drug response may emerge.

These findings with norepinephrine and catechol-amine metabolites are also consistent with empirical,experimental, and theoretical considerations suggest-

ing that CNS noradrenergic and peripheral norad-renergic systems, particularly the sympathetic nervoussystem, function as an integrated unit, so that severalindices of noradrenergic function would be expected tobe grouped together as markers (28, 30, 31).

The findings reported here which indicate that rela-tionships between markers for the functioning of nor-adrenergic systems and drug response type are foundin bipolar but not unipolar subjects have a remarkable

internal consistency. In all cases when relationshipswere found between norepinephrine and metabolites

and drug response for the total group of depressedpatients, a further subdivision of patients into bipolarand unipolar groups indicated that the relationship

was due to the bipolar patients. This was found withboth parametric and nonparametric statistical ap-proaches. These findings are also generally consistent

with other lines of evidence which suggest that of theclinically identifiable subgroups of depression, a disor-der in noradrenergic systems is most likely to be foundin bipolar subjects. For example, it has been reported

(32) that L-dopa regularly produces hypomania in

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Am J Psychiatry I 41 : 1 0, October 1984 1167

bipolar patients. Although differences in urinaryMHPG between bipolar depressed subjects, unipolar

subjects, and healthy control subjects were not foundin this collaborative study (28), Goodwin and Potter’sreview (33) of the literature on urinary MHPG

(N=312) indicated that urinary MHPG is most likelyto be lower in bipolar patients than in unipolar

depressive and healthy subjects. Also, one of the mostconsistent findings reported is that of a close relation-

ship between changing urinary MHPG and changingmood in cycling bipolar patients (34).

Three groups of investigators (5, 6, 10) found thathigh levels of urinary MHPG are associated with the

response to amitriptyline, whereas three others (7, 11,12) did not. In all six studies the depressed patientswere diagnostically heterogeneous. In our study, when

unipolar and bipolar patients were grouped togetherrelationships between urinary MHPG and response to

amitriptyline were not found. Similarly, no relation-

ship between MHPG and response to amitriptylinewas noted in unipolar patients. However, because the

data so strongly suggest that pretreatment norepineph-rine and metabolites relate to response only in bipolarpatients, the small number of bipolar patients in this

study who were treated with amitriptyline and forwhom biochemical values were available precluded anadequate statistical analysis. For this reason, the ques-

tion of relationships between pretreatment MHPG, aswell as other amines and neurotransmitter metabolites,

and response to amitriptyline in bipolar patients re-mains unanswered; it is an important area for future

research.The findings in this study are also consistent with

the postulated existence of a group of patients who canbe identified by their CSF S-HIAA values and areseparable from the group for whom norepinephrineand its metabolites serve as markers of response. Thatthese two biochemically identifiable groups are separa-ble is shown by the fact that when the patients weredivided into unipolar and bipolar subtypes CSF 5-

HIAA served as a marker for response only in theunipolar group, whereas the norepinephrine and me-tabolite markers were associated with response typeonly in the bipolar patients. Unexpectedly, however, it

was also found that a marker for the functioning of theadrenal medulla, metanephrine, was associated withthe response to amitriptyline or imipramine treatmentin the unipolar, but not the bipolar, group. Further, ashas been noted, the relationships between responsetype and metanephrine were in the opposite directionfrom those found with all other metabolites; i.e., highvalues of metanephrine were associated with a highincidence of therapeutic response. Although this find-ing with metanephrine is empirically robust, from atheoretical standpoint it is more difficult to explainthan the findings with norepinephrine and metabolites.

Contrary to expectations, no relationships betweenCSF S-HIAA and response to amitriptyline were foundin the depressed patients as a group or in either theunipolar or bipolar subtype. This finding was unex-

pected because it was originally speculated (15) thatdepressions with low serotonin levels might be particu-larly sensitive to treatment with amitriptyline becausethis drug is a potent blocker of S-HT reuptake, has

little effect on norepinephrine reuptake, and has alarger ratio of tertiary to secondary amine than imipra-mine and its product desmethylimipramine. Possibly

amitriptyline exerts its therapeutic actions primarilypostsynaptically-viz., aj receptors (35, 36)-or byincreasing the sensitivity of receptors (37) so that its

relationships with markers that primarily reflect pre-synaptic events (neurotransmitter metabolites) are not

seen.Next we will discuss possible artifactual causes for

some of the noted relationships between biochemicalmarkers and drug responsiveness. It is possible that

through an unknown mechanism the pretreatmentneurotransmitter levels of CSF S-HIAA or catechol-

amines and metabolites in some way predicted subse-quent therapeutic plasma or CSF levels of the antide-pressant drugs or their metabolites. Against this possi-

bility is the finding that there were no statisticallysignificant relationships between pretreatment neuro-transmitter metabolite values and plasma or CSF mea-

sures of drug level, drug metabolite level, ratio of drugto metabolite, or level of drug plus metabolite. Further,relationships between pretreatment neurotransmitter

metabolite values and subsequent drug response wereunlikely to occur as a function of plasma or CSF drugindices, since the drug treatment protocols required

doses that resulted in most patients having plasma and

CSF drug levels in the therapeutic range (unpublisheddata of J. Kocsis et al.).

The relationship between norepinephrine andmetabolites and response to both drugs or imipramineseparately in the bipolar patients could be invalidbecause the bipolar patients in this study had signifi-candy lower norepinephrine values than did the unipo-lar patients (28). This difference between the bipolarand unipolar patients raises the possibility that, ratherthan the imipramine response being related to norepi-nephrine and metabolites in the bipolar group per Se,the relationship between norepinephrine and metabo-lite values and drug response occurred because norepi-nephrine values were lower in the bipolar group.However, when we split the bipolar group into high-and low-norepinephrine groups, using the medianvalue from bipolar patients only, significant relation-ships between norepinephrine and the response toimipramine were still present. Furthermore, significant

differences between bipolar and unipolar patients werenot found for the norepinephrine metabolites CSFMHPG and urinary MHPG and VMA (28), and yet

these metabolites identified the type of imipramineresponse in bipolar but not unipolar patients.

Another important question is whether clinical or

demographic differences are associated with the sub-types defined by markers of adrenergic and serotoner-gic system function and drug responsivity. There isevidence from other reports (38-41) and this collabo-

NEUROTRANSMITTER METABOLITE I.EVELS AND ANTIDEPRESSANTS

1168 Am J Psychiatry 1 41 : I 0, October 1984

rative study (J. Croughan et al., unpublished data) that

the number of prior episodes is inversely related to afavorable response to tricyclic antidepressant treat-ment. It thus seems possible that the more chronically,and perhaps severely, depressed patients will be thosewho have the high values for the adrenergic and/or

serotonergic chemical markers.It might also be argued that these biochemical

markers identify a responsiveness to a drug not be-

cause they are associated with a disorder within aparticular neurotransmitter system but rather becausethey are a result of that particular behavioral state and

that this behavior is particularly sensitive to changewith a given drug. In this collaborative study (20 andunpublished data of M. Katz et al.) attention has been

given to a detailed rating of a series of behaviors thatmake up the depressive syndrome, and we plan toassess this issue of behavior, chemistry, and drug

interactions in detail in a subsequent paper.In this study we categorized the patients as having

either high or low metabolite values by doing a simplemedian split using values from depressed patients only.This method was chosen because it yielded equalgroups of subjects with high and low levels in situa-tions where the distributions were skewed, and it is a

simple way to divide patients and can be easily general-ized to other situations. Nevertheless, the median splitmay not be the best method to identify subtypes; otherstatistical approaches may provide better discrimina-tion. Also, other investigators who wish to use themedian split must take into account that values for anyof these metabolites will vary from laboratory to

laboratory, and each laboratory will need to compareits mean and median values with those we havereported here (see table 1 ) before assuming that thevalues we used for the median splits can be generalizedto other settings and situations.

Since significant relationships between neurotrans-mitters and metabolites and the type of drug responsehave been found, the question of the usefulness ofthese assays in routine clinical situations arises. In ourstudy predictability of response with amine or metabo-lite values was clearly not absolute, but rather therewere statistically significant relationships with theincidences of response and nonresponse. Further, theseassays were done with careful attention to drug wash-out, completeness of the 24-hour urine collections,

assays of consecutive urine samples, similarity of con-

ditions under which lumbar punctures were per-formed, and uniformity of the amount of CSF collect-ed. In addition, a given chemical assay was done by thesame laboratory, the method of assay for a particularchemistry was the same, and the number of assays was

sufficiently large to establish a median value for thisstudy. For these reasons, the results reported herecannot be used to support the position that neuro-transmitter metabolite assays should be routinely per-formed to determine the choice of an antidepressantdrug. However, we think that the results of this studyare sufficiently encouraging to suggest that a second

phase of investigation is warranted, i.e., studies of the

therapeutic usefulness of neurotransmitter metabolitelevels in helping to choose antidepressant drugs in

more usual clinical settings. Studies of this type couldprovide information relevant to questions such as,Under what routine clinical conditions are metabolite

measures useful in choosing antidepressant drugs? Arethey particularly helpful in choosing certain types ofantidepressants?

In the final portion of this paper we will discuss theresults in terms of possible underlying pathophysiolog-

ical mechanisms. Before proceeding to this issue wewill comment on the terminology used. First, muchevidence (42) indicates that levels of neurotransmittermetabolites provide an index of functional activity orimpulse flow in neuronal systems. This is particularlyso when one is able to obtain a sum or integral ofmetabolites over time, i.e., 24-hour urine values.Therefore, in this discussion metabolite values are usedto make inferences regarding the functional activity ofneuronal systems. Second, neuroanatomical, physio-logical, pharmacological, and biochemical evidence(30) suggests that impulse flow or functional activityof the sympathetic nervous system and catecholaminesystems in the CNS are closely coupled; i.e., an in-crease in impulse flow in CNS catecholamine systemsis linked to increased impulse flow in the sympatheticnervous system. Consistent with this is the findingpresented in this study that indicates similar relation-ships between CSF MHPG and urinary norepinephrineand its metabolites and the type of treatment response

seen with bipolar patients. For these reasons, the term

“noradrenergic systems” refers here to norepinephrinesystems generally, i.e., both the central and sympathet-ic nervous systems.

Because the findings with the bipolar and unipolargroups were different, we will discuss them separately,but we will also present an integrated hypothesis andsuggest a mechanism common to depression in both

clinical subtypes.In this study some bipolar patients were character-

ized by decrements in urinary norepinephrine andmetabolite levels whereas others had elevated values,and yet all of these patients were severely depressed.

Therefore, by definition the functional state of thenoradrenergic systems per se was not reh�ted to thepresence or absence of depression. However, the pre-

treatment functional state of the noradrenergic systemwas related to the ability of the tricyclic antidepressantdrugs to induce changes that led to recovery. For

example, of the 16 bipolar patients who had normal-to-low pretreatment urinary norepinephrine values 14recovered, and of the 15 patients with low pretreat-ment values for urinary MHPG 13 recovered. Giventhese associations we hypothesize that for bipolardepressed patients who have normal-to-low values ofnorepinephrine and low metabolite values there is arelative deficit of noradrenergic activity and that thisdeficit is corrected by the actions of the tricyclicantidepressants. Tricyclics’ actions on noradrenergic

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Am J Psychiatry 141 :10, October 1984 1169

systems are multiple (14, 43-51), and in some casesthe effects are in opposite directions, viz., blockade ofreuptake and down-regulation of �3 receptors, but we

suggest that for this clinically (bipolar) and biochemi-cally (decreased noradrenergic function) definedgroup, the tricyclics produce their therapeutic effectsby means of a net increase in noradrenergic function as

was postulated in the original catecholamine theoriesof depression (1, 2). Consistent with this hypothesis isthe finding with patients from this collaborative studythat after 4 weeks of treatment with tricyclics thebipolar depressed patients who responded had in-creases in urinary norepinephrine and those who didnot respond had decrements (C. Bowden et al.,“Changes in Urinary Catecholamines and TheirMetabolites in Depressed Patients Treated with Ami-

triptyline or Imipramine,’ ‘ unpublished observations).For the bipolar patients who were in a hypernorad-

renergic state, the tricyclic antidepressant drugs used inthis study were therapeutically less effective. It seemspossible that this hypernoradrenergic state may be a

second phase or a different form of the bipolar depres-sive illness. While the nature of the associated patho-physiology is unknown, this different state is charac-

terized by high pretreatment levels of norepinephrineand metabolites and a lesser ability of tricyclics toproduce the biological changes needed for recovery.

In summary, we suggest the following hypotheses.Bipolar depressed patients have an abnormality innoradrenergic systems. This abnormality is manifestedin two ways. In the first, biochemical markers suggestthat noradrenergic system function is low and for thesepatients tricyclic antidepressant drugs are able to pro-

duce an increase in noradrenergic system function thatleads to recovery. In a second phase, or a different

form of the illness, levels of norepinephrine and metab-olites are higher than normal and in this state thetricyclics are less able to induce the biological changesnecessary for recovery.

For the unipolar depressed patients no relationshipsbetween markers of noradrenergic function and re-sponse type were found. However, for this groupmarkers of CNS serotonergic (CSF S-HIAA) and ad-renergic (metanephrine) function and response to drug

treatment were present. We will discuss the findingswith CSF S-HIAA first. Both low and high values ofCSF S-HIAA were found for the unipolar patients, and

elevations or decrements in the functioning of seroton-ergic systems per se are not likely to be associated withdepression, since all patients were depressed. Rather, itappears that the pretreatment functional status of theserotonergic system determines whether or not imipra-mine will be able to produce changes which lead torecovery. We hypothesize that patients with low CSF

S-HIAA values have a decrement in serotonergic sys-tem function and the drug corrects this either by actingon the blockade of 5-HTreuptake (15) or by increasingthe sensitivity of S-HT postsynaptic receptors (37).This hypothesis, for this clinically (unipolar) and bio-chemically (low CSF S-HIAA) defined subgroup, is

consistent with the original S-HT theories of depres-sion which suggested that depression was associatedwith a deficit in brain S-HT (52, 53). It is also

consistent with earlier results which indicated thatpretreatment of depressed patients with S-HT precur-sors, particularly if CSF S-HIAA values were low,would produce clinical improvement in some patients

(54-56). As with the bipolar patients, we furtherhypothesize that there is a second phase or different

form of the unipolar depressions, the pathophysiologyof which is poorly understood but which is character-ized by a high CSF 5-HIAA level and the lesser abilityof imipramine to induce changes which result inrecovery.

The findings presented here are generally compatiblewith the earlier postulated existence of separate S-HTand norepinephrine depressions (15, 24) but extend itto suggest that they occur in different clinical subtypes,i.e., unipolar and bipolar patients, respectively. Thisearlier suggestion of S-HT and norepinephrine sub-types, however, left unanswered the question of how

separate alterations in two distinct neurotransmittersystems could produce the same general clinical pic-ture, i.e., depression, and did not take into account

unipolar-bipolar distinctions. Recent neuropsycho-pharmacological research is relevant to these issues,and we will discuss it next.

In experimental animals, lesions of S-HT neuronsproduced by 5,7-dihydroxytryptamine or parachloro-phenylalanine result in 1) a modest but significantincrease in brain �3 receptors, 2) a marked decrease inthe receptor affinity for the agonist isoprenaline, 3)prevention of the down-regulation of �3 receptors by

desmethylimipramine, and 4) a dissociation betweenthe number of 13 receptors and sensitivity of thenorepinephrine-sensitive adenylate cyclase (57-63).

Given these results it has been suggested that in theabsence of a S-HT input norepinephrine neurons areless functional and less able to change (60). These

findings have led to a “serotonin-noradrenaline linkhypothesis” of affective disorders (63). With this back-

ground in mind, as well as the data reported here, wesuggest the following. Unipolar patients who have lowCSF S-HIAA levels also have an accompanying lowfunctional capacity of noradrenergic systems, but thisis secondary to the change in serotonergic systemfunction, whereas for bipolar patients the low norad-renergic function is primary. Phrased differently, we

hypothesize that bipolar and unipolar patients bothhave low noradrenergic system functioning, hence the

overall similarity of the presenting clinical picture.However, in the unipolar patients the low noradrener-gic function is secondary to a primary change inserotonin systems, whereas with the bipolar patientsthe primary change is in the noradrenergic system.

In contrast to the findings with CSF S-HIAA andnorepinephrine and its metabolites, the finding ofrelationships between unipolar patients’ metanephrinevalues and type of treatment response was unexpectedboth empirically and theoretically. Nevertheless, the

NEUROTRANSMITTER METABOLITE LEVELS AND ANTIDEPRESSANTS

1170 Am J Psychiatry 141:10, October 1984

association between unipolar patients’ high urinarymetanephrine value and favorable response to imipra-mine or amitriptyline is reasonably robust and isunlikely to have been due to chance alone. It is possiblethat serotonergic systems may have a regulatory inter-action with adrenal medullary (adrenergic) systemsand hence the finding. At present there are, to ourknowledge, no available research data dealing withthis question and it remains an area for future basicand clinical research.

In summary, from the data reported here we con-dude the following: 1) There are relationships betweenthe type of drug response and pretreatment levels ofnorepinephrine and its metabolites as well as CSFMHPG in bipolar, but not unipolar, depressed pa-tients; normal-to-low values of norepinephrine andmetabolites are associated with a high incidence ofresponse and high values with a low incidence ofresponse. 2) There are relationships between the typeof drug response and pretreatment measures of CSF 5-

HIAA and urinary metanephrine in unipolar, but notbipolar, depressed patients; low values of CSF S-HIAAand high values of metanephrine are associated with ahigh incidence of response, whereas high CSF S-HIAAvalues and normal metanephrine values are associatedwith a low incidence. Finally, we discussed these

findings in terms of old and new theories of norepi-nephrine and serotonin neuronal system function indepression but we emphasize that whatever the ulti-mate fate of the specific hypotheses suggested here, ourdata indicate that amine hypotheses of depression

cannot be adequately tested with simple “too much”

or “too little” formulations. Rather, investigationsinto the role of norepinephrine or serotonin systemfunction in depression must use experimental designs

that take into account 1) the unipolar-bipolar dichoto-my, 2) biochemical markers of neurotransmitter sys-tern function, and 3) the therapeutic response type ofthe patient.

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