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CNS effects of citalopram, a new serotonin inhibitor antidepressant (a quantitative pharmaco-electroencephalography study)
Prog. Neuro-Psychopharmacal. & Biol. Psychiat. 1984, Vol. 8, pp. 397409 Printed in Great Britain. All rights reserved.
Copyright 9
0278-5846/84 $0.00 + .50 1984 Pergamon Press Ltd~
CNS EFFECTS OF CITALOPRAM, A NEW SEROTONIN INHIBITOR ANTIDEPRESSANT (A QUANTITATIVE PHARMACOELECTROENCEPHALOGRAPHY STUDY) TURAN M. ITIL I , GOPI N. MENON 2, M. MAHIR BOZAK3 and KURT Z. ITIL4 1Division of Biological Psychiatry, New York Medical College, Valhalla, NY, USA; :HZI-Euro~e and Consultant in Clinical Research, Amsterdam, The Netherlands; JHZI Neuropsychiatric Foundation and Medical Center, Istanbul, Turkey and 4HZI Research Center, Tarrytown, NY, USA (Final form, June 1983) Abstract I t i l , Turan M., Gopi N. Menon, M. Mahir Bozak and Kurt Z. I t i l : CNS effects of citalopram, a new serotonin i n h i b i t o r antidepressant (a quantitative pharmaco-electroencephalography study). Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1984, 8(3) : 397-409 1. 2. 3. 4. 5.
Citalopram, a new phthalane derivative and a specific serotonin re-uptake i n h i b i t o r in animal pharmacological tests, was evaluated in a double-blind, crossover, quantitative pharmaco-EEG (QPEEGTM) study in healthy human volunteers. The CNS effects of citalopram are linear, dose- and time-related, can s t a t i s t i c a l l y be differentiated from placebo, and indicate a rapid onset of effects with short duration. According to the Computer Data Bank, citalopram has a mode of action similar to mood elevators (antidepressants) with fewer sedative properties. Thus the therapeutic action of citalopram is predicted to be similar to desipramine and p r o t r i p t y l i n e from the t r i c y c l i c s , and fluvoxamine from non-tricyclics. According to data bank assessment, i t is hypothesized that the single antidepressant dose of citalopram is to be more than 25 mg, which should be given t . i . d , in c l i n i c a l t r i a l s .
Keywords: antidepressant, computer-analyzed EEG, citalopram, phtalane derivative, quantitative pharmaco-EEG, serotonin re-uptake blocker, talsupram Abbreviations: computerelectroencephalogram (CEEG); central nervous system (CNS); electroencephalogram (EEG); frequency deviation (FD); primary wave (PW); quantitative pharmaco-EEG (QPEEG); resting record (RR); record during reaction time (RT) Introduction Despite the development of a variety of new antidepressant drugs, including the so-called second generation of antidepressants, there is not a single antidepressant available which has a rapid onset of action without unwanted effects. In recent years the trend has been to develop antidepressants with "specific" modes of action on cerebral neurotransmitters. For instance, citalopram*, a potent serotonin re-uptake i n h i b i t o r , was predicted to be a potent antidepressant without significant side effects in animal pharmacological studies. Preliminary c l i n i c a l t r i a l s indicated that the compound was effective but the therapeutic dosage could not easily be established. In order to determine the actions of citalopram on human brain function and to define the effective dose range, this study was performed using the quantitative pharmaco-EEG (QPEEGTM) method ( I t i l et al, 1971).
(*)
Lundbeck A/S, Copenhagen, Denmark
397
T.M. Itil et al.
398
Quantitative pharmaco-EEG is a method which involves the use of d i g i t a l computer analyzed, scalp-recorded electroencephalograms (CEEGTM) and a series of s t a t i s t i c a l procedures to establish the central effects of a new compound in humans, predict i t s c l i n i c a l (psychiatric) usefulness, and estimate i t s effective (therapeutic) dose range and duration of effects after administration of a single oral dose ( I t i l 1974). This method has confirmed predictions based on animal pharmacology t r i a l s regarding the psychotropic properties of a series of antidepressants ( I t i l et al. 1977a, b; I t i l 1975; I t i l 1983), anxiolytics ( I t i l et al. 1971, I t i l et al. 1979, I t i l et al. 1972, I t i l et al. 1973, I t i l and Huque 1979)and neuroleptics ( I t i l et al. 1973, I t i l et al. 1980, I t i l et al. 1978). Furthermore, QPEEGhas been instrumental in the discovery and classification of the psychotropic properties of a series of compounds not predicted through conventional methods ( I t i l et al. 1972, I t i l et al. 1975, I t i l et al. 1979, I t i l and Herrmann 1978). The purpose of this study was to investigate the effects of citalopram and an e a r l i e r compound of the same chemical series, talsupram, on human brain function as established by the scalp-recorded and computer-analyzed EEG. More specifically the study was designed to answer the following questions: ( i ) Does citalopram produce significant CNS effects which are more than placebo? ( i i ) What is the minimum CNS-effective dose of citalopram? ( i i i } Is the quality (type of CNS effects) similar to that of established antidepressants? Materials and Methods Study Population Included in this study were 12 adult male volunteers aged 19 to 44 years (mean 31.5 years), Dru9 Information Two drugs were used in this study, namely: citalopram and talsupram. Citalopram is a new phthalane derivative. I t ' s chemical structure is given in Fig I. This drug is a specific serotonin re-uptake inhibitor in vivo and in v i t r o , which f a c i l i t a t e s serotonin transmission and which is two to lO times as potent as clomipramine (Hyttel 1977a, b; Christensen et al. 1977). I t has no monoamine oxidase-inhibiting a c t i v i t y , and is devoid of neuroleptic, sedative and amphetamine-like properties in animal studies. I t does not produce electrocardiographic changes and has very weak anticholinergic and antihistamine properties in in v i t r o studies. In humans, peak plasma levels are achieved two to three hours after an ~ s e (Fredericson Overo 1982). %he kinetics are linear and citalopram peak concentrations were reached within 2-4 hours after the daily dose. Preliminary studies in humans suggest that i t has antidepressant properties and is well tolerated (Gottlieb et al. 1980; Lindegaard Pedersen et al. 1982; Ofsti 1982). The other compound tested in this study, talsupram, is a potent noradrenaline uptake inhibitor of similar potency to desipramine and lO times more potent than imipramine (Lundbeck A/S). In in vitro studies with human blood platelets, i t s inhibitory effect on serotonin uptake is about one-tenth that of amitriptyline and imipramine. Clinical studies in patients indicated that talsupram has indeed antidepressant effects (Ravn and Rud 1969, Stromgren and Friderichsen 1971). Study Design All subjects were healthy, had been o f f a l l medication, including psychotropic and other centrally acting drugs and alcohol for at least eight weeks before the study. Coffee, tea and tobacco were not permitted for at least one hour before each study session and until after a l l tests were completed. Food intake was prohibited for at least two hours before, and tr,ree hours a f t e r , the test drugs were given, to avoid food-induced variations of drug absorption. Assessment Instruments
i)
Clinical Instruments: Routine clinical pharmacological assessments were done before, and one, three and six hours after, administration of each drug or dose. These included measurement of v i t a l signs, and rating scales such as the Psychosomatic Rating Scale and the Self-Rating Questionnaire for Sedation and Tranquilizing Effects.
QPEEG with citalopram
399
i i ) Laboratory Instruments: Hematology ( f u l l blood counts), blood chemistry (SMA-12), ECG, urinalysis were done before and after administration of each drug or dose. EEG Studies CNS effects were determined before, and one, three and six hours a f t e r each drug administration by computer-analyzed EEG. At each recording there was a two-minute adaptation period followed by two five-minute recording periods separated by a two-minute interval. During the f i r s t five minutes subjects sat quietly with t h e i r eyes closed. This was termed the "Resting" recording (RR). During the second five minutes of recording, an acoustic stimulus of 250 Hz at a sound level of 60 decibels was presented to the subjects at randomized intervals of seven, 14 and 21 seconds. Subjects were asked to respond to the tone by pressing a button. These reaction time measurements were intended to maintain the vigilance of the subjects rather than to measure the effects of the drugs on reaction times. This was termed the "Reaction Time" recording (RT). The EEG was recorded on a four-channel Grass Model 79 polygraph machine in accordance with the internationally accepted 10-20 system. The right occipital to l e f t ear, and l e f t occipital to right ear leads were recorded on chart paper as well as on an analog tape recorder (Tannberg), and were analyzed by a d i g i t a l computer (PDP 11/45) using period analysis and power spectral density programs (Shapiro et ai.1977). Period analysis programs consisted of average absolute amplitude and amplitude v a r i a b i l i t y (Drohocki) as well as average frequency, frequency deviation and eight frequency bands of the primary wave and of the f i r s t derivative analysis. Power spectral density analysis included 19 frequency bands, average frequency and frequency and amplitude v a r i a b i l i t i e s . Each consecutive 10-24 seconds of EEG was analyzed (312.5 points per second) and for each epoch 22 variables or measurements of cerebral biopot e n t i a l s were obtained. For each time period (pre-drug, one, three and six hr after drug administration), and for each type of recording (Resting and Reaction Time), the means and sigma of the 22 EEG variables for period analysis and for power spectral density analysis of the total of 20 - 30 epochs of 10.24 sec each, were computed. These 22 measurements of preand post-drug computerized biopotentials were used for s t a t i s t i c a l procedures. Each subject underwent seven testing sessions, each separated by a minimum interval of five days. The f i r s t testing session was a single-blind adaptation procedure wherein the subject received one placebo capsule. In each of the six subsequent sessions the subjects received single oral doses of 10 mg citalopram, 25 mg citalopram, 50 mg citalopram, 50 mg imipramine, 50 mg talsupram or placebo. The sequence was a double-blind crossover design u t i l i z i n g a l a t i n square randomization.
CITALOPRAM 9
TALSUPRAM :.
/H N,,, H2-CH2- CH2CH3
sCH3 g
~
CH2 CH2 CH2 N~CH3
F Fig. I .
Chemical structure of talsupram and citalopram.
T.M, Itil et a~.
400
Results CNS E f f i c a c s
Information
Quantitative CNS Effects. In order to assess the quantitative CNS effects, four types of s t a t i s t i c a l evaluations were made: i) CEEG changes from pre- to post-drug periods ii) Discrimination of drug effects from placebo iii) Dose-related CNS effects, and iv) Time-related CNS effects. ( i ) The changes of individual CEEGmeasurements from pre- to post-drug periods are shown in Table I . The most frequent s t a t i s t i c a l l y s i g n i f i c a n t ( t - t e s t ) changew in CEEGmeasurements are observed after 50 mg citalopram, followed by 50 mg imipramine, 50 mg talsupram, 25 mg citalopram and lO mg citalopram. Table l Summary of S t a t i s t i c a l l y Significant CEEG Changes of CEEG Measurements Drug
EEG P e r i o d Analysis
Power
EEG Spectrum
Name < .05
+ P. Spectrum
< .01
< .05
4
1
14
20
10 mg Citalopram
4
2
6
12
25 mg Citalopram
9
5
14
50 mg Imipramine
1"
< .01
Total P. Analysis
50 mg Citalopram
3
20
4
5
32
50 mg Talsupram
1
4
2
9
16
*
Number of variable which showed s t a t i s t i c a l change
( i i ) To discriminate drug from placebo, the changes induced by d i f f e r e n t drugs an~ dosages were c o m p ~ w-]t-ht-he changes induced by placebo, using multivariate randomized T s t a t i s tics (Table 2). According to EEG power spectral analysis data, 25 mg and 50 mg citalopram (p <.01), and to a lesser degree, 10 mg citalopram (p=.06) could be differentiated from placebo. Based on computer period analysis of EEG, citalopram 25 mg (p <.05) and 50 mg (p <.01) and imipramine 50 mg (p <.05) were differentiated from placebo. Citalopram 10 mg and talsupram 50 mg could not be s t a t i s t i c a l l y differentiated from placebo, based on multivariate s t a t i s t i c s .
QPEEG with citalopram
401
(iii) In order to determine the dose-related CNS effects of citalopram, linear regression analysis was performed for both power spectrum density and period analyses for individual subjects and for the groups. On power spectrum analysis, the group of subjects showed s t a t i s t i c a l l y s i g n i f i c a n t doserelated changes, p a r t i c u l a r l y at the one hr recording, in seven of the 22 CEEG measurements. As the dose increased the average frequency also s i g n i f i c a n t l y decreased, resulting in increased a c t i v i t y in the 1.3 to 9.0 cps range, and decreased a c t i v i t y in the 9 to 21 cps range. Similarly, on period analysis seven subjects showed s i g n i f i c a n t changes in relation to increasing doses of citalopram, while on regression analysis of the group data, two of the 22 measurements showed s t a t i s t i c a l l y s i g n i f i c a n t decreases of FD 50 - 90 and FD 90+ cps a c t i v i t y with increasing doses of citalopram (Table 3). ( i v ) Further support of CNS effects was sought by investigation of time-related changes, using linear regression analysis (Table 4). On group regression analysis of power spectrum analysis, p a r t i c u l a r l y during RT recording after citalopram 10 mg, four of the 22 measurements showed s t a t i s t i c a l l y s i g n i f i c a n t timerelated changes manifested by a decrease of the frequency deviation, increase of 7.5 - 9.0 cps a c t i v i t y and decrease of 22.5 - 29.0 cps a c t i v i t y . On period analysis, two of the 22 measurements showed a significant decrease o'f PW 26.6 - 40 cps a c t i v i t y and FD 20 - 26.6 cps activity. The Type of CNS Effects (Mode of Action). The CEEGprofiles of each compound were obtained for both period and power spectrum analyses as group and individual drug p r o f i l e s , using t-scoring. Each drug and dose was then classified with reference to the HZI Computer Data Bank drugs (System I c l a s s i f i c a t i o n ) , using correlation s t a t i s t i c s (Pearson Product Moment Correlation). Classification of the drugs was performed by comparison of the CEEG profiles of the period analysis data with the profiles of previously studied anxiety relievers (anxiolytic-hypnotics), vigilance enhancers (stimulant-psychostimulants), CNS depressants (sedatives-neuroleptics) and mood elevators (antidepressants-thymoleptics). The results are summarized in Table 5. As seen in Table 5, both 10 and 50 mg of citalopram, respectively, were classified by f i r s t choice as a mood elevator (antidepressant = thymoleptic) with mean s i m i l a r i t y c o e f f i cients of 0.50 and 0.62, respectively, with data bank t r i c y c l i c and other antidepressants. This indicates that citalopram in 10 and 50 mg doses increases both the slow and fast frequencies, and decreases 7.5 - 13 cps a c t i v i t y in the primary wave measurements, and decreases slow and increases fast frequencies in the f i r s t derivative measurements. Citalopram 25 mg also showed some s i m i l a r i t y to data bank mood elevators, but with a lower s i m i l a r i t y coefficient. Thus, i t could not be classified by t he computer as a mood elevator. Talsupram 50 mg was classified with a weak coefficient as a CNS depressant (sedatives/neuroleptics) and with the next s i m i l a r i t y coefficient as a mood elevator. This indicates that talsupram 50 mg produces more slow waves than fast a c t i v i t y . Thus, sedative properties overshadowed the mood elevating effects. Imipramine, the control compound, was primarily classified as a,CNS depressant and secondarily as a mood elevator (mean s i m i l a r i t y coefficients with data bank drugs 0.59 and 0.27, respectively). This c l a s s i f i c a t i o n indicated that 10 mg citalopram most resembled data bank neuroleptics in addition to thymoleptics (2 highest correlation coefficient with data bank drug groups), whereas 25 mg and 50 mg citalopram were instead similar to anxiolytics in addition to antidepressants (Figure 2). HZI System I I I c l a s s i f i c a t i o n , which is based on 820 subclasses of 124 CNS effective drugs from the computer data bank, indicated that citalopram more closely resembles the less sedat i v e antidepressants ( p r o t r i p t y l i n e , desipramine) and some other 5HT reuptake blocking drugs (imipramine, fluotracen, n o r t r i p t y l i n e and a m i t r i p t y l i n e ) , As seen in Table VI, citalopram showed high s i m i l a r i t y to antidepressants with both 5HT as well as norepinephrine reuptake blocking properties.
T.M. Itil et al.
402
Table 2 Discrimination of Drugs from ~lacebo Based on Multivariate Randomized T~ Statistics Power Spectrum
Placebo Period Analysis
10 mg Citalopram 25 mg Citalopram
p<. 01
p<. 01
50 mg Cita|opram
p<. 01
p<. 05
50 mg Talsupram p<. 05
50 mg Imipramine
Table 3 Summary of Dose-Related S t a t i s t i c a l l y Significant Changes 1, 3 and 6 Hours After 10 mg and 50 mg Citalopram, Based on Linear Regression Analysis (Power Spectral Density Analysis and Period Analysis) Frequency (cycles per second)
l Hour RR
3 Hour RT
RR
6 Hour RT
RR
RT
Mean frequency 1 . 3 - 3.0 6 . 0 - 7.5 7.5 - 9.0 9.0 - 10.5 18.0 - 19.5 19.5 - 21.0 5 0 . 0 - 90.0* More than 90.0* All results refer to power spectral density analysis except for those marked with an asterisk (*) which refer to period analysis. + = Significantly increased a c t i v i t y = Significantly decreased a c t i v i t y
QPEEG with citalopram
403
Table 4 Summary of Time-Related Significant CNS Effects 1, 3 and 6 Hours After Citalopram 10 mg, 25 mg and SO mg, Based on Linear Regression Analysis of Results from Power Spectral Analysis and Period Analysis
Citalopram Frequency (cycles per second)
I0 mg RR RT
25 mg RR RT
50 mg RR RT
Frequency deviation Power Spectrum Analysis 7.5 - 9.0 9.0-
10.5
22.5 - 24.0 Period Analysis PW 26.6 - 40.0 FD 20.0 - 26.6
+ = Significantly increased a c t i v i t y - = Significantly decreased a c t i v i t y
By examination of EEG changes from pre-drug to one, three and six hours during Resting and Reaction Time recordings, the most homogeneous mood elevating response was seen with c i t a l o pram 50 mg, followed by imipramine 50 mg, citalopram I0 mg and talsupram 50 mg. Safety Information C l i n i c a l and Laboratory Data. The r e s u l t s of c l i n i c a l examination, neurological assessment, laboratory t e s t s , ECG and EEG during and a f t e r the study showed no s i g n i f i c a n t abnorm a l i t i e s . Adverse trends were not i d e n t i f i e d in association with any of the drugs. Abnormal Psychosomatic Scale and S e d a t i v e - T r a n q u i l i z i n g S e l f - R a t i n 9 Scale Findings. The most f r e q u e n t l y repeated side e f f e c t s were drowsiness and sleepiness, which occurred with s i m i l a r frequency a f t e r placebo as a f t e r active drugs. Citalopram related side e f f e c t s were nausea, tremor, headache, retarded-sluggish behavior, and dry mouth, Talsupram was associated with dry mouth, tremor and d i f f i c u l t y in swallowing, whereas imipramine was most f r e quently associated with dry mouth and sleepiness. The symptoms were not severe and did not require any treatment. The subjective side effects were most commonly observed with 50 mg imipramine, which had the maximum sleep inducing effects of a l l the test drugs.
404
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QPEEG with citalopram
405
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NEUI~LE~CI :
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DRUG
CODE
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DRUG
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DRUG
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DRUG
4-28mg.
CITALOPRAM
DRUG
e-GOing.
TALSUPRAM
.1.0
PSYCHOSTIMULANT8
Fig. 2.
Two dimensional classification of different dosages citalopram and control compounds.
Table 6 The HZI CEEGData Base I I I Classification of Citalopram
(RANKED ACCOROING TO THE HIGHEST SIMILARITY COEFFICIENT)
NEW DOSAGE
STUDY DRUG
CLASSIFICATION
DATA
PERIOD
RIM. COEF.
EUCLID. DIRT.DOSAGE
3 HR
0,823
0.018
75 MG
BASE
DRUG
BIO.
AMINES
PERIOD
5 HT
3 HR
9149 3
9
J:
4" ( 9
9149
ii
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NE
04. 9
10 MG
|ll
IMIPRAMINII
J|
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|l
0.792
0.020
70 MG
21
||
n
0.791
o.ol0
2 0 0 MG
FLUOTIIACEN
I:
J|
||
i|
0.790
0.018
75 MG
NOIqTRIPTYLINII
II
0 9149
9
ii
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n
0,700
0.027
76 MG
AMITFIIImTYI-INIE
II
49
4'4"
50 MG
||
Jl
0.700
O.Ol I
16o MG
ViI.OXAZINM
II
o
(03
9149
406
T.M. Itil et ~ .
Discussion This study has shown that citalopram when given in single oral doses of 10 to 5D mg to healthy human volunteers does not have serious or severe side effects. All drugs tested in t h i s double-blind QPEEGstudy, including placebo, caused sedation and induced sleep. However, side effects such as nausea, tremor, headache, dry mouth and sluggish behavior were most frequently seen after citalopram 50 mg. The CNS effects of citalopram 25 and 50 mg are potent. Univariate, but p a r t i c u l a r l y multivariate, s t a t i s t i c s clearly demonstrated that these effectscould be discriminated from those of placebo and are s i g n i f i c a n t l y different. The CNS effects are dose related, p a r t i c u l a r l y during the f i r s t hour, as demonstrated by lesser high frequency fast waves with higher doses. The minimum CNS effective dose of citalopram is 25 mg. Time related CNS effects were observed primarily with citalopram 10 mg, suggesting that these may have occurred by chance. Time and dose effect s t a t i s t i c s suggest that citalopram has a rapid onset of CNS effects, the duration of which is short. The CNS effects of 50 mg, and to a lesser degree, 10 mg citalopram were classified by the HZI computer data bank as similar to those of mood elevators (antidepressants) of the data bank ( f i r s t choice c l a s s i f i c a t i o n ) . According to our r e l i a b i l i t y and v a l i d i t y studies, the f i r s t and second choice computer data bank classifications for antidepressants are s i g n i f i cantly better than chance (p<.O001, binomial s t a t i s t i c s ) ( I t i l 1982 ). Twenty-five milligram citalopram, although showing most s i m i l a r i t y to the antidepressants of the data bank, could not be classified as such because the s i m i l a r i t y coefficient was not high enough. Therefore, i t is predicted that the best therapeutic single dose of citalopram is between 25 mg and 50 mg. Talsupram 50 mg was classified between CNS depressants (neurolept i c s ) and anti-depressants with low s i m i l a r i t y coefficients for both drug groups. As in previous studies ( I t i l et al, 1977; I t i l et al, 1977; I t i l , 1975; I t i l and Soldatos, 1980; I t i l , 1981), this study also indicates that the CEEGc l a s s i f i c a tion of antidepressants has no significant relationship with the effects of these drugs on biogenic amines. The CEEG profiles of a m i t r i p t y l i n e , imipramine, fluvoxamine, mianserin and n o r t r i p t y l i n e are similar to one another. However, they show marked differences with regard to t h e i r effects on biogenic amines. Amitriptyline and n o r t r i p t y l i n e , but particul a r l y fluvoxamine, have predominantly i n h i b i t o r y effects on serotonin reuptake. Imipramine has almost equal effects on both norepinephrine and serotonin reuptake. Mianserin ( I t i l et al, 1972) and mesterolone ( I t i l et al, 1979) do not have s i g n i f i c a n t effects on biogenic amines ( I t i l , 1982). Citalopram, a specific serotonin reuptake i n h i b i t o r l i k e fluvoxamine ( I t i l et al, 1977), has CEEG profile similar to that of fluvoxamine. However, the CEEG p r o f i l e of citalopram is also very similar to that of mianserin ( I t i l et al, 1972), which has v i r t u a l l y no effects on the biogenic amines and, i f anything, increases norepinephrine reuptake. Talsupram 50 m9, a potent norepinephrine reuptake i n h i b i t o r , was classified between CNS depressants and mood elevators in this study. The CNS effects of talsupram 50 mg were not as potent as those of imipramine 50 mg, although the norepinephrine reuptake i n h i b i t i n g effects of talsupram were ten times more potent than those of imipramine (Lundbeck A/S). The s i m i l a r i t y of CEEG profiles of different antidepressants indicate that these drugs after single oral dose were adequately absorbed and metabolized and have crossed the bloodbrain barrier, and produce similar effects on cerebral neurons. As these effects are probably the result of common biochemical changes, one can postulate that drugs with similar CEEG profiles produce similar cerebral biochemical changes. The "shape" of the CEEG profiles, i . e . the changes of the frequency d i s t r i b u t i o n from pre to post drug periods, are known to be closely related to the type of therapeutic effects of drugs. Therefore, one could further hypothesize that these biochemical changes are closely related to the therapeut i c actions (e.g. antidepressant effects) of these drugs. The discovery of the nature of the biochemical substrate which is responsible for producing the "typical" bioelectrical effects (CEEG profiles) for antidepressants w i l l provide important information on the pathogenesis of depressive illness and may help to find specific treatments for specific types of depressive i l l n e s s . Meanwhile, routine application of QPEEG in early drug evaluation (Phase I studies) can provide important CNS efficacy information on a new potential psychotropic. This, in turn, can be of s i g n i f i c a n t use in designing e f f i c i e n t c l i n i c a l development programs.
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Conclusions Based on CEEG data bank c l a s s i f i c a t i o n (HZI System I c l a s s i f i c a t i o n ) , the CNS effects of citalopram in humans was found to be s i m i l a r to those of " c l a s s i c a l " mood elevators ( a n t i depressants). However, the further and more detailed c l a s s i f i c a t i o n with individual drugs from the computer data bank (HZI System I I I c l a s s i f i c a t i o n ) indicated that the mode of action o f citalopram p r i m a r i l y resembled less sedative antidepressants such as p r o t r i p t y l i n e and desipramine from the t r i c y c l i c antidepressants, and fluvoxamine, another n o n - t r i c y c l i c 5HT reuptake blocker antidepressant. The therapeutic dose of citalopram is hypothesized to be between 25 and 50 mg, to be administered t . i . d . I t was hypothesized that the mode of action (CNS effects) of an antidepressant in humans, as established by computer EEG profiles, cannot be related to the well-known biochemical properties of this compound: The antidepressants with s i g n i f i c a n t l y d i f f e r e n t biochemical effects produce very similar CEEG profiles. These effects produce very similar CEEG profiles. Therefore, i t is postulated that drugs with c l i n i c a l l y antidepressant effects produce a "typical" biochemical change which is s i g n i f i c a n t l y related to the therapeutic action of the drug, and is associated by a characteristic electrophysiological pattern (CEEG p r o f i l e ) although i t s properties might not be known to us. The discovery of the biochemical correlates of the antidepressant CEEG profiles in humans may help us to understand the etiology of depressive illness and to develop i t s "causal" treatment.
Ack.nowledgements The authors would like to thank the research personnel of the pharmaceutical division of Lundbeck A/S, Copenhagen, for providing a l l available information on citalopram before the study and for providing the drugs for the study, and the meticulousness of the staffs and research personnel of the HZI Research Center, HZI-Europe and HZI Neuropsychiatric Foundation, without whom this project could not have been completed. References
CHRISTENSEN, A. V., FJALLAND, B., PEDERSEN, V., DANNESKIOLD-SAMSOE, P. and SVENDSEN, O. (1977) Pharmacology of new phthalane (LU 10-171) with specific 5-HT uptake i n h i b i t i n g properties. European J. Clin. Pharm. 41: 153-162. FREDRICSON OVERO, K. (1982) Kinetics of citalopram in man; plasma l e v e l s in patients. In: Citalopram basic and c l i n i c a l studies, H y t t e l , J. (ed), Prog. Neuro-Psychopharmacology, J. Biol. Psychiat. 6: 311-318. GOTTLIEB, P., WANDALL~ T. and FREDRICSON OVERO, K. (1980) I n i t i a l , c l i n i c a l t r i a l of a new, specific 5-HT reuptake i n h i b i t o r , citalopram (Lu 10-171). Acta psychiat. Scand. 62: 236-244. HYTTEL, J. (197~) Effect of a s e l e c t i v e 5-HT uptake i n h i b i t o r , LU-IO-171 on rat brain 5-HT turnover. (1977) Acta Pharm et Toxicology, 40: 439-446. HYTTEL, J. (1977b) Neurochemical characterization of a new potent and selective serotonin uptake i n h i b i t o r . Psychopharmacology, 51: 225-233. ITIL, T . M . (1974) Quantitative~harmaco-electroencephalograph. In: Psychotropic Drugs and the Human EEG. Modern Problems in Psychopsychiatrz, Vol. 8. I t i l , T.M. (ed), pp. 43-75. Basle/New York, Karger. ITIL, T. M. (1975) Computer EEG Profiles of Antidepressants: Quantitative Pharmaco-EEG in the Development of New Antidepressive Drugs. Antidepressants ( I n d u s t r i a l Pharmacology), Vol. I I . Mt. Kisco/New York. Futura Publishing Company, pp. 319-351. ITIL, T. M., REISBERG, P., AMIN, A., WADUD, A. and HERRMAN, W.M. (1978) Pipothiazine Palmitate, a Long-Acting Neuroleptic: Clinical and Computerized EEG Effects. Current Therapeutic Research, 24 (6) 689-707.
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ITIL, T. M. (1981) The Use of Computerized Bio-Electrical Potentials (CEEG) in the Discovery of Psychotropics. Drug Development Research, Vol. I , No. 4 ITIL, T. M. (1982) The Significance of Quantitative Pharmaco-EEG in the Discovery and Classification of Psychotropic Drugs. In: Herrmann, W.M. (Ed.) EEG in Drug Research. Stuttgart/New York. Gustav Fischer Verlag, pp. 67-79. ITIL, T. M. (1983) Computer EEG in the Discovery of Antidepressants. In Burrows/Norman/ Davis (Eds.) Antidepressants, Elsevier Science Publishers, pp. 149-171. ITIL, T. M., AKPINAR, S., OZKUT, H., BALKI, N. and HERRMANN, W. M. (1979) c l i n i c a l and Computerized EEG Effects of U-31,920, a New Anxiolytic. Current Therapeutic Research, 16 (6), 642-659. ITIL, T. M., 8HATTACHARYA, A., POLVAN, N., HUQUE, M. and MENON, G. N. (1977a)Fluvoxamine (Du 23,000), a New Antidepressant. Quantitative Pharmaco-electroencephalography and Pilot Clinical T r i a l s . Progress in Neuropsychopharmacology i , 309-322. ITIL, T. M., CORA, R., AKPINAR, S., HERRMANN, W. M. and PATTERSON, C. (1979) "Psychotropic" Actions of Sex Hormones: Computerized EEG in Establishing the Immediate CNS Effects of Steroid Hormones. Current Therapeutic Research, 16 (11), 1147-1170. ITIL, T. ~I., GANNON, P., CORA, R., POLVAN, N., AKPINAR, S., ELVERI$, F. and ESKAZAN, E. (1971) SCH-12,041, a New Anti-Anxiety Agent (Quantitative Pharmaco-electroencephalography and Clinical T r i a l s ) . Physicians' Desk Manual (PDM), 3 (3-4), 26-35. Also in Behavioral Neuropsychiatry, 4 (4-5), 15-29, 1972. ITIL, T. M., GUVEN, F., CORA, R., HSU, W., POLVAN, N., UCOK, A., SANSEIGNE, A. and ULETT, G. A. (1971) Quantitative Pharmaco-electroencephalography Using Frequency Analyzer, and Digital Computer Methods in Early Drug Evaluations. In: Smith, W.L. (Ed.) Drugs, Development and Brain Functions. Springfield, l l l i n o i s . Charles C. Thomas. pp. 145-166. ITIL, T. M., FREDERICKSON, J. W., SCHNEIDER, S. J., FRANCIS, I. B. and KHAN, M. M. (1980) Clopipazan (SFK-69634), a New Neuroleptic Essentially Free of Extrapyrmmidal L i a b i l i t y : Quantitative Pharmaco-EEG and Open Label Clinical T r i a l . Current Therapeutic Research, 27, 7]9-730. ITIL, T. M., HERRMANN, W. M. and AKPINAR, S. (1975) Predication of Psychotropic Properties of Lisuride Hydrogen Maleate by Quantitative Pharmaco-Electroencephalography. International Journal of Clinical Pharmacology, 121, 221-223. ITIL, T. M. and HERRMANN, W. Mo (1978) Effects of Hormones on Computer-Analyzed Human Electroencephalogram. In: L~pton, M.A., Di~lascio, A. and Killam, K.F. (Eds.) Psychopharmacology: A Generation of Progress. Raven Press, New York, pp. 729-743. ITIL, T. M., HSU, W. and CIG, E. (1973) "Anxiolytic" Profile and B i o a v a i l a b i l i t y of Chloracepate Dipotassium Based on Quantitative Pharmaco-Electroencephalography. Aggressologie, 14 (3), 203-212. ITIL, T. M. and HUQUE, M. (1979) Computer EEG Profiles of Anxiolytics (Quantitative PharmacoEEG in the Development of New Anxiolytics). In: S. Fielding and H. Lal (Eds.). Industrial Pharmacology - Anxiolytics. Vol. 3, Mt. Kisco/New York, Futura Publishing Company, 281-316. ITIL, T. M., MARASA, J., BIGELOW and SALETU, B. (1973) Prediction of Neuroleptic Effects of CI-686 Based on Quantitative Pharmaco-Electroencephalography: Drug Profiles and Dose Response Curves Based on Computerized Bio-Potentials. Current Therapeutic Research, 16 (1), pp. 80-95. ITIL, T. M., POLVAN, N. and HSU, W. (1972) Clinical and EEG Effects of GB-94, a "Tetracyclic" Antidepressant. (EEG Model in Discovery of a Psychotropic Drug.) Current Therapeutic Research, 14 (7), 395-413. ITIL, T. M., POLVAN, N., ENGIN, L., GUTHRIE, M. B. and HUQUE, M. F. (19770)Fluotracen (SKF-28175), a New Thymo-Neuroleptic with Rapid Action and Long-Acting Properties (Quantitative Pharmaco-EEG and Clinical Trials in the Development of Fluotracen (SKF28175). Current Therapeutic Research, 21 (3), 343-360. ITIL, T. M., SALETU, B., MARASA, J. and MUCCIARDI, A.N. (1972) Digital Computer-AnalyZed Awake and Sleep EEG (Sleep Prints) in Predicting the Effects of a Troazolo8enzodiazepine (U-31,889). Pharmakopsychiatry, 5, 225-240. ITIL, T. M. and SOLDATOS, C. (1980) Clinical Neurophysiological Properties of Antidepressants In: Hoffmeister, F. and S t i l l e , G. (Eds.) Psychotropic Agents - Part I: Antipsychotics and Antidepressants. Berlin/Heidelberg/New York. Springer Verlag, pp. 437-469. LINDEGAARD PEDERSEN, 0., KRAGH-SORENSEN, P., BJERRE, M., FREDERICSON, OVERO, K. and GRAM, L. F. (1982) Citalopram, a Selective Serotonin Reuptake I n h i b i t o r , Clinical Antidepressive and Long Term Effect - A Phase I I Study. Psychopharmacology. 7__77: 199-204.
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LUNDBECK A/S, Talsupram: S c i e n t i f i c Information, Personal Communication, Copenhagen, Valby. OFSTI, E. (1982) Citalopram - A Specific 5-HT-Reuptake I n h i b i t o r as an Antidepressant Drug: A Phase I I Multicentre T r a i l . Prog. Neuro-Psychopharmacol. and Biol. Psychiat. 6: 327-335. RAVN, J. and RUD, C. (1969) Forelobige Erfaringer AF Behandling, AF Depressive Pa~ienter Med LU3-OIO OG LU 5-003. Nord. Psykiat. T. 23: 253-262. SHAPIRO, D. M., ITIL, T. M., HUQUE, M. F. and F~RBES, D. (1977) HZI System X: EEG Evoked Potential Analysis Systems. Electroencephalography and Clinical Neurophysiology, 43 (4) 553, etc. STROMGREN, L. S. and FRIDERICHSEN, T. (1971) LU 5-003 i , Antidepressiv. Terapi. Nord. Psykiat. T. 25: 119-128. Inquiries and reprint requests should be addressed to: Dr. Turan M. I t i l 150 White Plains Road Tarrytown, New York 10591 U.S.A.
Copyright 9
0278-5846/84 $0.00 + .50 1984 Pergamon Press Ltd~
CNS EFFECTS OF CITALOPRAM, A NEW SEROTONIN INHIBITOR ANTIDEPRESSANT (A QUANTITATIVE PHARMACOELECTROENCEPHALOGRAPHY STUDY) TURAN M. ITIL I , GOPI N. MENON 2, M. MAHIR BOZAK3 and KURT Z. ITIL4 1Division of Biological Psychiatry, New York Medical College, Valhalla, NY, USA; :HZI-Euro~e and Consultant in Clinical Research, Amsterdam, The Netherlands; JHZI Neuropsychiatric Foundation and Medical Center, Istanbul, Turkey and 4HZI Research Center, Tarrytown, NY, USA (Final form, June 1983) Abstract I t i l , Turan M., Gopi N. Menon, M. Mahir Bozak and Kurt Z. I t i l : CNS effects of citalopram, a new serotonin i n h i b i t o r antidepressant (a quantitative pharmaco-electroencephalography study). Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1984, 8(3) : 397-409 1. 2. 3. 4. 5.
Citalopram, a new phthalane derivative and a specific serotonin re-uptake i n h i b i t o r in animal pharmacological tests, was evaluated in a double-blind, crossover, quantitative pharmaco-EEG (QPEEGTM) study in healthy human volunteers. The CNS effects of citalopram are linear, dose- and time-related, can s t a t i s t i c a l l y be differentiated from placebo, and indicate a rapid onset of effects with short duration. According to the Computer Data Bank, citalopram has a mode of action similar to mood elevators (antidepressants) with fewer sedative properties. Thus the therapeutic action of citalopram is predicted to be similar to desipramine and p r o t r i p t y l i n e from the t r i c y c l i c s , and fluvoxamine from non-tricyclics. According to data bank assessment, i t is hypothesized that the single antidepressant dose of citalopram is to be more than 25 mg, which should be given t . i . d , in c l i n i c a l t r i a l s .
Keywords: antidepressant, computer-analyzed EEG, citalopram, phtalane derivative, quantitative pharmaco-EEG, serotonin re-uptake blocker, talsupram Abbreviations: computerelectroencephalogram (CEEG); central nervous system (CNS); electroencephalogram (EEG); frequency deviation (FD); primary wave (PW); quantitative pharmaco-EEG (QPEEG); resting record (RR); record during reaction time (RT) Introduction Despite the development of a variety of new antidepressant drugs, including the so-called second generation of antidepressants, there is not a single antidepressant available which has a rapid onset of action without unwanted effects. In recent years the trend has been to develop antidepressants with "specific" modes of action on cerebral neurotransmitters. For instance, citalopram*, a potent serotonin re-uptake i n h i b i t o r , was predicted to be a potent antidepressant without significant side effects in animal pharmacological studies. Preliminary c l i n i c a l t r i a l s indicated that the compound was effective but the therapeutic dosage could not easily be established. In order to determine the actions of citalopram on human brain function and to define the effective dose range, this study was performed using the quantitative pharmaco-EEG (QPEEGTM) method ( I t i l et al, 1971).
(*)
Lundbeck A/S, Copenhagen, Denmark
397
T.M. Itil et al.
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Quantitative pharmaco-EEG is a method which involves the use of d i g i t a l computer analyzed, scalp-recorded electroencephalograms (CEEGTM) and a series of s t a t i s t i c a l procedures to establish the central effects of a new compound in humans, predict i t s c l i n i c a l (psychiatric) usefulness, and estimate i t s effective (therapeutic) dose range and duration of effects after administration of a single oral dose ( I t i l 1974). This method has confirmed predictions based on animal pharmacology t r i a l s regarding the psychotropic properties of a series of antidepressants ( I t i l et al. 1977a, b; I t i l 1975; I t i l 1983), anxiolytics ( I t i l et al. 1971, I t i l et al. 1979, I t i l et al. 1972, I t i l et al. 1973, I t i l and Huque 1979)and neuroleptics ( I t i l et al. 1973, I t i l et al. 1980, I t i l et al. 1978). Furthermore, QPEEGhas been instrumental in the discovery and classification of the psychotropic properties of a series of compounds not predicted through conventional methods ( I t i l et al. 1972, I t i l et al. 1975, I t i l et al. 1979, I t i l and Herrmann 1978). The purpose of this study was to investigate the effects of citalopram and an e a r l i e r compound of the same chemical series, talsupram, on human brain function as established by the scalp-recorded and computer-analyzed EEG. More specifically the study was designed to answer the following questions: ( i ) Does citalopram produce significant CNS effects which are more than placebo? ( i i ) What is the minimum CNS-effective dose of citalopram? ( i i i } Is the quality (type of CNS effects) similar to that of established antidepressants? Materials and Methods Study Population Included in this study were 12 adult male volunteers aged 19 to 44 years (mean 31.5 years), Dru9 Information Two drugs were used in this study, namely: citalopram and talsupram. Citalopram is a new phthalane derivative. I t ' s chemical structure is given in Fig I. This drug is a specific serotonin re-uptake inhibitor in vivo and in v i t r o , which f a c i l i t a t e s serotonin transmission and which is two to lO times as potent as clomipramine (Hyttel 1977a, b; Christensen et al. 1977). I t has no monoamine oxidase-inhibiting a c t i v i t y , and is devoid of neuroleptic, sedative and amphetamine-like properties in animal studies. I t does not produce electrocardiographic changes and has very weak anticholinergic and antihistamine properties in in v i t r o studies. In humans, peak plasma levels are achieved two to three hours after an ~ s e (Fredericson Overo 1982). %he kinetics are linear and citalopram peak concentrations were reached within 2-4 hours after the daily dose. Preliminary studies in humans suggest that i t has antidepressant properties and is well tolerated (Gottlieb et al. 1980; Lindegaard Pedersen et al. 1982; Ofsti 1982). The other compound tested in this study, talsupram, is a potent noradrenaline uptake inhibitor of similar potency to desipramine and lO times more potent than imipramine (Lundbeck A/S). In in vitro studies with human blood platelets, i t s inhibitory effect on serotonin uptake is about one-tenth that of amitriptyline and imipramine. Clinical studies in patients indicated that talsupram has indeed antidepressant effects (Ravn and Rud 1969, Stromgren and Friderichsen 1971). Study Design All subjects were healthy, had been o f f a l l medication, including psychotropic and other centrally acting drugs and alcohol for at least eight weeks before the study. Coffee, tea and tobacco were not permitted for at least one hour before each study session and until after a l l tests were completed. Food intake was prohibited for at least two hours before, and tr,ree hours a f t e r , the test drugs were given, to avoid food-induced variations of drug absorption. Assessment Instruments
i)
Clinical Instruments: Routine clinical pharmacological assessments were done before, and one, three and six hours after, administration of each drug or dose. These included measurement of v i t a l signs, and rating scales such as the Psychosomatic Rating Scale and the Self-Rating Questionnaire for Sedation and Tranquilizing Effects.
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i i ) Laboratory Instruments: Hematology ( f u l l blood counts), blood chemistry (SMA-12), ECG, urinalysis were done before and after administration of each drug or dose. EEG Studies CNS effects were determined before, and one, three and six hours a f t e r each drug administration by computer-analyzed EEG. At each recording there was a two-minute adaptation period followed by two five-minute recording periods separated by a two-minute interval. During the f i r s t five minutes subjects sat quietly with t h e i r eyes closed. This was termed the "Resting" recording (RR). During the second five minutes of recording, an acoustic stimulus of 250 Hz at a sound level of 60 decibels was presented to the subjects at randomized intervals of seven, 14 and 21 seconds. Subjects were asked to respond to the tone by pressing a button. These reaction time measurements were intended to maintain the vigilance of the subjects rather than to measure the effects of the drugs on reaction times. This was termed the "Reaction Time" recording (RT). The EEG was recorded on a four-channel Grass Model 79 polygraph machine in accordance with the internationally accepted 10-20 system. The right occipital to l e f t ear, and l e f t occipital to right ear leads were recorded on chart paper as well as on an analog tape recorder (Tannberg), and were analyzed by a d i g i t a l computer (PDP 11/45) using period analysis and power spectral density programs (Shapiro et ai.1977). Period analysis programs consisted of average absolute amplitude and amplitude v a r i a b i l i t y (Drohocki) as well as average frequency, frequency deviation and eight frequency bands of the primary wave and of the f i r s t derivative analysis. Power spectral density analysis included 19 frequency bands, average frequency and frequency and amplitude v a r i a b i l i t i e s . Each consecutive 10-24 seconds of EEG was analyzed (312.5 points per second) and for each epoch 22 variables or measurements of cerebral biopot e n t i a l s were obtained. For each time period (pre-drug, one, three and six hr after drug administration), and for each type of recording (Resting and Reaction Time), the means and sigma of the 22 EEG variables for period analysis and for power spectral density analysis of the total of 20 - 30 epochs of 10.24 sec each, were computed. These 22 measurements of preand post-drug computerized biopotentials were used for s t a t i s t i c a l procedures. Each subject underwent seven testing sessions, each separated by a minimum interval of five days. The f i r s t testing session was a single-blind adaptation procedure wherein the subject received one placebo capsule. In each of the six subsequent sessions the subjects received single oral doses of 10 mg citalopram, 25 mg citalopram, 50 mg citalopram, 50 mg imipramine, 50 mg talsupram or placebo. The sequence was a double-blind crossover design u t i l i z i n g a l a t i n square randomization.
CITALOPRAM 9
TALSUPRAM :.
/H N,,, H2-CH2- CH2CH3
sCH3 g
~
CH2 CH2 CH2 N~CH3
F Fig. I .
Chemical structure of talsupram and citalopram.
T.M, Itil et a~.
400
Results CNS E f f i c a c s
Information
Quantitative CNS Effects. In order to assess the quantitative CNS effects, four types of s t a t i s t i c a l evaluations were made: i) CEEG changes from pre- to post-drug periods ii) Discrimination of drug effects from placebo iii) Dose-related CNS effects, and iv) Time-related CNS effects. ( i ) The changes of individual CEEGmeasurements from pre- to post-drug periods are shown in Table I . The most frequent s t a t i s t i c a l l y s i g n i f i c a n t ( t - t e s t ) changew in CEEGmeasurements are observed after 50 mg citalopram, followed by 50 mg imipramine, 50 mg talsupram, 25 mg citalopram and lO mg citalopram. Table l Summary of S t a t i s t i c a l l y Significant CEEG Changes of CEEG Measurements Drug
EEG P e r i o d Analysis
Power
EEG Spectrum
Name < .05
+ P. Spectrum
< .01
< .05
4
1
14
20
10 mg Citalopram
4
2
6
12
25 mg Citalopram
9
5
14
50 mg Imipramine
1"
< .01
Total P. Analysis
50 mg Citalopram
3
20
4
5
32
50 mg Talsupram
1
4
2
9
16
*
Number of variable which showed s t a t i s t i c a l change
( i i ) To discriminate drug from placebo, the changes induced by d i f f e r e n t drugs an~ dosages were c o m p ~ w-]t-ht-he changes induced by placebo, using multivariate randomized T s t a t i s tics (Table 2). According to EEG power spectral analysis data, 25 mg and 50 mg citalopram (p <.01), and to a lesser degree, 10 mg citalopram (p=.06) could be differentiated from placebo. Based on computer period analysis of EEG, citalopram 25 mg (p <.05) and 50 mg (p <.01) and imipramine 50 mg (p <.05) were differentiated from placebo. Citalopram 10 mg and talsupram 50 mg could not be s t a t i s t i c a l l y differentiated from placebo, based on multivariate s t a t i s t i c s .
QPEEG with citalopram
401
(iii) In order to determine the dose-related CNS effects of citalopram, linear regression analysis was performed for both power spectrum density and period analyses for individual subjects and for the groups. On power spectrum analysis, the group of subjects showed s t a t i s t i c a l l y s i g n i f i c a n t doserelated changes, p a r t i c u l a r l y at the one hr recording, in seven of the 22 CEEG measurements. As the dose increased the average frequency also s i g n i f i c a n t l y decreased, resulting in increased a c t i v i t y in the 1.3 to 9.0 cps range, and decreased a c t i v i t y in the 9 to 21 cps range. Similarly, on period analysis seven subjects showed s i g n i f i c a n t changes in relation to increasing doses of citalopram, while on regression analysis of the group data, two of the 22 measurements showed s t a t i s t i c a l l y s i g n i f i c a n t decreases of FD 50 - 90 and FD 90+ cps a c t i v i t y with increasing doses of citalopram (Table 3). ( i v ) Further support of CNS effects was sought by investigation of time-related changes, using linear regression analysis (Table 4). On group regression analysis of power spectrum analysis, p a r t i c u l a r l y during RT recording after citalopram 10 mg, four of the 22 measurements showed s t a t i s t i c a l l y s i g n i f i c a n t timerelated changes manifested by a decrease of the frequency deviation, increase of 7.5 - 9.0 cps a c t i v i t y and decrease of 22.5 - 29.0 cps a c t i v i t y . On period analysis, two of the 22 measurements showed a significant decrease o'f PW 26.6 - 40 cps a c t i v i t y and FD 20 - 26.6 cps activity. The Type of CNS Effects (Mode of Action). The CEEGprofiles of each compound were obtained for both period and power spectrum analyses as group and individual drug p r o f i l e s , using t-scoring. Each drug and dose was then classified with reference to the HZI Computer Data Bank drugs (System I c l a s s i f i c a t i o n ) , using correlation s t a t i s t i c s (Pearson Product Moment Correlation). Classification of the drugs was performed by comparison of the CEEG profiles of the period analysis data with the profiles of previously studied anxiety relievers (anxiolytic-hypnotics), vigilance enhancers (stimulant-psychostimulants), CNS depressants (sedatives-neuroleptics) and mood elevators (antidepressants-thymoleptics). The results are summarized in Table 5. As seen in Table 5, both 10 and 50 mg of citalopram, respectively, were classified by f i r s t choice as a mood elevator (antidepressant = thymoleptic) with mean s i m i l a r i t y c o e f f i cients of 0.50 and 0.62, respectively, with data bank t r i c y c l i c and other antidepressants. This indicates that citalopram in 10 and 50 mg doses increases both the slow and fast frequencies, and decreases 7.5 - 13 cps a c t i v i t y in the primary wave measurements, and decreases slow and increases fast frequencies in the f i r s t derivative measurements. Citalopram 25 mg also showed some s i m i l a r i t y to data bank mood elevators, but with a lower s i m i l a r i t y coefficient. Thus, i t could not be classified by t he computer as a mood elevator. Talsupram 50 mg was classified with a weak coefficient as a CNS depressant (sedatives/neuroleptics) and with the next s i m i l a r i t y coefficient as a mood elevator. This indicates that talsupram 50 mg produces more slow waves than fast a c t i v i t y . Thus, sedative properties overshadowed the mood elevating effects. Imipramine, the control compound, was primarily classified as a,CNS depressant and secondarily as a mood elevator (mean s i m i l a r i t y coefficients with data bank drugs 0.59 and 0.27, respectively). This c l a s s i f i c a t i o n indicated that 10 mg citalopram most resembled data bank neuroleptics in addition to thymoleptics (2 highest correlation coefficient with data bank drug groups), whereas 25 mg and 50 mg citalopram were instead similar to anxiolytics in addition to antidepressants (Figure 2). HZI System I I I c l a s s i f i c a t i o n , which is based on 820 subclasses of 124 CNS effective drugs from the computer data bank, indicated that citalopram more closely resembles the less sedat i v e antidepressants ( p r o t r i p t y l i n e , desipramine) and some other 5HT reuptake blocking drugs (imipramine, fluotracen, n o r t r i p t y l i n e and a m i t r i p t y l i n e ) , As seen in Table VI, citalopram showed high s i m i l a r i t y to antidepressants with both 5HT as well as norepinephrine reuptake blocking properties.
T.M. Itil et al.
402
Table 2 Discrimination of Drugs from ~lacebo Based on Multivariate Randomized T~ Statistics Power Spectrum
Placebo Period Analysis
10 mg Citalopram 25 mg Citalopram
p<. 01
p<. 01
50 mg Cita|opram
p<. 01
p<. 05
50 mg Talsupram p<. 05
50 mg Imipramine
Table 3 Summary of Dose-Related S t a t i s t i c a l l y Significant Changes 1, 3 and 6 Hours After 10 mg and 50 mg Citalopram, Based on Linear Regression Analysis (Power Spectral Density Analysis and Period Analysis) Frequency (cycles per second)
l Hour RR
3 Hour RT
RR
6 Hour RT
RR
RT
Mean frequency 1 . 3 - 3.0 6 . 0 - 7.5 7.5 - 9.0 9.0 - 10.5 18.0 - 19.5 19.5 - 21.0 5 0 . 0 - 90.0* More than 90.0* All results refer to power spectral density analysis except for those marked with an asterisk (*) which refer to period analysis. + = Significantly increased a c t i v i t y = Significantly decreased a c t i v i t y
QPEEG with citalopram
403
Table 4 Summary of Time-Related Significant CNS Effects 1, 3 and 6 Hours After Citalopram 10 mg, 25 mg and SO mg, Based on Linear Regression Analysis of Results from Power Spectral Analysis and Period Analysis
Citalopram Frequency (cycles per second)
I0 mg RR RT
25 mg RR RT
50 mg RR RT
Frequency deviation Power Spectrum Analysis 7.5 - 9.0 9.0-
10.5
22.5 - 24.0 Period Analysis PW 26.6 - 40.0 FD 20.0 - 26.6
+ = Significantly increased a c t i v i t y - = Significantly decreased a c t i v i t y
By examination of EEG changes from pre-drug to one, three and six hours during Resting and Reaction Time recordings, the most homogeneous mood elevating response was seen with c i t a l o pram 50 mg, followed by imipramine 50 mg, citalopram I0 mg and talsupram 50 mg. Safety Information C l i n i c a l and Laboratory Data. The r e s u l t s of c l i n i c a l examination, neurological assessment, laboratory t e s t s , ECG and EEG during and a f t e r the study showed no s i g n i f i c a n t abnorm a l i t i e s . Adverse trends were not i d e n t i f i e d in association with any of the drugs. Abnormal Psychosomatic Scale and S e d a t i v e - T r a n q u i l i z i n g S e l f - R a t i n 9 Scale Findings. The most f r e q u e n t l y repeated side e f f e c t s were drowsiness and sleepiness, which occurred with s i m i l a r frequency a f t e r placebo as a f t e r active drugs. Citalopram related side e f f e c t s were nausea, tremor, headache, retarded-sluggish behavior, and dry mouth, Talsupram was associated with dry mouth, tremor and d i f f i c u l t y in swallowing, whereas imipramine was most f r e quently associated with dry mouth and sleepiness. The symptoms were not severe and did not require any treatment. The subjective side effects were most commonly observed with 50 mg imipramine, which had the maximum sleep inducing effects of a l l the test drugs.
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Two dimensional classification of different dosages citalopram and control compounds.
Table 6 The HZI CEEGData Base I I I Classification of Citalopram
(RANKED ACCOROING TO THE HIGHEST SIMILARITY COEFFICIENT)
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STUDY DRUG
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406
T.M. Itil et ~ .
Discussion This study has shown that citalopram when given in single oral doses of 10 to 5D mg to healthy human volunteers does not have serious or severe side effects. All drugs tested in t h i s double-blind QPEEGstudy, including placebo, caused sedation and induced sleep. However, side effects such as nausea, tremor, headache, dry mouth and sluggish behavior were most frequently seen after citalopram 50 mg. The CNS effects of citalopram 25 and 50 mg are potent. Univariate, but p a r t i c u l a r l y multivariate, s t a t i s t i c s clearly demonstrated that these effectscould be discriminated from those of placebo and are s i g n i f i c a n t l y different. The CNS effects are dose related, p a r t i c u l a r l y during the f i r s t hour, as demonstrated by lesser high frequency fast waves with higher doses. The minimum CNS effective dose of citalopram is 25 mg. Time related CNS effects were observed primarily with citalopram 10 mg, suggesting that these may have occurred by chance. Time and dose effect s t a t i s t i c s suggest that citalopram has a rapid onset of CNS effects, the duration of which is short. The CNS effects of 50 mg, and to a lesser degree, 10 mg citalopram were classified by the HZI computer data bank as similar to those of mood elevators (antidepressants) of the data bank ( f i r s t choice c l a s s i f i c a t i o n ) . According to our r e l i a b i l i t y and v a l i d i t y studies, the f i r s t and second choice computer data bank classifications for antidepressants are s i g n i f i cantly better than chance (p<.O001, binomial s t a t i s t i c s ) ( I t i l 1982 ). Twenty-five milligram citalopram, although showing most s i m i l a r i t y to the antidepressants of the data bank, could not be classified as such because the s i m i l a r i t y coefficient was not high enough. Therefore, i t is predicted that the best therapeutic single dose of citalopram is between 25 mg and 50 mg. Talsupram 50 mg was classified between CNS depressants (neurolept i c s ) and anti-depressants with low s i m i l a r i t y coefficients for both drug groups. As in previous studies ( I t i l et al, 1977; I t i l et al, 1977; I t i l , 1975; I t i l and Soldatos, 1980; I t i l , 1981), this study also indicates that the CEEGc l a s s i f i c a tion of antidepressants has no significant relationship with the effects of these drugs on biogenic amines. The CEEG profiles of a m i t r i p t y l i n e , imipramine, fluvoxamine, mianserin and n o r t r i p t y l i n e are similar to one another. However, they show marked differences with regard to t h e i r effects on biogenic amines. Amitriptyline and n o r t r i p t y l i n e , but particul a r l y fluvoxamine, have predominantly i n h i b i t o r y effects on serotonin reuptake. Imipramine has almost equal effects on both norepinephrine and serotonin reuptake. Mianserin ( I t i l et al, 1972) and mesterolone ( I t i l et al, 1979) do not have s i g n i f i c a n t effects on biogenic amines ( I t i l , 1982). Citalopram, a specific serotonin reuptake i n h i b i t o r l i k e fluvoxamine ( I t i l et al, 1977), has CEEG profile similar to that of fluvoxamine. However, the CEEG p r o f i l e of citalopram is also very similar to that of mianserin ( I t i l et al, 1972), which has v i r t u a l l y no effects on the biogenic amines and, i f anything, increases norepinephrine reuptake. Talsupram 50 m9, a potent norepinephrine reuptake i n h i b i t o r , was classified between CNS depressants and mood elevators in this study. The CNS effects of talsupram 50 mg were not as potent as those of imipramine 50 mg, although the norepinephrine reuptake i n h i b i t i n g effects of talsupram were ten times more potent than those of imipramine (Lundbeck A/S). The s i m i l a r i t y of CEEG profiles of different antidepressants indicate that these drugs after single oral dose were adequately absorbed and metabolized and have crossed the bloodbrain barrier, and produce similar effects on cerebral neurons. As these effects are probably the result of common biochemical changes, one can postulate that drugs with similar CEEG profiles produce similar cerebral biochemical changes. The "shape" of the CEEG profiles, i . e . the changes of the frequency d i s t r i b u t i o n from pre to post drug periods, are known to be closely related to the type of therapeutic effects of drugs. Therefore, one could further hypothesize that these biochemical changes are closely related to the therapeut i c actions (e.g. antidepressant effects) of these drugs. The discovery of the nature of the biochemical substrate which is responsible for producing the "typical" bioelectrical effects (CEEG profiles) for antidepressants w i l l provide important information on the pathogenesis of depressive illness and may help to find specific treatments for specific types of depressive i l l n e s s . Meanwhile, routine application of QPEEG in early drug evaluation (Phase I studies) can provide important CNS efficacy information on a new potential psychotropic. This, in turn, can be of s i g n i f i c a n t use in designing e f f i c i e n t c l i n i c a l development programs.
QPEEG with citalopram
407
Conclusions Based on CEEG data bank c l a s s i f i c a t i o n (HZI System I c l a s s i f i c a t i o n ) , the CNS effects of citalopram in humans was found to be s i m i l a r to those of " c l a s s i c a l " mood elevators ( a n t i depressants). However, the further and more detailed c l a s s i f i c a t i o n with individual drugs from the computer data bank (HZI System I I I c l a s s i f i c a t i o n ) indicated that the mode of action o f citalopram p r i m a r i l y resembled less sedative antidepressants such as p r o t r i p t y l i n e and desipramine from the t r i c y c l i c antidepressants, and fluvoxamine, another n o n - t r i c y c l i c 5HT reuptake blocker antidepressant. The therapeutic dose of citalopram is hypothesized to be between 25 and 50 mg, to be administered t . i . d . I t was hypothesized that the mode of action (CNS effects) of an antidepressant in humans, as established by computer EEG profiles, cannot be related to the well-known biochemical properties of this compound: The antidepressants with s i g n i f i c a n t l y d i f f e r e n t biochemical effects produce very similar CEEG profiles. These effects produce very similar CEEG profiles. Therefore, i t is postulated that drugs with c l i n i c a l l y antidepressant effects produce a "typical" biochemical change which is s i g n i f i c a n t l y related to the therapeutic action of the drug, and is associated by a characteristic electrophysiological pattern (CEEG p r o f i l e ) although i t s properties might not be known to us. The discovery of the biochemical correlates of the antidepressant CEEG profiles in humans may help us to understand the etiology of depressive illness and to develop i t s "causal" treatment.
Ack.nowledgements The authors would like to thank the research personnel of the pharmaceutical division of Lundbeck A/S, Copenhagen, for providing a l l available information on citalopram before the study and for providing the drugs for the study, and the meticulousness of the staffs and research personnel of the HZI Research Center, HZI-Europe and HZI Neuropsychiatric Foundation, without whom this project could not have been completed. References
CHRISTENSEN, A. V., FJALLAND, B., PEDERSEN, V., DANNESKIOLD-SAMSOE, P. and SVENDSEN, O. (1977) Pharmacology of new phthalane (LU 10-171) with specific 5-HT uptake i n h i b i t i n g properties. European J. Clin. Pharm. 41: 153-162. FREDRICSON OVERO, K. (1982) Kinetics of citalopram in man; plasma l e v e l s in patients. In: Citalopram basic and c l i n i c a l studies, H y t t e l , J. (ed), Prog. Neuro-Psychopharmacology, J. Biol. Psychiat. 6: 311-318. GOTTLIEB, P., WANDALL~ T. and FREDRICSON OVERO, K. (1980) I n i t i a l , c l i n i c a l t r i a l of a new, specific 5-HT reuptake i n h i b i t o r , citalopram (Lu 10-171). Acta psychiat. Scand. 62: 236-244. HYTTEL, J. (197~) Effect of a s e l e c t i v e 5-HT uptake i n h i b i t o r , LU-IO-171 on rat brain 5-HT turnover. (1977) Acta Pharm et Toxicology, 40: 439-446. HYTTEL, J. (1977b) Neurochemical characterization of a new potent and selective serotonin uptake i n h i b i t o r . Psychopharmacology, 51: 225-233. ITIL, T . M . (1974) Quantitative~harmaco-electroencephalograph. In: Psychotropic Drugs and the Human EEG. Modern Problems in Psychopsychiatrz, Vol. 8. I t i l , T.M. (ed), pp. 43-75. Basle/New York, Karger. ITIL, T. M. (1975) Computer EEG Profiles of Antidepressants: Quantitative Pharmaco-EEG in the Development of New Antidepressive Drugs. Antidepressants ( I n d u s t r i a l Pharmacology), Vol. I I . Mt. Kisco/New York. Futura Publishing Company, pp. 319-351. ITIL, T. M., REISBERG, P., AMIN, A., WADUD, A. and HERRMAN, W.M. (1978) Pipothiazine Palmitate, a Long-Acting Neuroleptic: Clinical and Computerized EEG Effects. Current Therapeutic Research, 24 (6) 689-707.
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aZ.
ITIL, T. M. (1981) The Use of Computerized Bio-Electrical Potentials (CEEG) in the Discovery of Psychotropics. Drug Development Research, Vol. I , No. 4 ITIL, T. M. (1982) The Significance of Quantitative Pharmaco-EEG in the Discovery and Classification of Psychotropic Drugs. In: Herrmann, W.M. (Ed.) EEG in Drug Research. Stuttgart/New York. Gustav Fischer Verlag, pp. 67-79. ITIL, T. M. (1983) Computer EEG in the Discovery of Antidepressants. In Burrows/Norman/ Davis (Eds.) Antidepressants, Elsevier Science Publishers, pp. 149-171. ITIL, T. M., AKPINAR, S., OZKUT, H., BALKI, N. and HERRMANN, W. M. (1979) c l i n i c a l and Computerized EEG Effects of U-31,920, a New Anxiolytic. Current Therapeutic Research, 16 (6), 642-659. ITIL, T. M., 8HATTACHARYA, A., POLVAN, N., HUQUE, M. and MENON, G. N. (1977a)Fluvoxamine (Du 23,000), a New Antidepressant. Quantitative Pharmaco-electroencephalography and Pilot Clinical T r i a l s . Progress in Neuropsychopharmacology i , 309-322. ITIL, T. M., CORA, R., AKPINAR, S., HERRMANN, W. M. and PATTERSON, C. (1979) "Psychotropic" Actions of Sex Hormones: Computerized EEG in Establishing the Immediate CNS Effects of Steroid Hormones. Current Therapeutic Research, 16 (11), 1147-1170. ITIL, T. ~I., GANNON, P., CORA, R., POLVAN, N., AKPINAR, S., ELVERI$, F. and ESKAZAN, E. (1971) SCH-12,041, a New Anti-Anxiety Agent (Quantitative Pharmaco-electroencephalography and Clinical T r i a l s ) . Physicians' Desk Manual (PDM), 3 (3-4), 26-35. Also in Behavioral Neuropsychiatry, 4 (4-5), 15-29, 1972. ITIL, T. M., GUVEN, F., CORA, R., HSU, W., POLVAN, N., UCOK, A., SANSEIGNE, A. and ULETT, G. A. (1971) Quantitative Pharmaco-electroencephalography Using Frequency Analyzer, and Digital Computer Methods in Early Drug Evaluations. In: Smith, W.L. (Ed.) Drugs, Development and Brain Functions. Springfield, l l l i n o i s . Charles C. Thomas. pp. 145-166. ITIL, T. M., FREDERICKSON, J. W., SCHNEIDER, S. J., FRANCIS, I. B. and KHAN, M. M. (1980) Clopipazan (SFK-69634), a New Neuroleptic Essentially Free of Extrapyrmmidal L i a b i l i t y : Quantitative Pharmaco-EEG and Open Label Clinical T r i a l . Current Therapeutic Research, 27, 7]9-730. ITIL, T. M., HERRMANN, W. M. and AKPINAR, S. (1975) Predication of Psychotropic Properties of Lisuride Hydrogen Maleate by Quantitative Pharmaco-Electroencephalography. International Journal of Clinical Pharmacology, 121, 221-223. ITIL, T. M. and HERRMANN, W. Mo (1978) Effects of Hormones on Computer-Analyzed Human Electroencephalogram. In: L~pton, M.A., Di~lascio, A. and Killam, K.F. (Eds.) Psychopharmacology: A Generation of Progress. Raven Press, New York, pp. 729-743. ITIL, T. M., HSU, W. and CIG, E. (1973) "Anxiolytic" Profile and B i o a v a i l a b i l i t y of Chloracepate Dipotassium Based on Quantitative Pharmaco-Electroencephalography. Aggressologie, 14 (3), 203-212. ITIL, T. M. and HUQUE, M. (1979) Computer EEG Profiles of Anxiolytics (Quantitative PharmacoEEG in the Development of New Anxiolytics). In: S. Fielding and H. Lal (Eds.). Industrial Pharmacology - Anxiolytics. Vol. 3, Mt. Kisco/New York, Futura Publishing Company, 281-316. ITIL, T. M., MARASA, J., BIGELOW and SALETU, B. (1973) Prediction of Neuroleptic Effects of CI-686 Based on Quantitative Pharmaco-Electroencephalography: Drug Profiles and Dose Response Curves Based on Computerized Bio-Potentials. Current Therapeutic Research, 16 (1), pp. 80-95. ITIL, T. M., POLVAN, N. and HSU, W. (1972) Clinical and EEG Effects of GB-94, a "Tetracyclic" Antidepressant. (EEG Model in Discovery of a Psychotropic Drug.) Current Therapeutic Research, 14 (7), 395-413. ITIL, T. M., POLVAN, N., ENGIN, L., GUTHRIE, M. B. and HUQUE, M. F. (19770)Fluotracen (SKF-28175), a New Thymo-Neuroleptic with Rapid Action and Long-Acting Properties (Quantitative Pharmaco-EEG and Clinical Trials in the Development of Fluotracen (SKF28175). Current Therapeutic Research, 21 (3), 343-360. ITIL, T. M., SALETU, B., MARASA, J. and MUCCIARDI, A.N. (1972) Digital Computer-AnalyZed Awake and Sleep EEG (Sleep Prints) in Predicting the Effects of a Troazolo8enzodiazepine (U-31,889). Pharmakopsychiatry, 5, 225-240. ITIL, T. M. and SOLDATOS, C. (1980) Clinical Neurophysiological Properties of Antidepressants In: Hoffmeister, F. and S t i l l e , G. (Eds.) Psychotropic Agents - Part I: Antipsychotics and Antidepressants. Berlin/Heidelberg/New York. Springer Verlag, pp. 437-469. LINDEGAARD PEDERSEN, 0., KRAGH-SORENSEN, P., BJERRE, M., FREDERICSON, OVERO, K. and GRAM, L. F. (1982) Citalopram, a Selective Serotonin Reuptake I n h i b i t o r , Clinical Antidepressive and Long Term Effect - A Phase I I Study. Psychopharmacology. 7__77: 199-204.
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LUNDBECK A/S, Talsupram: S c i e n t i f i c Information, Personal Communication, Copenhagen, Valby. OFSTI, E. (1982) Citalopram - A Specific 5-HT-Reuptake I n h i b i t o r as an Antidepressant Drug: A Phase I I Multicentre T r a i l . Prog. Neuro-Psychopharmacol. and Biol. Psychiat. 6: 327-335. RAVN, J. and RUD, C. (1969) Forelobige Erfaringer AF Behandling, AF Depressive Pa~ienter Med LU3-OIO OG LU 5-003. Nord. Psykiat. T. 23: 253-262. SHAPIRO, D. M., ITIL, T. M., HUQUE, M. F. and F~RBES, D. (1977) HZI System X: EEG Evoked Potential Analysis Systems. Electroencephalography and Clinical Neurophysiology, 43 (4) 553, etc. STROMGREN, L. S. and FRIDERICHSEN, T. (1971) LU 5-003 i , Antidepressiv. Terapi. Nord. Psykiat. T. 25: 119-128. Inquiries and reprint requests should be addressed to: Dr. Turan M. I t i l 150 White Plains Road Tarrytown, New York 10591 U.S.A.