Intravenous nialamide in the treatment of depressed female patients

Intravenous Nialamide in the Treatment of Depressed Female Patients By

KURT NUSSBAU~I, BARBARA A. \VlTTIG, TnO:\IAS A~D ALBEHT

A.

E.

HA~Lo:\'

KUHLA~D

IGH DOSAGE parenteral usc of the newer antidepressant drugs of the monoamine oxidase inhibitor and imipramine types is based on the need to expedite the treatment of depressed patients. These compounds act slowly and generally take from 10 to 21 days before producing a desired response.' For the potentially suicidal patient this is a particularly long, inherently dangerous period. The question arises whether a more rapid response might be obtained with higher dosage, particularly if a drug such as nialamide is utilized which causes fewer side effects than other J\IAO inhibltors.s-" Clinical investigators have attempted recently to study the effects of this drug administered parenterally at high dosage levels. One of the advantages of the intravenous administration of an antidepressive drug lies in the possibility of obtaining an effective blood level rapidly. However, this advantage can be negated to considerable extent by rapid detoxification in the liver and excretion by the kidneys. In order to maintain a continued high blood level for several hours, Dunlop,' working with nialamide, administered by slow intravenous drip a solution of 500 to 1000 mg. of the drug dissolved in 1000 cc. of 5 per cent glucose in normal saline. Five to eight infusions were administered to each patient over a period of 10 to 16 days. In his more recent work," Dunlop has not exceeded 750 mg. because at the 1000 mg. level several patients reported anergia, somnolence and fatigue. This procedure is reported to have been highly successful with each of the 40 patients treated! and to have lessened the delay encountered in oral use of J\IAO inhibitors at previously recommended dosages. Undesirable side effects, including hypotension and exacerbation of schizophrenic-like symptoms, were observed in only two patients in this group. A clinical trial was also carried out by Lang," who treated 16 patients with 250 to 500 mg. of intravenous nialamide in a series of one to four treatments. The drug was dissolved in distilled water at a ratio of 250 mg. per 20 cc. and then administered in a solution of 2.5 per cent glucose in normal saline. The author claimed reversal of symptoms in all his patients in an average of five to six days, although three required supplementary ECT. Again, the low toxicity of intravenous nialamide is evident in the report of only two cases of hypotension due to unjudicious activity following treatment, one case of febrile reactions, and two easily reversible onsets of edema following treatment. The favorable clinical results reported by Dunlop and Lang, i.e., shortened time lag before response, high rate of symptom reversal, and a treatment relatively free from undesirable side effects, point to the need for a controlled

H

From the Research Department, Spring GraGe State Hospital, Baltimore, Md.

105 CO~I1'IIEI1EXSl\'E

I'SYClIlATIIY, VOL.

·t, No.

i

(AI'IIIL), Hl63

106

KUSSBAU~[,

WITIIG, IIAKLO:\", KURLAND

study of intravenous nialamide. The following controlled, double-blind project was therefore undertaken. PILOT STUDY

Sinc e the parenteral administration of nialamide is a relatively new pro cedure, and the do sage proposed is considerably higher th an the recommended oral dosage of 100 to 300 mg . d aily,',s a pilot study was performed to standardize the technique of administration and to observe closely the psychi atric and physiologic reactions on a non-double-blind basis. Six pati ents suffering from d epression were treated: three with drug and three with placebo. Following closely the protocol pr ep ared by the pfizer Labor atori csf treatment consistcd of two hour intravenous drips of 1000 cc. of 5 per cent glucos e in physiological salin e, with the addition of 500 mg. of nialamide for th e drug group, given on four successive days. The patients were subjecte d to continuous psychiatric and nursing observations. Blood pressure readings were obtained immediately prior to treatment and every 30 minutes during treatment. Following infusion, a rest period of at least 30 minutes was imposed to obviate the possibility of postural hypotension as reported by Lang.v No untoward side effects were noted in any of the six patients. Improvement within seven days of the first treatment was observ ed in two out of three patients in the drug group and one out of three patients in the placebo group. The response of the one placebo patient was not as dramatic in quality as two of the three drug patients. These results were considered favorable enough to justify going ah ead with the formal study. !\!AL."-: STUDY

Procedure '''hite female patients whose diagnoses included neurotic and psychotic depressions and schizo-affective schizophrenia, all with a predominantly depressed affect, were scre ened by the ward or admitting psychiatrists and referred to the special treatment area set up for this invcstigation. The area was located in a modern admission and active treatment building restricted to females. It was felt that b), concentrating both patients and treatment in one area of the hospital, man)' of the practical problems inherent in a doubleblind study of this kind could be obviated and a high degree of ward personnel interest and cooperation obtained. The patients remained in this same setting throughout the treatment and follow-up phases. The treatment room itself allowed for simultaneous treatment of four patients. Upon admission to the study, patients were rendered drug-free for a period of one week and received no adjunctive phrenotropic drugs during the course of the investigation. The drug-free period provided an opportunity for the following: psychiatric observations to confirm the presence of depression ; psychiatric screening to eliminate those patients with complicating organic pathology, alcoholism and drug addiction; and initial baseline evaluations of criterion measures. This interval also permitted elimination of those depressed patients who showed sp ontaneous improvement prior to the drug phase. Upon completion of the initial drug-free interval, patients were randomly assigned to two treatment groups, one of which received 500 mg. of nialamide" "Nialamide supplied as Niamkl by courtesy of Pfizer Laboratories, New York, New York.

1l'11IAVE:\"OUS

"IALA~IIDE

I" FE:'>IALE DEPnESSIVES

107

i.v. in 1000 cc. of 5 per cent glucose in physiologic saline and the other the same infusion but without nialamide. The dosage of nialamide was increased to 750 mg. during the eleven-month course of the study due to further accumulated evidence regarding toxicity and clinical effectiveness. Treatment for both drug and placebo groups consisted of a series of two-hour treatments on four successive days. Double-blind procedures were used throughout treatment and evaluation. After treatment, a follow-up observation period. of at least ten days was maintained for each patient. The treatment team consisted of a psychiatrist and psychiatric aide, with ward personnel available as needed. Two psychiatrists were available for consultation throughout the study. Precautions of prior physical examinations, regular blood pressure readings prior to and throughout the treatment at 30 minute intervals and at least one-half hour bed rest follOWing treatment were maintained. Patients, as well as personnel, who inquired were told that the medication was in general favorable use and would, perhaps, be more effective received intravenously than orally. As the study progressed, some concern developed on the wards regarding the fact that placebo patients received no medication during the combined drug-free, treatment and evaluation follow-up period. This problem was resolved, at no expense to the intravenous aspect of the investigation, by plaCing subsequent patients of both groups (approximately 80 per cent) on oral nialamide, 200 to 300 mg. per day during the follow-up period, and introducing the prescription of a placebo capsule, as a tranquilizing or sleep-inducing agent, when required. Ward personnel were not informed that this additional prescription was an inert substance. Apart from the time required for treatment, all patients remained free to participate in routine hospital activities..The only restriction imposed by the study was the curtailment of weekend privileges immediately following the i.v. series.

Evaluating IIIStTIIIllCllts Criteria of change were provided hy laboratory examinations and various parameters of psychopathology, particularly those of depression, obtained through psychiatric interviews, patient self report, and psychological testing. These parameters are implicit in the description of the tools used to obtain them: 1. A global psychiatric evaluation of change, plus clinical notes dealing separately with change and systematized hy locally devised nine-point scales in four general areas: Behavior, Affect, Thinking, and Physical Complaints. 2. A Clohal Depression score, ranging from 0 to 27, obtained by summing the scores of the following four-point scales of target symptoms: Indifference or Fatigue, Sadness, Despair, Hypochondriasis, Anxiety, Insomnia, Retardation, and Suicidal Tendencies. 3. Beck Depression Illve/ltory,~) designed to yield a total morbidity score through patient self report ratings in 21 areas of depression. 4. The Minnesota Multiphasic Pcrsonallu] lncentonj (~I~IPI ),10 a personality measure providing scores on validating, clinical, and experimental scales, defined for the most part in terms of psychiatric diagnostic categories or

108

XUSSBAU~I,

WITTIG,

IIANLO~,

KURLAND

behavioral types, and yielding patterns and levels of psychopathology. From past research on depressed female patients with this instrument.Pv" reductions in clinical scale numbers 2, 7, 1 and 3 (Depression, Psychasthenia, Hypochondriasis, and Hysteria) were judged to be the most appropriate },I},IPI measures of a drug's antidepressant activity. One day prior to the initiation of treatment a baseline evaluation composed of the above battery of measures was obtained on each patient. A senior research psychiatrist completed all of the psychiatric measures after interviewing the patients. The psychometric measures were obtained in independent testing sessions by a research psychologist. Within the three days following the final intravenous injection, a post-treatment evaluation was made using the same battery. This evaluation provided the essential data for the analysis of differential treatment effectiveness. At the end of the follow-up period, a final evaluation was performed, utilizing only the clinical notes of the research psychiatrist and his global evaluation of change. \Vith but few unavoidable exceptions all of these evaluation procedures were performed by the same psychiatrist and psychologist. Routine blood, urine and liver function studies (cephalin-flocculation, thymol turbidity, and serum transaminase) were performed during the weeks immediately preceding and following treatment. RESULTS

A total of 35 female patients was referred for treatment over a period of eleven months. Of these, 30 completed the prescribed treatment course. Five patients were dropped from the study for various reasons. One patient was unable to continue her series of infusions due to the poor condition of her veins. Four .patients were discontinued because various environmental pressures interfered seriously with assessment of treatment response. Pre-Treatment Evaluation. Table 1 presents relevant descriptive information regarding the 30 patients who completed the study. Sixteen of these patients received intravenous nialamide and 14 placebo. All but three of the 30 patients were referred for treatment immediately upon, or shortly after, admission. In the randomization 'process the three long-term patients in the study, who were transferred from other areas of the hospital, were fortuitously assigned to the placebo group. The two groups otherwise appeared comparable. The various representative diagnoses were as proportional as one might expect under the circumstances (in all cases the predominant symptom being depression). Since they were recent admissions, the majority of patient in both groups had received no medication prior to their referral to the study, although approximately half had histories of previous depressive episodes with concomitant treatments. No statistical differences were found between the means of the two groups with regard to age (43.4 vs. 46.3), education (10.5 vs. 10.6), and initial degree of depression as rated by the psychiatrist (17.8 vs. 14.6). All but one patient (#20) were either married, or at one time had been married. Only four patients, two drug and two placebo, indicated a full time occupation other than housewife. Mean scores on the Beck Depression Inticntort] were 28.9 and 30.1 for the nialamide and placebo groups, respectively. The difference between these

109

Il"TRAYEl"OUS NIALA::\IIDE IN FE::\IALE DEPRESSI\'ES

Table I.-Patient Characteristics and Psychiatric Summary

--'-----

Case No. & Diagnosis

Age

1 2 3 4 5 6 7 8 9 10 11

PDR PDR PDR NDR IPD PDH PDR PDH PDH NDH PDH

62 43 27 34

12

PDH PDH

13 14 15 16

17 18 19

SHD NDH PDR (Illeans)

52

11 9 12 12 8 6

40

13

33 46 53

8 9 12 12

41 34

11 11

74

39

33 32

52 (43.4)

45 34

SHD MDD PDH

58

20 PDR

58

21

49 31

IPD 22 SRD 23 PDH 24 MDD 25 PDR 26 PDH 27 IPD 28 NDR 29 30

NDH PDH (Illeans)

Weeks Years Since Educn- Marital Adrnistion Status sian

40 57 51 60

55 35 33 42 (46.3)

10 12 12 (10.5)

12 5 7 12 12 7 16 10 9 12 12 10 16 8 (10.6)

V{ W III M W III M Sep, III Div. III M III

Previous Medication

Pre

Post

NIALAIIlIDE GROUP' 1 Tofranil 16 15 None 2 None 7 2 14 None 2 21 None 3 24 'Ihorazine 1 26 1 None None 20 2 None 1 16 Sparine 11 10 Elavil & 23 2 Thorazine 18 None 1 2 None 20

M III W

4

ot 1

Thorazine None None

III III

M S M M M Sep, III W W M III M

PLACEBO GROUP 2 None 45 Tofranil 2 Tofranil & Equanil 2 None 2 None 134 Thorazine 65 Librium 2 None 1 None 2 None 1 None 1 None 1 3 (19)

5 4 1

13 17 25 18

3 9

16 18

20

None None

Clinical Evaluation of Change

+ ++ +

N.C. N.C. N.C.

+

4 13

(17.8)

(2)

A bbrevtn tions: PDR == Psychotic Depressive Reaction

=

Global Depression Score

+++ N.C. +++

++

12 21

N.C. N.C.

14

N.C.

11 17 (11.6)

+

+

15 9 15

12

N.C.

o

+++

16 17

13

N.C.

23

8 19

+ N.C.

15 15 11 17 13

5 2 10 17 6

++ ++ N.C.

14

5

13

7 18 (14.6)

N.C.

N.C.

++

+

1 10 (8.6)

+++ +

Side Effects

Dizziness Headache None Dlaainess f None None None None None None Slight Dizziness None Numb fingers None None None

None None None

None None None None None None None None Dizziness & VomitingNone None

Evaluation Code: N.C. No change = Mild improvement = Moderate improvement = Marked improvement

+ ++

=

SR:9 Schizophrenic Reaction with Depression NDR Neurotic Depressive Reaction IPD = Involutional Psychosis, Depressed MDD = lIlanic Depressive, Depressed *The first 8 patients received 500 mgs, Nialamide during each of 4 intravenous treatments; the remaining 8. 750 mgs, [Due to the acute nature of this patient's illness, treatment was initiated the day after admission. tThis patient also complained of a slight feeling of "pins and needles" in the extremities.

=

+++

means was not statistically significant. According to the Beck normative data, both groups would be described as severely depressed. Of the 30 completed cases, 19 (nine drug and ten placebo patients) produced valid pre- and posttreatment ~I~IPI profiles. The initial mean profiles for these patients, including the three validity scales, ten clinical scales and experimental scales A (Anxiety) and R (Repression), are presented in figure 1, along with the profile found by Dahlstrom and Prangel l to he typical of depressed female

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patients. As might be expected, the profile peak for both the drug and placebo groups was clinical scale number two D (for Depression). Except for a slightly higher psychotic triad level in the drug group, the two profiles from the present study were quite similar to the referent profile in both level and configuration. The initial Welsh code for the total 19 patients, plus one patient who completed the pretreatment testing only, was 2"7834'16-9/5 F-KL. Post-Treatment Ecaluation. The post-treatment evaluation of patients revealed little or no differences between nialamide and placebo treatment groups in terms of psychiatric, or clinical, criteria. According to the psychiatrist's global measurement of change, approximately equal proportions of patients fell into the various categories of improvement (see table 1), while slightly less than half of the patients in both groups (seven out of 16 nialamide patients and six out of 14 placebo patients) were judged to have remained unchanged following treatment. Analysis (by t) of mean difference between change scores for the general areas of Behavior, Affect, Thinking and Physical Complaints also revealed no significance between the two groups. As for the target symptoms of depression, in both groups significant mean reductions occurred in the symptoms of Sociability, Indifference, Sadness and Insomnia (using an alpha level of .01 because of the combination of restricted scale range and small u's ). A significant reduction also occurred in the symptom Despair for the nialamide group. In none of these cases, however, was there a Significant differential treatment effect, as revealed by covariance F-ratios which were uniformly below 1.00 (initial scores used as covariates). Likewise, global depression mean scores based on the target symptoms were significantly less after the termination of intravenous treatment for both groups, hut there was no significant differential treatment effect. Since two nialamide patients were unable to complete the Beck Depression Inventory at the post-treatment evaluation, results with this instrument are based on 14 patients in each group. Mean reductions from 27.9 to 22.1 and 30.1 to 25.6 occurred for the nialamide and placebo groups, respectively, both reductions Significant at the .01 level. Descriptively, both groups could be viewed as being moderately depressed at the end of treatment. Again, analysis of covariance results revealed no Significant difference between nialamide and placebo treatment cffects. Results with the ~IMPI are illustrated in figure 2, which presents the posttreatment profiles of the nialamide and placebo groups. At the termination of intravenous treatment the two profiles bear essentially the same relationship to each other as before treatment. On the four target scales, numbers 2, 7, 1, and 3, neither treatment effected significant mean changes in either direction, nor, correspondingly, were there any differential effects between treatments. With the alpha level, set at .05, the only significant MMPlpre- to posttreatment mean changes were an increase in the correction factor K (a suppressor variable intended as a measure of test taking defensiveness) from a T score of 52.00 to 55.44 for the nialamide group and a decrease in scale 10 (Si, Social Introversion) from 64.20 to 60.00 for . the placebo group. These changes were not indicative of differential treatment effects, however, as revealed by

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INTRAVENOUS NIALAMIDE IN FE),IALE DEPRESSIVES

113

covariance analysis F-ratios of .97 and 1.24, respectively. A final covariance analysis of MMPI data was performed on "Total Level," a total morbidity score based on the average of the eight most relevant clinical scales. The results of this analysis again revealed no significant differences between the two groups. Follow-Up Evaluation. The follow-up psychiatric evaluation, performed from ten to 14 days after the full scale post-treatment evaluation, revealed essentially the same information as previously. Of the 16 patients initially receiving intravenous nialamide treatment, four were judged to have shown marked improvement, one moderate improvement, and five mild improvement at the end of the follow-up period. Five patients were considered unchanged, and two appeared worse. Results with the 14 patients originally receiving intravenous placebo treatment followed the same pattern. Three were judged as markedly improved, three as moderately improved, and one as mildly improved. Seven patients were considered unchanged. As for the psychiatrist's rating of change in the general areas of Behavior, Affect, Thinking, and Physical Complaints, there were, again, no discernible differences between the two groups. Intercorrelations Among Variables. Intercorrelations among the main criterion variables over the course of the study offer pertinent information regarding over-all patient response in terms of these variables. Initially the productmoment correlation between the clinical rating of Global Depression and the Beck Depression Inventory was .66, which increased to .73 at the end of treatment. The correlation between the change scores of these measures was .67. Considering the type of devices involved and the restricted range of the sample, the extent of these correlations appears to indicate that similar underlying dimensions are being tapped by both instruments. Initial and final correlations between these two measures and MMPI Depression (smaller n's involved in both cases; .44 required for significance at the .05 level) were .50 and .37 for Global Depression and .75 and .69 for the Beck. Change score correlations were .22 and .28, respectively. The self report variance of the :MMPI Depression scale is apparent in these results. The reductions in these correlations following treatment and the low change score results reflect the fact that less change was demonstrated on M~IPI Depression as compared to the psychiatrist's ratings and patients' self reports as recorded by the psychologist. Considering the empirical aspect of its construction, the 1I~IPI was conceivably less influenced by the total overall milieu or placebo effects of the present treatment procedures. Side Effects. Side effects were minimal in the intravenous treatment series. Patient #1 experienced dizziness at the end of the first treatment. Patient #4 complained of dizziness, faintness, and a pins and needles sensation in the fingers one hour after the first treatment. Patient #11 complained of dizziness and cramps in both legs 30 minutes after the beginning of the first treatment, the remaining three treatments proceeding uneventfully. Patient #13 complained of mild numbness of the fingers of the left hand during the third treatment. Patient #2 developed a frontal headache on the second treatment day which was possibly the result of a slight head cold. Patient #28, who re-

114

l\USSBAU;\[, WITTIG, I1Al\LOX, KURLAND

ceived placebo, developed faintness, dizziness, and abdominal cramps following the fourth treatment. The latter became worse at the evening meal and she was unable to retain her food. This phenomenon was thought not to be a drug effect (the psychiatrist did not know at that time that the patient was on placebo), but was considered to be due to the patient's intense dislike of her husband, who had visited her during the same afternoon. In this particular case, the psychiatrist incorrectly surmised that the patient was on active drug because of the considerable improvement shown. As with so many of the other patients, there was an increased tendency for this patient to nap or sleep during the four treatment days, a phenomenon that was attributed to the drug until after the blind was broken. From the above it is evident that side effects observed in drug patients may also occur in placebo patients, usually for some reason which can be explained dynamically. A feeling of numbness, of pins and needles sensation, and of cramps in the legs occurred only in those patients in our program who received active nialamide. Most patients were able to get up within 30 minutes after termination of infusion without experiencing any abnormal sensation. Laboratory findings remained normal in all patients. DISCUSSIOX

The observation by previous invcstigatorsv? that nialamide can safely be given intravenously in large doses with minimal side effects has received further confirmation in our data. However, the expectation that this method might accelerate or increase the efficacy of the drug in depressive reactions has not been supported. This suggests that, in part at least, the strikingly favorable responses cited by Lang and Dunlop might be reflections of the difficulties involved in isolating pharmacological action from the over-all psychological effects of attention, care, and dramatic medical aura surrounding intravenous treatment of any type. The prescribed treatment of the present study closely approximated those described by Lang and Dunlop. Where there were differences, they cannot be considered sufficient to explain our discrepant results. Although the dosage level was higher than that used by Lang, this difference should presumably have resulted in even more favorable reactions. Also, compared to Dunlop's method of five to eight treatments on alternate days, the present investigation called for treatment on four consecutive days at approximately the same infusion rate. Treatment on alternate days was not considered practical by the present investigators, since a longer time span would: increase the probability . of spontaneous remission, tell us little about the expediency of the method, and attenuate blood levels in the intervening days even if ancillary oral nialamide were prescribed. The addition of oral nialamide during the follow-up phase of the present study provided a total drug intake approximately equal to that of Dunlop's patients, yet still failed to result in statistically differential drug response. Another recent study bearing discussion is that by Olson,"! in which high

11'TIlAVEl'OUS

"'IALA~IIDE

I'"

FE~IALE

DEPRESSIVES

lIS

dosage level was also related in increased effectiveness. In a comparison of low and high dosage levels of oral nialamide (100 to 300 mg. per diem) Olson found a significantly greater decrease (p < .001) in the MMPI Depression Scale mean score of the high dosage group than was shown by the low dosage group (-6.9 and - l.8, respectively). As inspection of figures 1 and 2 reveals, there is no corroborative evidence in term s of the Depression Scale mean scores of the present drug and placebo groups. Also, on the basis of the psychiatric evaluations and Beck scores appearing in table 1, no differential response appears to have been effected by the change in dosage level of nialamide from 500 to 750 mg. per infusion . Since there were only one or two patients in some of the diagnostic categories, the population of the present study is admittedly too small to provide any definitive information regarding differential effects of nialamide in terms of diagnostic groups. However, this aspect of the data does suggest the only trend of a positive nature. Of the psychotic depressive reactions receiving nialamide, seven were rated as improved and four unimproved on the psychiatrist's global rating of depression, whereas of those receiving placebo, two were rated as improved and four unimproved . No interpretation of this seemingly inverse improvement ratio is possible until further validating evidence becomes available . Corresponding to Dunlop's findings, the three depressed schizophrenics included in the sample (one received nialamide) all responded with exacerbation of schizophrenic symptoms, and slight but temporary amelioration of depressive affect. A few additional comments are in order. One patient ( #23) who had shown a remission on placebo and was subsequently readmitted to the hospital in another depressive episode was treated again by infusion on a doubleblind basis. She improved again considerably, but her improvement was not of the same high quality as during and after the first treatment course. When the blind was ended it was revealed that she was on nialamide during her second therapeutic infusion. Although the statistical analysis indicated no significant differences between the two groups, it was considered important to examine carefully the data on all patients showing a marked response to treatment (4 drug, 4 placebo). The positi ve reactor always chall enges the attention of the investigator to search for specific constellations or patterns which might function as a guide for selective treatment. However, no such differentiating factors were found in the clinical data from either drug or placebo patients. SIDI~rARY

Thirty-five white, depressed, female patients were randomly assigned to double-blind intravenous nialamide (500-750 mgs.) or placebo treatment administered in (or as) infu sions of 1000 ce. of 5 per cent glucose in normal salin e on four consecutive days. The 16 drug and 14 plac ebo patients completing treatment were evaluated in terms of glob al pathology and certain target symptoms of depression before and after treatment and at the end of a ten-day

xussnxuxr,

116

WITTIG, HAN LON,

KunLAND

follow-up period during whi ch most patients received oral nialamide. Con trary to pr evious clinical findings, no differential treatment effects were noted. Side effects were again found to be negligible. ACKNOWLEDG~IENTS

The au thors wi sh to acknowledge th e administrative assista nce of Fr iend s of Psychiatric Research , Inc. a nd th e cooperati on of th c administration and staff of Spring Grov e Stat e H ospit al, Baltimore, Ma ryland , Chas, Pfizer & Co., Inc ., New York, New York, supplied both nialamid e and pl acebo pr ep arations as well as pert inent information regarding intra venous treat men t proced ures.

HEFERENCES 1. Ayd, F. J.: A critique of antidep ressan ts. Di s. Nerv, Syst. 22:32-36, 1961. 2. - : T oxicology of antidepr essant s. In Nodi ne, J. H., and 1 Ioyer, J. H., ( cds . ) : Psychosomatic Medi cine, First Hahnemann Symposium. Phil adelphia, Lea & Fcbiger, 1962. 3. Krakowski , A .. J.: Efficacy and safety of nialamide in the treatment of d epr essive synd romes. Dis. Ncr v. Syst. 22: 161-167, 1961. 4. Dunlop , E. : Intra ven ous usc of nialami de in depr ession. Psychosornat . 2: 1-3, 1961. 5. - : Comparative eva luation of hi gh dosage parenteral th erap y in depressive sta tes. Toronto, Canada , American Psychiatric Assn. Meetin g, May 1962. 6. Lan g, H. D.: Preliminary report on paren teral Niarnkl in depr essions. New York, Eastern Psychiatric Assn. Meetin g, June 1961. 7. Pfizer Laboratories: Niam id Brand of Nialamid e. New York, revised D ec. 1960 . 8. - : P~otocol for Study of Niamid Intravenous Solution as Therap y for

D epr essed Pati ents. New York, 1961. 9. Deck, A. T., W ard, C. H ., Mendelson, 1I., 110ck, J ., and Erbaugh, J.: An inventory for measuring depression. Arch. Gen. Psychiat, 561-571, 1961. 10. Hathaway, S. R., and 1lcKinley, J. C.: Minne sota Multi ph asic Personality Invcntory. Manual. New York, The Psychi atr ic Corp ., rev. 1951. 11. Dahlstrom, \V. G., a nd Prang e, A. J., [r. : Charact ers 01 depr essive and pa ranoid schizophrenic reactions on th e 1linncsota Multlph asic Person alit y In ventory. J . Nerv, & Merit. Dis . 131: 513-522, 1960. 12. Pacella, D. L., Piotrowski, Z., and Lewis, N. D. C.: Th e effects of electric convulsivc th erapy on cer tain p ersonality trait s in psychi atri c pati ents. Am. J. Psychiat. 104:8 3-91, 1947. 13. Rosen, A. : Differ en tiation of di agnostic group s by individu al 11~IPI sca les. J . Consult. Psycho!. 22:453-457, 1958. 14. Olson, G. \V.: Applicati on of an objective method for measuring the action of antidepr essant medications. Am. ]. Psychiat. 118: 10·t4-1045, 1962.

Kurt Nussbaum, M.D. , Senior Research Psychiatrist, Spring Grove State Ho spital, Instructor , Johns Hopkins Medical School, Baltimore, Md. Barbara A. Wittig, B.A ., Research Psychologist, Spring Groce Stat e Hospital, Baltimore, Md. Thomas E . Hanlon, Ph.D., Chief Research Psychologist, Spring Gro ve State Ho spital, Baltimore, Md. Albert A. Kurland, M.D. , Director of Research, D epartment of Mental Hygiene, State of Maryland.