Turan M. Itil

Clinical antidepressant activity of cyclazocine—a narcotic antagonist

Cyclazocine is a benzomorphan derivative with analgesic and antinarcotic activity. During a clinical evaluation in the treatment of opiate dependence, elation, insomnia, and increased libido with administration and a “grippe‐like” syndrome on acute withdrawal were recorded as secondary effects. In the scalp‐recorded electroencephalogram (EEG), desynchronization, decreased alpha abundance, and increased fast and theta activities were recorded concurrently. Because the clinical and EEG patterns were most similar to those with the tricyclic antidepressants, a clinical trial in depressive disorders was undertaken. In an open clinical trial in severely depressed chronic mentally ill patients, improvement in depressive symptoms and in clinical evaluations occurred within 4 weeks in 8 of 10 subjects, receiving 1.0 to 3.0 mg. of cyclazocine daily. In a clinical trial in imipramine treatment failures in an outpatient mental health clinic, 10 of 19 patients improved in depressive symptoms within 8 weeks at dosages of 1.0 to 3.0 mg. daily. In both studies, secondary effects were common, suggesting a narrow therapeutic range. Cyclazocine is an active antidepressant as well as an active antinarcotic agent. The antidepressant activity is correlated with the EEG patterns and is consistent with recent EEG classifications of psychoactive drugs. The antidepressant activity does not seem to be related to the antinarcotic activity. In the treatment of opiate dependence, the efficacy of cyclazocine may be related in part to its antidepressant activity.

EEG Profiles of Fenfluramine, Amobarbital and Dextroamphetamine in Normal Volunteers

A quantitative EEG study in volunteer adults was undertaken to distinguish single oral administrations of 50 and 100 mg amobarbital, 10 mg dextroamphetamine, 40 mg fenfluramine and placebo. Four hour EEG recordings were monitored by frequent auditory reaction time tasks. The EEG changes were measured by digital computer period analysis.In the analysis, each drug was distinguished from placebo, and from each other, with the best discriminations for 50 mg amobarbital and dextroamphetamine, and the poorest discrimination of fenfluramine from 50 mg amobarbital.These observations are consistent with the clinical pharmacology of the compounds and suggest further applications of quantitative EEG for the classification of psychoactive drugs.

Fluvoxamine (DU-23,000), a new antidepressant. Quantitative pharmaco-electroencephalography and pilot clinical trials

Abstract Based on a quantitative pharmaco-EEG study in healthy volunteers and open pilot trials in depressive patients with fluvoxamine, the following was established: 1. 1. Fluvoxamine, a potent serotonin re-uptake inhibitor, has significant effects on human brain function, as measured by Computer Analyzed EEG. Milligram per milligram basis, the potency of the CNS effects of fluvoxamine were lesser than that of imipramine. The minimum CNS effective single dose of fluvoxamine was established to be 50 mg. 2. 2. Computer EEG profiles of fluvoxamine resemble those of imipramine from this study and to those of desipramine and protriptyline from the computer data base. Thus, “stimulant” type of antidepressant effects of fluvoxamine are predicted. 3. 3. In two open uncontrolled clinical trials the antidepressive effects of fluvoxamine in some patients were observed. 4. 4. Because of the high variability of the therapeutic effects and “stimulant” type of side effects in some patients, a well selection of population in future trials will be required.

The use of electroencephalography in the practice of psychiatry

Abstract It is inconceivable today that an internist diagnose heart disease without ECG scrutiny of cardiac function, or liver disease without investigation of hepatic function. By the same token, it is imperative that psychiatrists, especially those prescribing drugs, be concerned with cerebral function. Although the EEG is the only easy, noninvasive, and economic method for continuous monitoring of cerebral function, its application in psychiatry has been very limited. However, thanks to progress in psychopharmacology, the development of computer analysis, and the increased need for techniques of objective assessment in psychiatry, in recent years use of the EEG has been rediscovered. Even without computer analysis, the EEG can provide significant information for differential diagnosis, for selection of type and dosage of psychotropic drugs, and for monitoring drug treatment.

Clinical Profiles of Tardive Dyskinesia

associated with the appearance of the syndrome. The most frequent and consistent association of course, has been with long-term neuroleptic drug therapy. However, it is recognized that some individuals who have never received neuroleptics develop conditions resembling tardive dyskinesia,2j3 and that the syndrome can also be exacerbated by a variety of sympathomimetic agents including L-DOPA and amphetamine treatment.j Furthermore, there is enormous variability in terms of the temporal and quantitative factors relating neuroleptic usage to the development of the syndrome. Some patients have been reported as having developed the syndrome only 4-6 months after pharmacotherapy was initiated. w In contrast, the majority of patients never develop the syndrome at all. The major epidemiological factors which have been thought to be positively related to the development of the oral dyskinetic syndrome are female sex, aging, a history of somatic therapy, and preexisting brain damage.8*Y However, more recent evidence has led some investigators to question each of these assumptions. Four recent studies failed to confirm that females were relatively predisposed,‘“-‘3 two authors question the significance of age as a contributing factor,14J5 and several investigators have seriously called into question the role, if any, of ECT, insulin coma therapy, and preexisting brain damage in the development of the syndrome.‘3*‘4~‘6-‘8 Very recently, an attempt has been made to associate tardive dyskinesia with abnormal peripheral nerve conduction using peripheral reflex magnitude criterialy but the results await confirmation. There have been no studies in which factors of age and sex have been controlled, and in which an attempt was then made to distinguish phenomenological and electrophysiological, as well as historical criteria which

CNS effects of citalopram, a new serotonin inhibitor antidepressant (a quantitative pharmaco-electroencephalography study)

Citalopram, a new phthalane derivative and a specific serotonin re-uptake inhibitor 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 statistically 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 protriptyline from the tricyclics, and fluvoxamine from non-tricyclics. According to data bank assessment, it is hypothesized that the single antidepressant dose of citalopram is to be more than 25 mg, which should be given t.i.d. in clinical trials.

Male hormones in the treatment of depression: Effects of mesterolone

Abstract 1. 1. Based on the scalp-recorded and computer-analyzed electroencephalogram, in high dosages antidepressant and in low dosages “psychostimulant” properties of mesterolone, a synthetic male hormone, were predicted. 2. 2. Open, uncontrolled clinical trials suggest dose-related antidepressant properties of mesterolone. The higher the dosage the more therapeutic effects were established. 3. 3. A double-blind placebo-control study suggests that the symptoms of anxiety, lack of desire, lack of drive and impaired satisfaction may have benefit from low dosages of mesterolone.

Analgesic-antiinflammatory drugs inhibit orbicularis oculi reflexes in humans via a central mode of action

1. A cross-over single blind study examined the possible central effects of non-opioid analgesic drugs on the trigeminal reflexes. 2. The corneal reflex and blink reflex (R1, R2) were recorded electromyographically and response areas measured in healthy volunteers before and after intramuscular injection of piroxicam (40 mg); and after intravenous injection of lysine acetylsalicylate (500 mg). After the last drug recording the subjects received intravenous naloxone (2 mg) followed 5 minutes later by further reflex testing. Saline was used as a placebo in control experiments. 3. Both analgesics reduced the corneal reflex: piroxicam induced a 27% and lysine acetylsalicylate a 21% a reduction that naloxone did not reverse. Neither drug reduced the early or the late component of the blink reflex. 4. The marked inhibitory changes that the two non-narcotic analgesics produced on the corneal reflex--a nociceptive response--indicate a centrally-mediated action. 5. Naloxones failure to reverse the induced analgesia argues against opiate receptor mediation.

Drug treatment of human aggression

Abstract Antiaggressive and pro-aggressive properties of a variety of psychotropic and other centrally effective compounds were reviewed. 1. 1. Among the sedative psychotropic compounds, neuroleptics and benzodiazepine anxiolytics are the most frequently used drugs in human aggressive and violent behavior. Antiaggressive effects of lithium is an important new finding. 2. 2. The drug of choice for the aggressive state of children and adolescents is predominantly psychostimulants, particularly if the aggression is associated with the minimal brain dysfunction. 3. 3. In episodic outbursts with or without clinical seizures, anticonvulsant drugs should first be tried specifically if patients have abnormal EEG findings. 4. 4. Narcotics, marijuana and hallucinogenic compounds do not have any clinical significance in the treatment of aggressive syndromes. 5. 5. Most of the compounds with antiaggressive properties also possess pro-aggressive effects. Aggression producing effects of benzodiazepine and anxiolytics, anti-epileptics and psychostimulants can be very significant in clinical practice.

Flu-like illness after discontinuance of imipramine

Withdrawal symptoms following discontinuance of tricyclic antidepressants have been described by several authors (Anderson and Kristiansen 1959; Mann and MacPherson 1959; Kramer et al. 1961; Shatan 1966; Sathhananthan and Gerson 1973; Brown et al. 1978; Gualtieri and Staye 1979; Dilsaver and Feinberg 1982). These symptoms frequently occur within 24-48 hr after the cessation of therapy with these compounds. The common symptoms reported are general somatic malaise (muscle aches, coryza, excessive sweating), gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain), and neuropsychiatric (drowsiness, apathy, irritability, agitation, and recurrence of depressed mood). Some studies (Anderson and Kristiansen 1959; Kramer et al. 1961) involving adult patients reported that 21%-55% of the patients developed some symptoms after imipramine was discontinued. It is hypothesized that these symptoms are due to cholinergic overdrive or overactivity and can be successfully treated with anticholinergic agents (Dilsaver and Feinberg 1982; Dilsaver et al. 1983). In the course of research programs where the abrupt discontinuation of antidepressant drugs was required, we observed several patients with withdrawal symptoms of different degree. These will be reported here.