Toxicology of Antidepressant Drugs: Tricyclic Antidepressants

Animal Toxicity General Toxicology The LD 50 values for a number of tricyclic antidepressants, when administered to mice and rats in single oral or parenteral doses, are listed in Table Acute LD50 valuesa of some tricyclic antidepressants. Acute poisoning by tricyclic antidepressants usually leads to symptoms of central excitation followed at the higher and lethal dose levels by central inhibition. The symptomatology includes muscular weakness, twitching, stupor, respiratory disorders, ataxia, and tonic-clonic convulsions. Table Acute LD50 valuesa of some tricyclic antidepressants Imipramine Doxepine Nortriptyline Viloxazine Maprotiline Mouse i.v. p.o. 35 666 15- 20 148-178 26 327 60 1000 31 660- 900 Rat i.v. p.o. 22 625 13- 19 346-460 22 502 60-77 2000 38- 52 760-1050 a The values given are for LD50, single administration, in mg/kg body weight It is evident from Table Acute LD50 valuesa of some tricyclic antidepressants or from the reports of Pluviage () and of Ueki et al. () that no major differences in the acute toxicity of tricyclic antidepressants are apparent. Information on animal studies relating to the tolerance of tricyclic antidepressants Read more […]

Tricyclic Antidepressants: Teratology

Antidepressants comprise only a small portion in the vast assortment of drugs that may be taken by pregnant women. In a sample of 3,072 subjects, the number of gravid women receiving antidepressant drugs was estimated to be in the order of 0.1 % (). Similar to other drugs that are used much more frequently during pregnancy (), particularly during the first trimester (the most sensitive period of embryonal development), some antidepressants have been suspected to carry a teratogenic risk. In a short note published 1972, McBride reported on one child with amelia and mentioned two others with a similar limb deformity he felt were caused by imipramine taken by the mothers in early pregnancy. Two further cases were subsequently reported (). Doubt was, however, cast upon the validity of the McBride’s notion of a causal relation between imipramine or other tricyclic antidepressants such as amitriptyline and congenital abnormalities. The Australian Drug Evaluation Committee (1973) and the results of further clinical and epidemiologic studies failed to associate the ingestion of these drugs in early pregnancy with malformations (). Likewise, neither on account of the review presented by one manufacturer () nor on the basis Read more […]

Tricyclic Antidepressants: Intoxication in Man

Effects of Acute Overdose Most of the numerous publications on acute intoxication with tricyclic antidepressants deal with attempted suicide in adults or with accidental selfpoisoning in children. Taking into account the difficulty in establishing the dose ingested – particularly in the case of children and of successful suicides – it is not surprising that it is difficult to predict the severity of an acute intoxication from the dose apparently taken. In children, fatalities have occurred with doses below 500 mg and survival with doses as high as approximately 1,700 mg. In adults, doses below 1,000 mg may already prove fatal but survival has been reported with doses up to 4,000 mg or higher (). In children, the critical dose level for imipramine seems to lie around 500 mg. Of a survey comprising 34 cases, only two children who had ingested less died whereas only three with larger doses survived (). Adults, who have ingested 1,000 – 2,000 mg still have a good chance of recovery whereas the risk of a fatality becomes far greater at levels of over 2,000 mg (). In relation to body weight, an LD50 value for imipramine has been determined for children at 40 – 50 mg/kg and for adults at 30 – 50 mg/ kg (). The symptoms Read more […]

Differential Drug Effects as a Function of the Controlling Consequences

One of the central themes during the initial period in the development of behavioral pharmacology was the issue of whether motivational factors influence the effects drugs have on behavior. Though seemingly a straightforward question, the translation of this problem into an experimentally addressable form was, and continues to be, somewhat difficult. Motivational concepts almost inevitably pose formidable experimental problems, and studies designed to resolve those problems have often yielded equivocal results. Typically, however, the question has been approached experimentally by comparing the effects of various drugs on behavior controlled by different types of events, e.g., food presentation and escape from electric shock. Presumably, different events and the behavioral consequences associated with them engendered different motivational states. The influence of motivational factors as determinants of drug action should then be reflected by differential changes in overt behavior when the organism is given certain drugs. This approach had one rather substantial problem that was not always recognized. Behavioral consequences are important in several different ways, not only when they differ on some hedonic dimension, Read more […]

Benzodiazepines in the Treatment of Alcoholism

This post comprises three sections that cover the main aspects of benzodiazepines and alcohol: (1) the basic pharmacology of benzodiazepines; (2) use of benzodiazepines in the treatment of withdrawal; and (3) the use of benzodiazepines in treating alcoholics. The basic studies suggest that a major site of action of alcohol may be the GABA/benzodiazepine receptor complex and that compensatory alterations in this complex may underly withdrawal. In the section on alcohol withdrawal, interactions between the GABA/benzodiazepine receptor complex, sympathetic nervous system, and hypothalamic-pituitary-adrenal axis are discussed. Use of benzodiazepines in the treatment of the alcohol withdrawal syndrome are reviewed, including the possibility that the benzodiazepines may prevent withdrawal-induced “kindling”. Lastly, we review indications for, and efficacy of, benzodiazepines in long-term treatment of patients with alcoholism. Benzodiazepines are not indicated for the treatment of alcoholism. Furthermore, they have very few indications in alcoholics and their dependency-producing potency has to be appreciated when they are used in patients with alcoholism. The benzodiazepines () are a group of compounds that were first Read more […]

Drug Impairment Reviews: Opiates and Minor Tranquilizers

STUDY: Gordon, N.B. Reaction Times of Methadone-Treated Heroin Addicts. Psychopharmacologia, 16:337-344. 1970. Site: Rockefeller University and Yeshiva University, New York City, New York. Subjects: The subjects were divided into six groups. Groups 1 and 3 both had been maintained for at least 1 year on methadone for the treatment of heroin addiction. Group 1 had 18 males whose average age was 32.5 years; group 3 had 9 females whose average age was 33.5 years. Group 2 consisted of 20 unpaid male volunteers who did not use drugs; they averaged 32.5 years. The participants in groups 4 and 5 had recently withdrawn from narcotic drugs. The 20 males in group 4 averaged 31.5 years and had withdrawn 14 days earlier. The 19 males in group 5 averaged 30 years and had withdrawn 4 days earlier. Group 6 consisted of 9 females whose average age was 23 years. They were paid volunteers from the nonprofessional hospital staff, and did not use drugs. Method: Measurements were taken under controlled laboratory conditions; urines were tested (details were not given) for drugs to assure conformity to group. Variations of reaction time were tested in a button-pressing situation: (a) simple reaction time (one of six stimuli); (b) Read more […]

Desipramine and Imipramine Alone and Together with Alcohol in Relation to Driving Safety

STUDY: Landauer, A.A., and G. Milner. Desipramine and Imipramine Alone and Together with Alcohol in Relation to Driving Safety. Pharmacopsychiatric Neuropsychopharmakologia, 4:265-275. 1971. Site: Department of Psychology, University of Western Australia, and Mental Health Services of Western Australia. Subjects: Twenty-seven medical students served as paid experimental subjects. Their mean age was 23.1 years (S.D. = 1.5), and mean weight was 73.7 kg (S.D. = 8.7). Method: In this controlled laboratory study, the subjects were randomly divided into three groups of nine each. The three groups received either imipramine, desipramine, or placebo, the drugs being administered in tablet form, one at night before the experiment and the second on the morning of the experimental day – i.e., at a 12- to 14-hour interval. Alcohol was diluted with lime juice, syrup, and water and had to be drunk in less than 15 minutes Subjects were required not to drink alcoholic beverages on the day before the test. On test day, after a light breakfast, a medical examination, and the second tablet dose, they were asked to complete a questionnaire rating themselves on their present state, and on anything felt or experienced since Read more […]

Stage IV. PCP-induced depression

PCP-induced depressionis a very frequent condition that many clinicians miss, particularly when it comes after a stage III PCP-precipitated psychotic reaction. The clinician is so relieved when the psychosis is over that s/he discharges the patient with relatively little followup and without realizing that in this depression the individual has high suicide liability or may use other types of drugs to alleviate the depression. A paradox with Phencyclidine is that it does give an energizing, numbing, consciousness-altering effect which the patient perceives as antidepressant. Clinically, it appears that many of these patients have prolonged cerebral dysfunction, as well as depression. The complaints of memory impairment subside as the depression clears. The patients who we have treated have indicated that they feel less depressed as they think their “brain damage” is clearing. It becomes very difficult to figure out whether depression clears as the cerebral dysfunction itself clears or as their concern over the cerebral dysfunction waves. In addition, some of the symptoms may be the result of the depression rather than the cause. PCP-induced depression can last from one day to several months, and can follow any of Read more […]

Treatment of Alcoholism: Experience with Benzodiazepines

The treatment of alcoholism depends on the phase of the disease which the physician is called on to treat: acute intoxication, acute withdrawal, or chronic alcoholism. When should anti-anxiety drugs be used? Almost never for intoxication, almost always during withdrawal, and sometimes during the treatment of chronic alcoholism. Acute intoxication First, acute intoxication, excluding pathological intoxication, but including stupor and coma, should never be treated with any depressant drug. Potentiation of the CNS depression due to the high level of blood alcohol would inevitably lead to a worsening of the condition. Alcohol plus sedative drugs are often a lethal combination. The intoxicated individual should simply be allowed to sleep it off, preferably in the protective environment of his own home. Alcoholic coma may require haemodialysis, although providing a clear airway, fluids, vasopressor drugs, steroids and meticulous nursing care usually will suffice. The one exception which requires sedative treatment is pathological intoxication. This condition of wild excitement in which the patient is a danger to himself and others probably represents an idiosyncratic reaction to a relatively small amount of alcohol. Read more […]

Benzodiazepines in Masked Depressions

Depressive illness is gradually becoming the pathology-symbol of our era of crisis, showing ever-growing epidemic proportions in its several forms and clinical manifestations: endogenous (MDP and involutional melancholia), reactive (depressive reactive psychosis), neurotic (neurotic depressions), symptomatic (in other psychiatric disturbances) and many organic diseases. In 1977, in Sao Paulo, Brazil, the prevalence of depressive illness was considered by all the physicians (more than 7000, mostly non-psychiatrists) interviewed by our group, to have increased by 83 %. In the past decades, besides an increase in the prevalence of depressive illness, a kind of ‘mutation’ has been noted in depressive symptomatology translated as a more frequent phenomenon of ‘depressive somatization’. This brings patients to seek repeated somatic examination, searching in vain for physical changes that lead to expensive and varied clinical and surgical treatments. Although thymopathic masking can appear in different forms (obsessions, aggressiveness, alcoholism, toxicomania, etc.), the term ‘masked depression’ usually refers to a depressive illness in which classic psychopathological symptoms of depression do exist, but are masked Read more […]