Treatment Of Depressive Illness Research Articles

5-Hydroxytryptamine: the effects of impaired synthesis on its metabolism and release in rat.

1 Control rats given L-tryptophan (100 mg/kg) showed a smaller increase of brain 5-hydroxytryptamine (5-HT) than its metabolite 5-hydroxyindoleacetic acid (5-HIAA). However, when brain 5-HT concentrations were depleted by 40-50% after treatment with the synthesis inhibitor p-chlorophenylalanine (PCPA) (150 mg/kg) L-tryptophan caused a considerable increase in 5-HT but no change in 5-HIAA. Similar results were obtained following depletion of brain 5-HT by pretreatment with p-chloroamphetamine (10 mg/kg).2 Electrical stimulation of the median raphe nucleus of control rats significantly increased 5-HIAA in the hypothalamus, hippocampus and striatum. However, stimulation of PCPA (200 mg/kg) pretreated animals did not significantly increase 5-H1AA either 24 or 72 h after administration of the drug.3 Pretreatment of rats with PCPA (200 mg/kg) increased striatal synaptosomal uptake of [(3)H]-5HT by 30% and reduced 5-HT concentration in the rest of the brain by 62%.4 PCPA (150 mg/kg) markedly reduced the acute behavioural response (-76%) to p-chloroamphetamine (10 mg/kg) although brain 5-HT was only moderately reduced (-36%). L-Tryptophan (100 mg/kg) given 15 min before p-chloroamphetamine restored both brain 5-HT and the behavioural effects of p-chloroamphetamine in PCPA pretreated rats and enhanced the behavioural response to p-chloroamphetamine in control rats.5 The results suggest that newly synthesized 5-HT is less rapidly metabolized in rats with low brain 5-HT. The possible reasons for this and the relevance of the results to the use of L-tryptophan in the treatment of depressive illness are discussed.

Suicide in psychiatric patients.

The study relates to suicides occurring in Shropshire during 1965 to 1973 inclusive. Psychiatric patients who had committed suicide were compared with others, matched by sex and age who had not done so. The suicide group included a higher proportion of members who had behaved violently, experienced a broken marriage (through death, separation or divorce) or earlier had deliberately harmed themselves, often by dangerous means. Of the psychiatric patients who committed suicide 63 per cent had seen a doctor within a month beforehand, yet very few were receiving adequate physical treatment for depressive illness at the time of their death. Immigrants from eastern Europe were found to be particularly prone to suicide.

L-tryptophan in the treatment of depressive illness.

L-tryptophan in the treatment of depressive illness.

The Therapeutic Efficacy of Electroconvulsive Therapy (Ect) a Double Blind Controlled Trial of Ect and Simulated Ect

A double-blind controlled trial of ECT versus simulated ECT is described. The results show that real ECT is significantly superior to simulated ECT in the treatment of depressive illness.

A Comparison of the Cardiac Effects of Mianserin and Amitriptyline in Man

In the course of a double-blind comparative trial of mianserin versus amitriptyline in the treatment of depressive illness, E.C.G. was recorded before and after three weeks of treatment in 27 female patients. Mianserin had no consistent effect on heart rate, PR interval, QRS width, or T wave amplitude. This is consistent with other data suggesting that mianserin lacks cardiotoxic effects. In contrast, amitriptyline treatment was associated with increases in heart rate and PR interval, and these effects were statistically significant in comparison to the mianserin group. This finding is consistent with the known cardiotoxicity of amitriptyline.

Three Double-Blind Comparative Trials of Mianserine (ORG GB 94) and Amitriptyline in the Treatment of Depressive Illness

The results of double-blind comparative trials carried out simultaneously in three Finnish hospitals are presented. The antidepressant activity and side-effects of mianserine (ORG GB 94) and amitriptyline were compared. No statistically significant differences were found between the two treatments. It was found, however, that mianserine had clearly less anticholinergic side-effects than amitriptyline.

Family practitioners' knowledge about treatment of depressive illness

Family practitioners' knowledge about treatment of depressive illness

SUICIDE IN BRISBANE, 1956 TO 1973: THE DRUG‐DEATH EPIDEMIC

A study of suicide in Brisbane between the years 1956 and 1973 reveals that there was a sharp rise in the incidence of deaths from barbiturate overdosage, which reached a peak in the mid 1960s. Since then there has been a steady decline in suicide rates from drug overdose and a smaller fall in the rate of other forms of suicide. The decline in the incidence of deaths from carbon monoxide poisoning since 1967 may be due to the use of non-toxic domestic gas. The frequent association between barbiturate suicides and previous ingestion of alcohol indicates the danger of the practice and the probability that many of the victims had major drinking problems. An examination of suicide deaths and the prescribing of barbiturates, benzodiazepines and antidepressant drugs between 1962 and 1973 suggests that the fall in suicide rates was due to the better recognition and treatment of depressive illnesses and to the introduction of the safer benzodiazepines in place of barbiturates. The study indicates that placing restrictions on non-violent methods of suicide does not necessarily result in an increase in suicides from violence.

Amnesia for remote events following electroconvulsive therapy

Psychiatric patients undergoing a series of electroconvulsive therapy (E.C.T.) treatments for depressive illness were given a test of remote memory for public events, covering the years 1940–1969. Patients tested 40–80 min after their first treatment did nearly as well on this test as did a control group of medical inpatients. Patients tested 40–80 min after their fifth treatment were markedly impaired across nearly the entire time period sampled by the test. Patients were not impaired on the verbal portion of the Wechsler Adult Intelligence Scale. The results suggest that the amnesic effects of E.C.T. can extend to remote memory, as well as to recent memory.

On the pharmacology and biochemistry of the amine-uptake mechanism in human blood platelets.

1. The uptake of 5-hydroxytryptamine (5-HT) by human blood platelets in vitro has been studied with the object of identifying the biochemical mechanisms involved.2. Drugs active in adrenergic systems are only moderate inhibitors of uptake, although prenylamine is as active as the less potent tricyclic anti-depressive drugs; phenoxybenzamine is almost inactive as a competitive inhibitor but is effective if pre-incubated with the platelets beforehand. This parallels its pharmacological pattern of action.3. Inhibitors of oxidative phosphorylation do not inhibit 5-HT uptake, but iodoacetate inhibits, if pre-incubated with the platelets; p-chloromercuribenzoate does also, when the platelets are suspended in synthetic medium, but not in plasma.4. Ouabain causes significant inhibition at 10(-7)M; by 10(-6)M it achieves its maximal effect, namely 40% inhibition; in K(+)-deficient medium, uptake falls to 30% of normal; the K(+)-dependent fraction of the uptake includes the ouabain-sensitive component. Mg(++) has no effect.5. A drug not possessing the imipramine structure, which has been tried in the treatment of depressive illness, 4-phenyl bicyclo (2,2,2) octan-1-amine, is a highly potent inhibitor of 5-HT uptake.

Combinations of antidepressant drugs in the treatment of depressive illness.

Seventy-three inpatients and 11 outpatients, aged 16-76, were treated with modified sleep, combined antidepressant drugs and ECT. Every patient had treatment with psychotropic drugs prior to referral to the Yorkton Psychiatric Centre. Side effects encountered during the treatment were minimal. Concomitant ECT was also used with combined antidepressant drugs, and recovery of all patients from anesthesia during ECT was uneventful. Results of treatment on global assessment showed considerable improvement in 52 patients, 30 improved, and no change in 2 patients. The average stay in hospital was 19.5 days.

Single versus divided daily dose of trimipramine in the treatment of depressive illness.

A group of 56 patients with depressive illnesses were administered either a single daily dose or a divided daily dose of trimipramine on a random basis. Results of the treatment showed several advantages for the use of a single daily dose: a trend toward better therapeutic improvement, a significant decrease in the side effects of insomnia and fatigue, and more regular consumption of the medication.

Trial of a Sustained Release Form of Amitriptyline in the Treatment of Depressive Illness

Amitriptyline is a widely used antidepressant and its effectiveness has been shown, e.g. in comparison with imipramine in double blind trial (Burt et al., 1962; Hordern et al., 1963, 1964). A disadvantage of currently prescribed tricyclic antidepressants is the necessity for administering the drug three times a day. It has been shown that general medical and in particular psychiatric patients fail to take their medication either in the prescribed dose or at all (Benstead and Theobald, 1952; Haler, 1952; Park and Lipman, 1964; Parkes et al., 1962; Porter, 1969). This failure rate may be as high as 50 per cent (Dixon et al., 1957; Willcox et al., 1965). Even in psychiatric in-patient studies there was still a high failure rate in taking prescribed psychiatric drugs (Hare and Willcox, 1967). A regimen consisting of a single daily dose is more reliably taken than one consisting of thrice daily dosage (Coppen et al., 1969; General Practitioner Clinical Trial 1970).

Clinical trial of mebanazine--a new monoamine oxidase inhibitor.

At the time when this investigation was being considered (June, 1961) the efficacy of the monoamine oxidase inhibitors in the treatment of depressive illnesses was already well recognized. It was also evident from a study of the published papers on this group of drugs that their use was accompanied by a number of side-effects which often raised problems in treatment. The clinical trial of a new drug of this class which, from the pre-clinical toxicity studies in animals, held promise of being less toxic than M.A.O. inhibitors already in clinical use was therefore considered worth while. Such a trial also seemed a useful opportunity to follow up previous observations with phenelzine (Gilmour, 1960) and the suggestion of Sargant (1961) that, given concurrently, M.A.O. inhibitors may potentiate the effect of E.C.T. and reduce the number of exposures necessary, and that their continuance after a course of E.C.T. has been completed may reduce the relapse rate.

VASCULAR CRISES ASSOCIATED WITH MONOAMINE-OXIDASE INHIBITORS.

The authors gave 1,223 courses of antidepressant medication, and in 692 courses MAO inhibitors were used. Prior to Sept. 7, 1963, 8.4% of patients receiving MAO inhibitors experienced acute hypertensive crises featured by intense occipital headache and palpitation. After Sept. 7, 1963, patients receiving MAO inhibitors were advised not to eat cheese and the incidence of acute reactions fell to 3.3%. Of the 8 reactions in the latter series, 5 followed the ingestion of cheese, despite our warning, 2 followed the taking of cream in fairly large quantity and one occurred immediately after drinking 17 oz. of draught beer on an empty stomach after sunbathing. The highest incidence of these reactions occurred with tranylcypromine, but nevertheless this drug is being used more frequently than any other MAO inhibitor and is regarded as indispensible in the treatment of depressive illness. Acute vascular crises, when they occur, are immediately relieved with intravenous phentolamine, but where the associated cervic...

Pertofran

The antidepressant action of imipramine (Tofranil - Geigy) is probably due not to the direct action of the drug itself, but to one of its metabolites, desmethylimipramine (B. B. Brodie et al., Med. exp. 1961, 5, 454), which has been given the Approved Name desipramine. This substance is now marketed as Pertofran (Geigy). It has been suggested but not proved that imipramine takes several weeks to work because this time-lag is necessary for the active metabolite to accumulate. If this is true, desipramine might be expected to act more quickly than imipramine in the treatment of depressive illness.

A clinical comparison of phenelzine and electro-convulsive therapy in the treatment of depressive illness.

The mono-amine oxidase inhibitors, of which phenelzine (“Nardil”) is one example, were introduced for the treatment of depressive illness as a result of the observation that iproniazid, which is a mono-amine oxidase inhibitor, produced euphoria and increased mental alertness in some tuberculous patients to whom it was given. Trials of iproniazid in mental illness were carried out (Loomeret al., 1957; Cesarman, 1959), but it was found to be very liable to give rise to side-effects, being particularly toxic to the liver. Other less toxic mono-amine oxidase inhibitors such as phenelzine, which is chemically related to iproniazid, were later developed.

Clinical Features of Depression and the Response to Imipramine (“Tofranil”)

Since it was first reported by Kuhn in 1957, the value of imipramine in the treatment of depressive illness has become generally recognized and confirmed by clinical trials (Blair, 1960; Daneman, 1961; Rees et al., 1961). It continues to hold an important place in therapy despite the introduction of many other antidepressant drugs and the occasional adverse report (Ashby & Collins 1961). Nevertheless the indications for its use are by no means established. It has been claimed that certain types of depression respond better than others: “psychotic” better than “neurotic” (Azima, 1959), “endogenous” better than “reactive” (Ball and Kiloh, 1959). Yet the difficulty of making these categorical distinctions, and of making reliable comparisons between the findings based upon them by different workers remains notorious. It is clear, however, that only a proportion of depressed patients respond well to imipramine. It is also certain that within the group which does respond well are to be found representatives of every type and degree of depressive state. There is evident need, therefore, for information that will help to indicate which characteristics of an individual will render him more or less susceptible to imipramine, and there does not appear to have been any study particularly devoted to this. In this paper we give the results of correlating certain clinical features of depression with the response to treatment by this drug.

Demonstration of anti-depressant or stimulant properties of imipramine in experimental animals.

IMIPRAMINE (I) is a drug that is related chemically to the major tranquillizers of the phenothiazine group such as chlorpromazine (II). As distinct from chlorpromazine, however, imipramine is claimed to be of considerable value in the treatment of depression, particularly of the endogenous type1–3. Pharmacologically, imipramine has many of the properties of chlorpromazine although it is quantitatively less potent. Thus in the mouse, imipramine, like chlorpromazine, reduces motor activity, prolongs hexobarbitone sleeping time, and causes a fall in rectal temperature4,5. Both imipramine and suitable doses of chlorpromazine counteract the hypothermia, ptosis, bradycardia, and diarrhœa caused by reserpine administration in rats6, and both drugs produce sedation in the cat and dog4. In the curarized cat, both drugs block the electrocortical desynchronization caused by electrical stimulation of the mesencephalic reticular formation4, although it has been suggested7 that this action of imipramine is due to atropine-like properties rather than to chlorpromazine-like sedation. Slight qualitative differences have been observed between chlorpromazine and imipramine in their action on the electrical activity recorded from certain sub-cortical areas in the rabbit. The resemblance between the pharmacological actions of these two drugs has led to the view6 that the differences between the pharmacological effects of chlorpromazine and imipramine are, at present, only quantitative, rather than qualitative. Furthermore, unlike other drugs, such as iproniazid and nialamide, used at present in the treatment of depressive illnesses, imipramine is not an inhibitor of mono-amine oxidase9. There appeared, therefore, to be no pharmacological basis for its important clinical anti-depressant properties.

Prognostic factors in the electro-shock treatment of depressive states. II.-The application of specific tests.

During the past ten years varying degrees of prognostic value have been claimed, directly or indirectly, for a number of specific factors in connection with the treatment of depressive illnesses by E.C.T. These have included the blood pressure responses to adrenaline and methacholine (Funkensteinet al., 1948, 1950); the “sedation threshold” to intravenous sodium amylobarbitone (Shagass, 1954; Shagass and Jones, 1958); EEG changes under thiopentone following electroshock (Roth, 1951; Rothet al., 1957); and psychological tests based on items derived from the Minnesota Multiphasic Personality Inventory (Pearson, 1950; Feldman, 1957, 1958; Welsh, 1952). Other studies have been made on the prognostic value of adrenocortical activity (Faureet al., 1957); serum calcium levels (Gour and Chaudhry, 1957); the “amytal test” (Kahnet al., 1956); and the administration of methylamphetamine (“methedrine”) (Rudolf, 1956). Some of the techniques employed appear too complicated or unreliable in their interpretation to be of any practical clinical value, although a few are of great theoretical value in the contributions to further knowledge of the rationale of E.C.T.