Autonomic Side Effects Research Articles

Heart Rate Variability in Depressed Patients and Differential Effects of Paroxetine and Amitriptyline on Cardiovascular Autonomic Functions

Twenty-four unmedicated patients with episodes of major depression (DSM-III-R) and an age- and sex-matched group of 24 normal subjects underwent a heart rate analysis. The battery of cardiovascular reflex tests included the coefficient of variation while resting (CVr) and during deep breathing (CVdr), a spectral analysis of heart rate variability, the Valsalva test, and the posture index. The depressed patients showed no significant abnormalities in any of the tests as compared to the healthy subjects. The 24 patients were randomly allocated for treatment with either amitriptyline or paroxetine. During treatment with 20 mg paroxetine per day, patients showed no changes in cardiovascular autonomic function tests after 14 days. However, treatment with 150 mg amitriptyline per day decreased all heart rate parameters significantly due to anticholinergic side effects, except heart rate, which increased significantly. As autonomic side effects are a potential hazard of antidepressant therapy, the data suggest that paroxetine is an appropriate antidepressant for cases with pre-existing cardiovascular autonomic neuropathy.

Fluoxetine/Norfluoxetine Concentrations in Human Milk

Drug therapy for mothers with postpartum depression is complicated by the need to consider the effect of drugs taken by the mother on the nursing infant. In many cases abrupt weaning of the infant is prescribed so that drug therapy may begin, but this may precipitate conflicting feelings of guilt and cause hormonal upset in the mother, both of which may exacerbate the mood disorder. Traditional antidepressants are excreted in human milk, and the effects of these drugs on the infants of nursing mothers are unknown.1 Most of the tricyclic antidepressants have autonomic side effects that may affect both milk

Effects of concomitant cholinergic and adrenergic stimulation on learning and memory performance by primates

Physostigmine and other centrally-acting acetylcholinesterase inhibitors are currently being examined for their potential in the treatment of Alzheimer's Disease. The ability to employ this class of agents is limited by the potential for debilitating and dangerous side effects. Clonidine and related drugs have recently been demonstrated to enhance memory performance in monkeys. Clonidine also inhibits the function of cholinergic neurons in specific brain regions and reduces certain side effects of physostigmine. Seven adult macaque monkeys performing a delayed matching-to-sample (DMTS) task received regimens of increasing doses of clonidine and physostigmine on separate occasions to determine the ‘best dose’ of each agent in terms of enhanced memory performance. The best doses were combined as a single administration and performance compared to that using the two drugs alone. The combination regimen of clonidine and physostigmine was more effective than either drug alone in enhancing memory performance. Part of the benefit may have been due to the ability to employ significantly higher doses of physostigmine on the combination regimen. A single injection of the combination resulted in enhanced performance both on the day of administration as well as on the following day. These results are consistent with the ability of clonidine to limit the expression or intensity of certain physostigmine-induced autonomic side effects, while allowing the cognitive beneficial effects of the cholinesterase inhibitor.

The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms

The effect of the selective serotonin reuptake inhibitor paroxetine on diabetic neuropathy symptoms was examined in comparison to imipramine and placebo in a randomised, double-blind, cross-over study. Paroxetine was given as a fixed dose of 40 mg/day, while the dose of imipramine was adjusted to yield optimal plasma levels of imipramine plus desipramine of 400–600 nM. Paroxetine significantly reduced the symptoms of neuropathy as measured by both observer- and self-rating, but was somewhat less effective than imipramine. However, patients showing a weaker response to paroxetine than to imipramine had lower plasma concentrations of paroxetine than patients with similar response to the 2 drugs. On imipramine 5 patients dropped out because of intolerable side effects and 4 of 19 patients completing the study reported withdrawal symptoms after discontinuing imipramine. On paroxetine no patients dropped out due to side effects and no withdrawal symptoms were reported. Self-rating showed no depressive symptoms at baseline, and no changes during the study. Neither paroxetine nor imipramine caused changes in objective measures of peripheral nerve function. In conclusion, 40 mg paroxetine/day significantly reduced the symptoms in peripheral diabetic neuropathy and it was suggested that by dose adjustment on the basis of drug level monitoring, paroxetine may become as effective as imipramine. Paroxetine was devoid of the often disturbing autonomic side effects limiting the use of imipramine in several patients.

Tetrahydroaminoacridine–Lecithin Combination Treatment in Patients with Intermediate-Stage Alzheimer's Disease

We studied the efficacy and safety of oral tetrahydroaminoacridine (THA) combined with lecithin in 52 patients with Alzheimer's disease. The maximal tolerated dose of THA (up to 100 mg per day) was determined during an eight-week titration period, after which the tolerated dose of THA or placebo was given during two sequential randomized periods of treatment lasting eight weeks each. Highly purified lecithin (4.7 g per day) was administered during all phases of the study. Efficacy was expressed in terms of scores on the Mini-Mental State (MMS) test, the modified MMS test, the Hierarchic Dementia Scale, the Rapid Disability Rating Scale-II, and the behavioral scale of Reisberg et al. Safety was assessed by careful clinical monitoring as well as serial measurements of liver aminotransferases. Forty-six patients completed the titration period, and 39 completed the double-blind period, during which only the MMS score showed a small but significant increase (P less than 0.05) after four weeks of treatment with THA. Autonomic side effects of THA were common but mild. Reversible elevations of serum aspartate and alanine aminotransferase levels to three or more times the upper limit of normal occurred in 17 percent of patients; most of the patients affected were women. A liver biopsy performed in one patient showed resolving focal liver-cell necrosis. These studies fail to demonstrate a significant clinical benefit of THA given orally in a maximal dose of 100 mg per day over a period of eight weeks in combination with lecithin.

Inhibitory effects of amitriptyline on the stimulation-induced Ca 2+ increase in parotid acini

The present study demonstrates the effects of the antidepressant, amitriptyline, and the acetylcholine antagonist, atropine, on the stimulation-induced rise in cytosolic, free Ca 2+ (Ca 2+). The changes in Ca i 2+ of collagenase-isolated rat parotid acini were measured by means of the Ca 2+ -sensitive dye, fura-2. It was found that stimulation by carbachol resulted in a maximal increase of 582 ± 34 nM (mean ± S.E.) in Ca i 2+ with a k S of 5.8 ± 1.3 μM. Adrenaline caused a rise of 380 ± 22 nM in Ca i 2+ with a k S of 0.5 ± 0.2 μM. Amitriptyline and atropine were found to inhibit the carbachol-induced rise in Ca i 2+ with dissociation constants (k I of 105 and 1.25 nM, respectively, in the absence of agonist. The adrenergic-induced rise in Ca i 2+ was inhibited by amitriptyline with a k I of 45 nM. Amitriptyline was found to inhibit both receptor classes by a competitive or mixed type of inhibition. Similarly, atropine exerted the same type of inhibition on the acetylcholine receptor. Amitriptyline and atropine were found to be mutually exclusive for competing for substrate binding on the receptor. These findings are consistent with a common binding site for amitriptyline and atropine on the acetylcholine receptor, possibly in close proximity with, but different from the substrate binding site. The stimulation-induced cell shrinkage evoked by the loss of electrolytes and water from the acini was measured by a 90° light scattering signal. It was found that this method makes possible the detection of autonomic side-effects of antideprassants on acini suspended in protein-containing media.

High dose tranylcypromine for refractory depression

As many as 15% of depressed patients have a refractory illness. We initiated an openlabel study using high doses of tranylcypromine (TCP) at a range of 90 mg to 180 mg daily, in fourteen refractory depressives who failed to respond to a minimum of three prior treatment regimens. Ail were outpatients with a mean t SD Hamilton depression score (HDS) of 24 -t 5. The mean age was 43 t 6 years (range 27 to 64 years), and the mean -+ SD illness duration was 18 t 12 years. The number of previous treatment failures ranged from three to 22 with a mean ? SD of 9 2 5. Response was defined as a > 50% reduction from the initial HDS and a final HDS < 10. Nine of the 14 subjects (64%) had a complete response, and three had a partial response. The mean ? SD maximum TCP dosage for the entire patient group was 128 +27 mg, and for the responders was 113 + 14 mg. Response was not a function of severity or duration of present episode, nor was it related to the number of prior treatment failures. The side effect profile was favorable, and most autonomic side effects occurred at moderate TCP doses and diminished at high doses. Interestingly, there was no difference in blood pressure at pretreatment and at the maximum TCP dose. These observations are of clinical significance and suggest the need for further controlled studies using high doses of tranylcypromine in refractory depression.

Potentiation of pentazocine analgesia by low-dose naloxone.

The analgesia produced by combinations of low-dose naloxone with pentazocine or morphine was studied in 105 patients with moderately severe postoperative pain after standardized surgery for removal of impacted third molars. Pain intensity was quantified using a visual-analogue scale. To eliminate the release of endogenous opioids produced by the placebo component of open drug administration, all injections were made by a preprogrammed infusion pump. The analgesia produced by pentazocine, an agonist-antagonist opiate-analgesic acting predominantly at the kappa opiate receptor, was potentiated by low-dose naloxone, whereas the analgesia produced by morphine, a mu-agonist, was attenuated by low-dose naloxone. To evaluate whether similar potentiation would be present in an animal model, and specifically, in the absence of diazepam, which patients receive, we performed an analogous experiment in rats in which nociceptive threshold was determined using the Randall-Selitto paw-withdrawal test. The results were completely analogous to the clinical results: pentazocine analgesia was potentiated by low-dose naloxone, whereas morphine analgesia was attenuated by low-dose naloxone. These data demonstrate a novel interaction between opiates, and suggest a rationale for opiate combinations to produce potent analgesia with fewer autonomic side effects and less abuse potential than presently available analgesics.

Citalopram: Clinical effect profile in comparison with clomipramine. A controlled multicenter study

The selective serotonin reuptake inhibitor citalopram was compared with clomipramine in a multicenter clinical study. From a total of 150 depressed patients (age 18–65 years), 114 patients with a Hamilton Depression Scale (HDS) total score≧18 at the end of a 1 week placebo period were started on treatment with either citalopram (40 mg/day) or clomipramine (150 mg/day) (fixed, single daily dose). Patients stratified according to diagnostic rating (Newcastle Inventory, endogenous/non-endogenous) were randomly allocated to treatment groups using double blind principles. In total, 102 patients completed more than 2 weeks, treatment and were included in the analyses of therapeutic effect. The two drug groups were comparable in terms of sex, age, and departmental distribution. Categorical measurements of therapeutic effect based on the HDS total score showed that in the endogenously depressed patients a significantly higher percentage of patients on clomipramine (n=37) than on citalopram (n=38) were classified as complete responders (HDS total≦7) after 3, 4 and 5 weeks of treatment. In the non-endogenously depressed patients (clomipramine: n=15, citalopram: n=12) rather similar numerical differences were observed (P<0.05 at 5th week). In the total patient group the percentage of complete response after 5 weeks was about 60 in the clomipramine group (n=52) and about 30 in the citalopram group (n=50) (P<0.005). The better effect of clomipramine seemed to be related in particular to the sleep items, but other items covering depression, retardation and anxiety/agitation also contributed to the difference in total score that was also seen in patients with low initial scores on the sleep items. Citalopram was devoid of the typical autonomic side effects and orthostatic hypotension seen with clomipramine. Symptoms of nausea/vomiting and headache became somewhat worse in the citalopram- and somewhat better in the clomipramine-treated patients. Participating centers: 1Department of Psychiatry, Odense University Hospital, Odense, 2Department of Psychiatry, Rigshospitalet, University of Copenhagen, Copenhagen, 3Departments of Psychiatry, Frederiksborg General Hospital, Hillerod, 4Department A and C, Psychiatric University Hospital, Arhus, 5Department of Psychiatry, Bornholm General Hospital, Ronne, 6Department of Clinical Pharmacology, Odense University, Odense Participating clinicians: J. Andersen2, P. Bech2,3, S. Benjaminsen1, M. Bjerre1, S. Bojholm5, P. Christensen1, A. Gjerris2, L. Hansted4, E. Jensen3, P. Kragh-Sorensen1, C.B. Kristensen1,3, P. Kyneb4, D. Loldrup3, O.F. Madsen4, O.L. Pedersen1, O.J. Rafaelsen2, S. Rasmussen3, N. Reisby4, F. Sevaj3, P. Simonsen4, H.Y. Thomsen1, P. Vestergaard4 Coordination and drug assay: L.F. Gram6 Statistical consultants: O. Aaskoven, P. Allerup Data-collection and -processing: C. Sanchez Steering Committee: P. Bech, L.F. Gram (chairman), P. Kragh-Sorensen, O.J. Rafaelsen, N. Reisby, P. Vestergaard

A Controlled Clinical Trial of Fluspirilene, A Long-Acting Injectable Neuroleptic, in Schizophrenic Patients with Acute Exacerbation

A 4-week double-blind controlled clinical trial was carried out in which fluspirilene, an injectable diphenylbutylpiperidine neuroleptic given weekly, was compared to chlorpromazine in the treatment of 40 newly admitted schizophrenic patients with acute exacerbation. Similar therapeutic improvement was obtained with both drugs, but men needed a significantly higher mean dose of fluspirilene (23 mg/week) than women (13 mg/week). Fluspirilene induced more parkinsonism than chlorpromazine, but less drowsiness, dizziness, and dry mouth. The difference between the sexes in the potency of fluspirilene and its greater potential to induce parkinsonism may be related to its lesser presynaptic and D1-dopamine receptor blocking properties. The low incidence of autonomic side effects confirms the relative specificity of fluspirilene for dopamine receptors.

Evaluation of Bupropion Hydrochloride: The First of a New Class of Atypical Antidepressants

Bupropion hydrochloride is a new antidepressant that differs clinically and pharmacologically from the tricyclic antidepressants and the monoamine oxidase inhibitors. Pharmacokinetically, bupropion is an intermediate-lived drug with a half-life of about 12 hours. Its antidepressant activity in man has been demonstrated in double-blind, placebo and active drug-controlled studies. Onset of antidepressant action occurs in one to three weeks. Bupropion has a greater effect on the neuronal reuptake of dopamine than of other biogenic amines. At a recommended dose of 450-600 mg/day, the side effect profile of bupropion also distinguishes it from other antidepressants. It does not bind to cholinergic receptors in vitro at clinically relevant concentrations and does not produce appreciable autonomic side effects. The exception is dry mouth, which is reported in 13% of patients. The mechanism underlying this effect is unclear. Bupropion is devoid of cardiovascular effects (e.g., impaired intracardiac conduction, reduced myocardial contractility, decreased peripheral resistance, orthostatic hypotension) in both human and animal studies. The drug is nonsedating and antagonizes the effects of commonly used sedatives, such as alcohol and diazepam. It does not produce weight gain. In susceptible patients, activating effects can occur. Given this profile, bupropion should be less toxic than conventional antidepressants when taken in overdoses; however overdose experience with the drug is limited.

Pharmacotherapy and suicide risk in schizophrenia.

The authors examined drug prescribing patterns and incidence of side effects in schizophrenic patients who committed suicide as compared with a matched control group. The groups did not differ in type of drug prescribed, though patients in the suicide group received significantly higher doses of fluphenazine enanthate. Extrapyramidal reactions occurred more frequently among the patients in the suicide group in the thirty days preceding suicide, and autonomic side effects less frequently, than in control patients for a corresponding period prior to discharge. The authors conclude that the probability of suicide is not related to the type of drug prescribed.

Second generation antidepressants: The pharmacological and clinical significance of selected examples

AbstractUntil recently, tricyclic antidepressants and monoamine oxidase inhibitors were the only therapies available for mental depression. These compounds, while effective, have significant cardiovascular and autonomic side effects and it was recognized that there was room for improvement. As a result of the labors of chemists and pharmacologists over the last 10 years, new or “second generation” compounds are being studied in man. Many of these compounds are structurally, biochemically, and pharmacologically distinct from tricyclic compounds and monoamine oxidase inhibitors and therefore hold out the promise of more effective therapy with fewer side effects. As an interesting offshoot of these structural, biochemical, and pharmacological differences it appears that the prevailing catecholamine theory of affective disorders and of the mode of action of therapeutic agents is challenged. Iprindole, mianserin and bupropion are discussed as examples of second generation antidepressants.

Trazodone and amitriptyline in treatment of depressed inpatients

Trazodone (TZ), a 'new generation' antidepressant and amitriptyline (AMT) were administered in a double-blind controlled study to 43 depressed inpatients. The Hamilton Depression Rating Scale (HAM-D), the AMDP-system and the Bf-s self-rating questionnaire were used for documentation of psychopathological changes and autonomic side effects. The Newcastle-Scale for definition of a neurotic and an endogenous subgroup of depression was retrospectively applied. No significant improvement was noticed on the Bf-s self-rating questionnaire in the TZ group as compared to the AMT group (p less than 0.001). The global HAM-D score decreased significantly in the TZ group (p less than 0.05) as well as in the AMT group difference (p less than 0.01) emerged during the trial in favour of AMT. Core symptoms of depression were significantly improved in the AMT group but not in the TZ group: depressed mood (p less than 0.001), psychic anxiety (p less than 0.001) and retardation (p less than 0.05). TZ was faster actin than AMT in controlling agitation. Results of this clinical study demonstrate TZ to have sedative and some anxiolytic properties but only negligible antidepressant efficacy.

Pimozide in the treatment of newly admitted schizophrenic patients

Pimozide, a specific dopamine blocking agent, was compared with chlorpromazine in a 4-week double-blind study of the treatment of 40 schizophrenic patients newly admitted to hospital through the emergency room. Dosage was adjusted according to therapeutic effect and during the final week ranged from 10--70 mg/day (median 30 mg/day) for pimozide and 600--1,500 mg/day (median 900 mg/day) for chlorpromazine. Pimozide was found to exert somewhat less of an overall therapeutic effect than chlorpromazine, particularly in highly agitated patients. Women responded better to either treatment than men. A weighted mean of the doses given to male and female patients during the final week suggests that in the treatment of acutely ill patients the mg dose equivalency of pimozide in terms of chlorpromazine is approximately 1:25, considerably lower than estimates from maintenance studies. Pimozide induced significantly more parkinsonian symptoms but less autonomic side effects than chlorpromazine. It is suggested that the weaker presynaptic dopamine blocking effect of pimozide might be responsible for its reduced potency in the treatment of acute schizophrenic symptoms.

Binding affinity of levomepromazine and two of its major metabolites of central dopamine and alpha-adrenergic receptors in the rat.

N-Monodesmethyl levomepromazine and levomepromazine sulfoxide have previously been found in higher plasma concentrations than the parent drug in patients who received oral doses of levomepromazine. In the present study levomepromazine, N-monodesmethyl levomepromazine and levomepromazine sulfoxide have been assayed for their binding affinity to rat striatal dopamine receptors and to alpha-adrenergic receptors in rat cortex, and compared with the potency of chlorpromazine and some of its metabolites in the same systems. Levomepromazine sulfoxide was relatively inactive in the dopamine receptor binding test but much more active in the alpha-adrenergic receptor binding test, where it had a binding affinity similar to 7-hydroxy chlorpromazine. Levomepromazine and N-monodesmethyl levomepromazine were active in both systems, having a slightly higher potency than chlorpromazine in the alpha-adrenergic binding test, and a somewhat lower potency than chlorpromazine in the dopamine receptor binding test. The results indicate that N-monodesmethyl levomepromazine may significantly contribute to the antipsychotic effects of levomepromazine while the sulfoxide metabolite lacks neuroleptic potency, and that both metabolites may contribute to the autonomic side-effects of the drug.

Neuroleptic drug interactions with norepinephrine alpha receptor binding sites in rat brain

Alpha adrenergic receptor sites in mammalian brain tissue can be labeled by the binding of [ 3H]WB-4101 (2-([2′,6′-dimethoxy] phenoxyethylamino) methyl benzodioxan), a potent α-adrenergic antagonist. Numerous neuroleptic drugs of phenothiazine, butyrophenone and thioxanthene classes are potent in competing for [ 3H]WB-4101 binding, with affinities resembling those of classic α-antagonists such as phentolamine and phenoxybenzamine. The potencies of neuroleptics in competing for WB-4101 binding sites correlate closely with their potencies in antagonizing norepinephrine and epinephrine induced lethality in rats, confirming that affinity for WB-4101 binding sites predicts α-receptor antagonism in vivo. The relative affinities of neuroleptics for WB-4101 binding sites and for dopamine receptors as labeled by [ 3H]haloperidol provides an index of the relative propensities of these drugs for eliciting autonomic side effects such as orthostatic hypotension and sedation.

Antipsychotic effects, side effects and effective dosis of the butyrophenone lenperone (AHR 2277).

Three open studies with Lenperone were performed. 50 hospitalized schizophrenic patients were treated 20-30 days with Lenperone. The therapeutic effective dose was 30-50 mg/day. The highest daily dosage was 90 mg. Patients were examined on fixed observation days and the findings were documented by means of the AMP system. AMP data were analyzed at symptom and syndrome level and compared using an analysis of covariance. In the described dosage Lenperone acted only little sedating, strong antipsychotic and caused only a few single extrapyramidal and little autonomic side effects. The dosage is limited because of the effect on heart and blood circulation. Lenperone caused a good improvement of depressive symptoms in the schizophrenic patients. Lenperone was well tolerated and slowed a rapid onset of its antipsychotic effect. It caused a steady improvement of productive schizophrenic symptoms. For better knowledge of the profile of the effects of Lenperone, a trial in depressive paranoid syndromes, for example schizoaffective psychoses, would be interesting; a double-blind trial in comparison to a well-known antipsychotic would be very useful.

An investigation into the use of anafranil in phobic and obsessional disorders.

A multicentre clinical trial of clomipramine in the treatment of obsessional and phobic disorders in general practice is described. All phobias showed an improvement in situational anxiety, interference and autonomic side effects. With the exception of two cases of animal phobia there was also improvement in general anxiety and avoidance. Obsessional cases showed an overall improvement in all symptom areas.

PERORAL AND PARENTERAL ADMINISTRATION OF LONG‐ACTING NEUROLEPTICS: A DOUBLE‐BLIND STUDY OF PENFLURIDOL COMPARED TO FLUPENTHIXOL DECANOATE IN THE TREATMENT OF SCHIZOPHRENIA

Fifty-six out of 60 schizophrenic patients completed a double-blind study of two long-acting neuroleptics, penfluridol (peroral) and flupenthixol decanoate (parenteral). Half of the patients were on maintenance therapy of flupenthixol prior to the study, the other half on penfluridol. The actual double-blind study (12 weeks) was commenced after a preliminary period of 4 weeks, the patients in the two main groups being randomly divided into two further groups, one continuing the medication unchanged, the other changing to the alternative drug. It was found possible to make a sudden switch from penfluridol to flupenthixol decanoate and vice versa without any significant change in the condition of the patient. The same dosage (in 70% of the patients from 40 to 80 mg) of penfluridol was used per week as was employed for flupenthixol decanoate per fortnight. Changes in the intensity of the symptoms (total Brief Psychiatric Rating Scale (BPRS) score) were moe pronounced in the preliminary period (during unchanged treatment) than on changed medication in the blind period. Both drugs induced approximately the same degree of akathisia, Parkinsonism and autonomic side effects. The practical consequences of equipotent therapeutical effect of a peroral and parenteral long-acting neuroleptic are briefly discussed.