Lack of effect of tricyclic antidepressants on serum prolactin levels

A previous report indicated that the tricyclic antidepressants imipramine and amitriptyline markedly increased plasma prolactin levels in man. We found no increases after acute or chronic treatment with either drug in usual clinical doses. The results indicate that blockade of serotonin reuptake does not affect basal prolactin levels in man.     

The effect of tricyclic antidepressants and neuroleptics on the peripheral and central action of norepinephrine in reserpine-treated mice

The effect of exogenous norepinephrine on the ptosis induced by reserpine and its modification by tricylic antidepressants and neuroleptics were studied in reserpine-pretreated mice.S.c. injection of norepinephrine (0.3–5 mg/kg) reversed dose-dependently the ptosis induced by reserpine. The maximal effect was obtained 15 min after norepinephrine administration. Tricyclic antidepressants (2.5 and 5 mg/kg i.p.) potentiated the effect of norepinephrine. In contrast neuroleptics (1 and 5 mg/kg i.p.) antagonized it.Intracerebral injection of norepinephrine (5–20 μg) also reversed dose-dependently the ptosis induced by reserpine, and the maximal effect was obtained within 5 min. Tricyclic antidepressants potentiated the effect of norepinephrine, but neuroleptics antagonized it.Among tricyclic antidepressants, the potentiating action of secondary amines was stronger than that of tertiary amines. Chlorpromazine blocked the action of norepinephrine more strongly than did the same dose of haloperidol.     

Tricyclic antidepressants: effects on the firing rate of brain noradrenergic neurons.

The spontaneous activity of the norepinephrine-containing cells of the locus coeruleus was recorded in chloral hydrate-anesthetized rats. The effect of seven tricyclic antidepressants on the firing rate of single cells in the locus coeruleus was studied. All the drugs tested, except iprindole markedly decreased the rate of firing of the noradrenergic cells. Antidepressants having a secondary amine in the side chain, desipramine, nortriptyline and chlordesipramine, were more potent than their respective tertiary amine analogues, imipramine, amitriptyline and chlorimipramine. Alteration of the rate of drug metabolism by pretreatment with SKF-525A or phenobarbital did not change the doses of tertiary antidepressnats required to decrease norepinephrine cell firing. Depletion of the norepinephrine stores by pretreatment with alpha-methyl-p-tyrosine and reserpine markedly increased the dose of desipramine required to depress the norepinephrine cells. The results are in good agreement with previous studies showing that secondary amine antidepressants are more potent than their tertiary amine homologues in blocking the uptake of norepinephrine into brain and peripheral tissues. Despite their lower potency it is concluded that tertiary antidepressants act on noradrenergic neurons in their unchanged form and not via secondary amine metabolites formed during the recording experiments since alterations in liver metabolism did not influence the response. The findings are consistent with the suggestion made from studies on transmitter turnover that antidepressants by inhibiting reuptake of norepinephrine cause a stimulation of postsynaptic receptors which decreases the activity of the presynaptic neurons by a feed-back mechanism. This view is further supported by the finding of an inverse relation between the norepinephrine content of the brain and the dose of desipramine required to decrease the firing rate of the noradrenergic neurons.     

No evidence for central histamine-receptor involvement with the hypotensive effect of clonidine in cats

In conscious hypertensive cats, intraventricular (i.c.v.) administration of clonidine (25 μg), induced hypotension and bradycardia. Pretreatment with metiamide (2 mg i.c.v.) did not significantly antagonise either the hypotension or bradycardia induced by clonidine (25 μg), but induced marked behavioural changes. Central pretreatment with mepyramine (200 μg, i.c.v.) or procaine (600 μg i.c.v.), reduced the hypotension evoked by clonidine (25 μg), but no antagonism of the clonidine-induced bradycardia was apparent. Central phentolamine (200 μg, i.c.v.) or tolazoline (200 μg, i.c.v.) antagonised the hypotension and bradycardia evoked by i.c.v. clonidine.     

Enhancement of central norepinephrine and 5-hydroxytryptamine transmission by tricyclic antidepressants

The relative abilities of 1–3 mg/kg of desipramine (DES), imipramine (IMIP), amitriptyline (AMI), and chlorimipramine (CI-IMIP) to enhance synaptic transmission mediated by either NE or 5-HT were determined by testing their effects directly on NE or 5-HT transmission to sympathetic preganglionic neurons in unanesthetized, spinal cats. Effects on NE transmission were assessed on intraspinal excitatory pathwasy which utilize NE as a transmitter. Effects on 5-HT transmission were assessed on 5-HT-mediated depression of spinal sympathetic reflexes produced by 30 mg/kg of 5-HTP.Both DES and IMIP markedly enhanced transmission through the intraspinal excitatory NE pathways whereas AMI and CI-IMIP depressed transmission. However, both AMI and CI-IMIP modestly enhanced transmission in cats depleted of central 5-HT by pretreatment with parachlorophenylalanine. The relative potencies of the four drugs on excitatory NE transmission were DES>IMIP>AMI>CI-IMIP. Each of the four drugs also enhanced the 5-HTP-induced depression of spinal sympathetic reflexes, but their relative potencies on 5-HT transmission were just the opposite to those found on NE transmission. Therefore, all four drugs enhanced transmission by both NE and 5-HT, but their relative selectivities for the two transmitters differed markedly and were complementary. In general, the results support those of previous studies based on less direct methods for assessing inhibition of amine reuptake by tricyclic antidepressants.     

Moclobemide,a new reversible MAO inhibitor — interaction with tyramine and tricyclic antidepressants in healthy volunteers and depressive patients

Moclobemide is a new, short-acting, reversible MAOI, preferentially affecting type A MAO. We have studied the interaction of moclobemide with tyramine and tricyclic antidepressants in healthy volunteers and depressive patients.Neither tyramine capsules (50 mg) nor cheese and wine meals (65 mg tyramine) produced a significant change in blood pressure and heart rate after single or repeated doses of moclobemide in volunteers. In contrast, after 1 weeks' treatment with tranylcypromine pressure response to cheese and wine meals was severe. Blood pressure sensitivity to IV tyramine was slightly increased (1.5–2 fold;P<0.05 versus predrug) during moclobemide treatment in patients and volunteers. This increase was neutralised by concomitant administration of desipramine in volunteers. Amitriptyline was well tolerated when given to patients after or together with moclobemide.In conclusion, moclobemide appears relatively safe with respect to tyramine sensitivity and interaction with tricyclics.     

Biphasic effect of tricyclic antidepressants on the release of norepinephrine from the adrenergic nerves of the rabbit heart

The release of norepinephrine (NE) from the right atrium of the rabbit heart was used as a model to investigate biphasic effects due to tricyclic antidepressants, similar to those clinically observed in the treatment of depression and known as therapeutic window. Strips of the atrium were loaded with³H-NE, and then superfused by Krebs solution. The basal release and the electrical stimulation evoked release of³H-NE were measured in the presence and absence of four clinically used tricyclic antidepressants: imipramine, amitriptyline, desipramine and nortriptyline. In addition, guanethidine, an adrenergic neuron blocker, was also studied. At lower concentrations (0.5–10 µM) tricyclic antidepressants increased, whereas higher concentrations (50–100 µM), inhibited the evoked release of NE. This inhibition was not prevented by the alpha₂ adrenoceptor antagonist yohimbine, excluding the possibility of alpha₂ adrenoceptormediated inhibition of NE release. In higher concentrations the tricyclic antidepressants increased the basal release of NE in a Ca-independent way. Secondary amine derivatives were more potent inhibitors of the evoked release, and enhance the resting basal release of NE to a greater extent than the tertiary ones. Similarly, guanethidine (1–50 µM) also decreased the evoked release and increased the basal release of NE in a concentration dependent manner. Yohimbine failed to counteract the inhibition caused by guanethidine and the increment of the basal release was Ca-independent. It is concluded that the effect of tricyclic antidepressants in potentiating the release of NE is masked by their adrenergic neuron blocking properties, i.e. they inhibit the release of NE. Our findings are consistent with paradoxical clinical observations that some tricyclic antidepressants have therapeutic value only in lower plasma concentrations and they become ineffective at higher concentrations.     

Dose responses and relationships between anticholinergic activity and mood with tricyclic antidepressants

A pilot study showed that single doses of imipramine (100 mg) produced a maximum reduction in salivation after 3 h which persisted for 72 h after drug. Effects after 3 h were reproducible in 3 subjects and differed from control levels on all 6 occasions of testing. A double-blind study in 6 subjects was then carried out to ascertain whether a dose response measured by salivary flow could be obtained for imipramine and dimethacrin, a developmental drug with fewer anticholinergic effects in animals. A further objective was to study the effects of both drugs on subjective feelings of mood, appetite, and dry mouth in order to make correlations between these effects and the anticholinergic activity. Results showed a linear log-dose response reduction in salivation for imipramine which differed significantly from placebo and dimethacrin. Significant changes on the Clyde Mood Scale in sleepiness and friendliness factors occurred only with imipramine, raising the question of whether there is a causal relationship between the central actions of imipramine and its anticholinergic activity. The significant decrease in friendliness with imipramine as compared to placebo suggests that anticholinergic activity is unlikely to be responsible for antidepressant effect, but may account for the drug's sedative action.     

The influence of ageing on serum levels of tertiary tricyclic antidepressants

The influence of ageing on serum levels of tertiary tricyclic antidepressants (TCAs) was studied in 385 psychiatric inpatients treated daily with one of three TCAs: 157 patients with amitriptyline (154 ± 47 mg, mean dose ± SD), 183 with doxepin (177 ± 59 mg) and 45 with clomipramine (153 ± 51 mg). The patients were divided into three age groups: 125 of them were aged < 35 years, 218 were 35–65 years and 42 were > 65 years. The numbers of blood samples for gas-chromatographic monitoring of steady-state concentrations of serum tertiary and secondary TCAs were 192 for amitriptyline, 240 for doxepin and 138 for clomipramine. The concentrations of serum amitriptyline and nortriptyline rose in an age-related manner. The serum clomipramine and norclomipramine concentrations were higher in the middle-aged than in the young patient groups, whereas serum doxepin and nordoxepin concentrations changed less markedly with advancing age. The variations of serum amitriptyline and nortriptyline concentrations were not greater in old patients than in middle-aged ones. Neither were the variations in doxepin and nordoxepin concentrations enlarged with advancing age (but those in clomipramine and norclomipramine concentrations were wider in middle-aged than in young patients). The number of too high (‘toxic’) TCA concentrations was inconsistently greater in the elderly than in the two younger age groups. The results suggest that the liability of old patients to the adverse effects of TCAs is not—at least with all TCA treatments—due to the enlarged variation in serum drug levels or to the increased frequency of ‘toxic’ serum TCA concentrations.     

A comparison of plasma and serum levels of two tricyclic antidepressants: Imipramine and desipramine

This study was performed to determine the difference, if any, between serum and plasma levels of the tricyclic antidepressant drugs imipramine and desipramine. Serum and plasma samples were drawn simultaneously from patients taking either of these drugs. Statistical analysis indicated no difference in the drug levels; that is, serum and plasma levels were identical.     

Modifications of central 5-hydroxytryptamine binding sites in synaptic membranes from rat brain after long-term administration of tricyclic antidepressants.

The effects of single and long-term administration of tricylic antidepressants, imipramine, desmethylimipramine (desipramine), amitriptyline and dimetacrine on 5-hydroxytrptamine (5-HT) binding sites in synaptic membranes from rat brain were studied. There were two types of specific [³H]-5-HT binding sites; one with high affinity and the other with low affinity. Intraventricular injection of 5,6-dihydroxytryptamine did not modify the binding parameters. In in vitro experiments, 5-HT, tryptamine derivatives and 5-HT antagonists were found to be effective displacers of [³H]-5-HT binding while all antidepressants studied were ineffective in displacing the binding at 10^?6 M. Single i.p. administration of antidepressants did not affect significantly the specific binding. In contrast, administration of antidepressants for 3 weeks produced a significant decrease in the maximal numbers of binding sites, without affecting the dissociation constants of the specific binding. It is suggested that the modification of central 5-HT binding sites caused by long-term administration of tricylclic antidepressants is due to persistent exposure of the binding sites to elevated concentrations of 5-HT, a consequence of the 5-HT uptake inhibition by the antidepressants. These observations could have some implication for the new theory proposed recently that in depression, there is an involvement of synaptic 5-HT with a hypersensitive receptor in the postsynaptic membranes.     

Further evidence for central histamine H2-receptor involvement in the hypotensive effect of clonidine in the rat

In urethane-anaesthetised rats, the administration of the specific histamine H₂-receptor antagonist metiamide intracerebroventricularly (i.c.v.) raised the blood pressure and increased the heart rate. Metiamide (i.c.v.) antagonised the hypotensive effect of clonidine (i.c.v.) in an apparently competitive manner. 4-Methylhistamine i.c.v. did not significantly change the blood pressure. The results are consistent with the concept that the hypotensive effect of clonidine is at least partly due to a stimulation of cerebral H₂-receptors. The existence of cerebral H₂-receptors mediating hypotensive effects is supported by the hypertensive effect of metiamide but not by the lack of hypotensive effects of 4-methylhistamine.     

Reliable HPLC method for therapeutic drug monitoring of frequently prescribed tricyclic and nontricyclic antidepressants

A new high-performance liquid chromatography method is presented for the determination of 10 frequently prescribed tricyclic and nontricyclic antidepressants: imipramine, amitriptyline, clomipramine, fluoxetine, sertraline, paroxetine, citalopram, mirtazapine, moclobemide and duloxetine. The simple and accurate sample preparation step, consisted of liquid:liquid extraction with recoveries ranging between 72% and 86%, except for moclobemide (59%). Separation was obtained using a reverse phase Select B column under isocratic conditions with UV detection (230 nm). The mobile phase consisted of 35% of a mixture of acetonitrile/methanol (92:8, v/v) and 65% of 0.25 mol L(-1) sodium acetate buffer, pH 4.5. The standard curves were linear over a working range of 2.5-1000 ng mL(-1) for moclobemide, 5-2000 ng mL(-1) for citalopram, duloxetine, fluoxetine, 10-2000 ng mL(-1) for sertraline, imipramine, paroxetine, mirtazapine and clomipramine. The intra-assay and inter-assay precision and accuracy were studied at three concentrations (50, 200, and 500 ng mL(-1)). The intra-assay coefficients of variation (CVs) for all compounds were less than 8.8%, and all inter-CVs were less than 10%. Limits of quantification were 2.5 ng mL(-1) for moclobemide, 5 ng mL(-1) for citalopram, duloxetine and amitriptyline, and 10 ng mL(-1) for mirtazapine, paroxetine, imipramine, fluoxetine, sertraline, and clomipramine. No interference of the drugs normally associated with antidepressants was observed. The method has been successfully applied to the analysis of real samples, for the drug monitoring of ten frequently prescribed tricyclic and non-tricyclic antidepressant drugs.     

Role of the ventral surface of the brain stem in the hypotensive action of clonidine.

The areas S of the ventral surface of the brain stem and the immediately surrounding zone were superficially destroyed by the means of electro-coagulation, in 14 cats. This destruction produced a drop in blood pressure, which was transient in 9 and definitive in 4 animals; in one cat only the arterial pressure did not change after the destruction. In 6 animals which have been sham-operated, clonidine (15 mug/kg, i.v.) always induced a marked fall in blood pressure whereas in 10 animals which had maintained or recovered a normal blood pressure after the destruction of the area S, clonidine (15 mug/kg) injected intravenously no longer produced any decrease of the arterial pressure. These results suggest that the integrity of the areas S is necessary for the development of the hypotensive action of clonidine. This hypotensive drug may act, at least at the level of the ventral surface of the brain stem, through inhibition of a vasopressive structure.     

High affinity binding of tricyclic antidepressants to histamine H1-receptors: Fact and artifact

Six tricyclic antidepressants were tested for their ability to inhibit the binding of the histamine H₁-receptor antagonist [³H]pyrilamine to membrane fractions from whole rat brain. Calculated inhibition constants (K_i) for the antidepressants were in the range of 2.6 × 10^?11 to 2.3 × 10^?7M and correlated very well with their equilibrium dissociation constants derived from biological assays of the H₁-receptor. Increasing the concentration of receptors present in the binding assay resulted in an overestimation of the calculated K_i's for doxepin, amitriptyline, and nortriptyline, but not for the lower affinity compounds of the series, imipramine, protriptyline, and desipramine. These results indicate: (1) the importance of receptor concentration in determining the potency of compounds which competitively inhibit, with very high affinity, the binding of a radioactively labeled ligand; (2) the need to correlate binding data with biological data.     

Effect of tricyclic antidepressants on the uptake of noradrenaline and 5-hydroxytryptamine by rat brain slices incubated in buffer or human plasma

Summary A method is described for measuring the inhibition of transmitter uptake into noradrenaline (NA) and 5-hydroxytryptamine (5-HT) neurons incubated in plasma from patients receiving tricyclic antidepressants. The potency was determined of the tricyclic antidepressants nortriptyline and chlorimipramine in inhibiting NA and 5-HT uptake by rat brain slices incubated in buffer or human plasma. As expected, nortriptyline produced greater inhibition of NA than of 5-HT uptake, and chlorimipramine had more effect on 5-HT uptake. These drugs caused 10 to 100 times more inhibition of monoamine uptake from buffer than from plasma, probably because they were bound to plasma proteins. Plasma from patients taking nortriptyline inhibited NA uptake by brain slices 35—55% of the value found in each subject in a pretreatment sample. During long term therapy the concentration of a drug in plasma should be in equilibrium with its concentration at central receptor sites. Thus, it seems likely that the present results reflect the inhibition of uptake by the central monoaminergic neurons of patients taking tricyclic antidepressants. The method also permits evaluation of inter-individual differences in the effects of various antidepressants on NA and 5-HT nerve terminals. It can also be used to evaluate the relative effects of various antidepressants on these two monoaminergic systems.     

Compliance with tricyclic antidepressants: the value of four different methods of assessment

AIMS: To assess the advantages and disadvantages of four methods for studying compliance with antidepressants: self-report scores, tablet counts, a microprocessor (MEMS) container system and the assay of nordothiepin and dothiepin concentrations in plasma. METHODS: The techniques were used in 88 patients commencing tricyclic antidepressants in the setting of UK general practice. RESULTS: The MEMS system proved to be the most informative technique allowing identification of the precise time of container opening, the demonstration of 'drug holidays' and early cessation of therapy. Self-report scores (Morisky) proved a useful screening technique with a sensitivity of 72.2% and specificity of 74.1% for > or = 80% compliance. Although tablet counts were possible in 84 patients (95. 5%) they were unreliable in 19 (21.6%). Blood concentration assays proved the least acceptable method to patients and were possible in only 53 (60.2%). A ratio of nordothiepin:dothiepin > or = 1.1 claimed, by others, to identify noncompliance was only reliable when concentrations were low. CONCLUSIONS: Both the MEMS system and self-report scores proved useful methods for identifying noncompliant patients in the setting of UK general practice. Although compliance was higher than reported in previous studies with 70 patients (79.5%) completing 6 weeks treatment, general practitioners tended to prescribe subtherapeutic doses.     

Reduced hypotensive effect of clonidine after lesions of the nucleus tractus solitarii in rats

Bilateral electrolytic lesion of the area of the nucleus tractus solitarii (NTS) in rats produced a sustained increase in blood pressure and reduced the hypotensive response to a single dose of clonidine (30 μg/kg, i.v.). The same dose of clonidine evoked a much larger drop in blood pressure in another group of rats in which an equivalent increase in blood pressure was produced by bilateral section of the vagosympathetic trunks and occlusion of both carotid arteries. It is concluded that the dorsal part of the medulla oblongata in the area of NTS is an important link in the hypotensive action of clonidine.     

A study of the effects of clonidine on the EEG in rats treated with single and multiple doses of antidepressants

The influence of repeated and single administrations of desipramine, amitryptiline, and mianserin on the EEG effects of clonidine has been investigated in rats implanted with chronic cortical electrodes. Clonidine induced a dose-dependent EEG synchronization in control animals. Signs of behavioral depression occurred after administration of moderate (0.1 mg/kg) and higher (0.2 mg/kg) doses of clonidine. Single doses of desipramine and amitryptiline attenuated the clonidine effect, while mianserine potentiated clonidine-induced synchronization. Antidepressants given once daily for 14 days completely (desipramine and amitryptiline) or partially (mianserin) reduced the effect of clonidine. Antidepressants alone produced only a slight effect on cortical EEG pattern.     

A reappraisal of the interaction between tricyclic antidepressants and reserpine-like drugs

The administration of tricyclic antidepressants followed by reserpine-like drugs elicits a pattern of stereotyped locomotor activity. Using desmethylimipramine (DMI) followed by tetrabenazine (TBZ), activity could be reliably elicited only in young rats, and only by using very high doses of TBZ. The latency of onset of activity was up to 5h. Animals rendered active by DMI-TBZ failed to perform a wellestablished operant task. The activity syndrome was apparently unaffected by pre- or posttreatment with the dopamine antagonists spiroperidol or pimozide, but partial antagonism was obtained with the noradrenaline antagonists phentolamine and phenoxybenzamine. The findings are discussed in relation to the mechanism of action of the effect and its relevance to the clinical action of tricyclic antidepressants.