The presence of affective symptoms in panic disorder has often been reported. Data from The Cross-National Collaborative Panic Study (second phase) were analysed to address the role of dysthymia in panic disorder with respect to previous illness, current psychopathology and the outcome during an 8-week study of alprazolam and imipramine. A group of dysthymic patients without current or past major depressive episode was studied. The prevalences of dysthymia varied markedly across participating sites: 2–13%. Only a few clinical characteristics of dysthymic panic disorder patients were found. They had suffered from panic disorder for a few years more than patients without affective disorder and they were slightly older. The outcome after the 8-week drug trial was not significantly different from that of patients without affective disorder. Hence, dysthymia was not suggested to be of major clinical relevance for the phenomenology of panic disorder or for the outcome of drug treatment.

Calcium channel blockers increase the capacity of the urinary bladder. The antienuretic activity of verapamil was examined in young adult enuretics. Eleven drug-free, healthy, sleep-related enuretic males, were treated for two weeks with verapamil (240 mg, per os, at 9 pm). Verapamil failed to display an antienuretic effect.

In the course of the international development of tianeptine (T), depressed patients were recruited by 15 centres from Belgium, Italy, Portugal, Spain and Switzerland in a double-blind parallel group study versus placebo (P) and imipramine (I). Efficacy and safety of tianeptine are evaluated in the treatment of major depressions (single episode or recurrent) and depressed bipolar disorders. The initial severity of the depression is controlled by a MADRS score equal to or greater than 25. Rapid placebo responded are excluded during a placebo pre-inclusion period (duration: 1 week). After an increasing daily dose period (3 days), depressed patients are treated, until the 14th day (D14), at a constant daily dose (T: 37.5 mg; I: 150 mg; P: 3 capsules). After D14 and until the end of the 6th week, a flexible dosage can be used in accordance with the therapeutic efficacy and/or the potential adverse events (T: 25–50 mg; I: 100–200 mg; P: 2–4 capsules). The antidepressant efficacy is regularly evaluated by rating scales (MADRS, HSCL). Anxiety linked to depression is evaluated by the Hamilton Anxiety Rating Scale. The safety is controlled by clinical examination, laboratory parameters and a check-list of side-effects. Preliminary results are presented and discussed showing the interest of surveillance of trials in progress.

Stress elicits adaptive responses from the brain, but it can also lead to maladaptive consequences. For example, stress can precipitate mental illness, including depression. Prolonged stress also causes damage to neurons in the hippocampus. Antidepressant drugs must be evaluated, not only for their ability to potentiate adaptive responses, but also to inhibit maladaptive consequences of stress. Ongoing research in our laboratory has compared the atypical tricyclic antidepressant, tianeptine, with the typical tricyclics, desipramine and imipramine, with respect to the effects of isolation and repeated restraint stress. Tianeptine and desipramine similarly attenuated isolation stress-induced increases in locus coeruleus and midbrain tyrosine hydroxylase mRNA levels and isolation-stress induced decreases in preproenkephalin mRNA levels in striatum and nucleus accumbens. However, tianeptine and imipramine differed in their effects in the cerebral cortex and hippocampus on 5HT2, and 5HT1A receptor levels but, surprisingly, produced similar effects on levels of the serotonin transporter labelled with [3H] paroxetine. Tianeptine also prevented stress-induced reductions in the length and number of branchpoints of dendrites of CA3 pyramidal neurons in hippocampus; comparison with effects of typical tricyclics are ongoing. Tianeptine also blocked effects of corticosterone treatment to reduce branching and length of CA3 dendrites. These actions of tianeptine may be due to interactions between 5HT and excitatory amino acids in the mossy fiber terminals on CA3 pyramidal neurons. Taken together, these results indicate that tianeptine has unique properties compared to some other antidepressant drugs, but shares in common with those drugs the ability to attenuate stress effects on tyrosine hydroxylase gene expression and on the serotonin transporter. It remains to be seen whether these actions are the basis of a common antidepressant action.

Two cases of bipolar psychosis presented a rapid manic switch following administration of tricyclic antidepressants. In both cases the oxidation capacity was genetically deficient. The role of oxidation deficit is discussed in the pathogenesis of switch process and preventive measures are considered.

This case report describes a patient on tranylcypromine who erroneously received a single dose of imipramine and subsequently developed a fatal serotonin syndrome. Both the clinical features and the pathophysiology of the serotonin syndrome are discussed.

In the course of the international development of tianeptine (T), depressed patients were recruited by 18 centres from Belgium, Italy, Mexico, Portugal, Spain and Switzerland in a double-blind parallel group study versus placebo (P) and imipramine (I). Efficacy and safety of tianeptine were evaluated in 187 depressed inpatients (56% female, 44% male), who fulfilled criteria for either major depression, single episode (24.6%) or recurrent (66.8%), or depressed bipolar disorder (8.6%). After a seven-day run-in placebo pre-inclusion period, patients were treated in double-blind conditions with tianeptine (37.5 mg/d) or imipramine (150 mg/d) or placebo for 14 days, including an increasing daily dose period of three days. After the fourteenth day and until the end of the sixth week of treatment, a flexible dosage was introduced in accordance with the therapeutic efficacy and/or the potential adverse events (T: 25–50 mg/d; I: 100–200 mg/d; P; 2–4 capsules). Discontinuation of treatment occurred in 57 patients (30.5%) with more inefficacy on placebo and tianeptine (P: 16/23; T: 11/17; I: 7/17), and more side-effects on imipramine (P: 1/23; T: 1/17; I: 7/17). Final MÅDRS scores in intention-to-treat analysis were 22.3 ± 1.5, 17.3 ± 1.6 and 18.4 ± 1.5 for placebo, tianeptine and imipramine, respectively. Statistical analysis demonstrated the antidepressive efficacy of tianeptine and imipramine versus placebo (P = 0.012 and P = 0.034, respectively), and no difference between tianeptine and imipramine. In patients treated for 42 days (n = 129) the MÅDRS scores dropped from 62.3% on tianeptine, 54.2% on imipramine and 48.5% on placebo. These results confirmed the efficacy of tianeptine (37.5 mg/d) in the treatment of major depression and depressed bipolar disorder when compared to placebo. No difference was found between tianeptine and imipramine (150 mg/d) for the efficacy and between tianeptine and placebo for all safety criteria. The following adverse events were significantly more frequent with imipramine than with tianeptine or placebo: dry mouth (P < 0.001), constipation (P = 0.007), and hot flushes (P = 0.011). No difference in adverse events was found between tianeptine and placebo. While the usual cardiovascular signs of tricyclic antidepressants were observed in the imipramine group, no difference between tianeptine and placebo was shown in respect to heart rate or blood pressure (supine or standing). The assessment of haematological, renal, metabolic and hepatic parameters confirmed the safety of tianeptine.

Atypical depression differs from typical (endogenomorphic) depression not only in terms of the primary determinant, mood reactivity, but also by the presence of at least one of four atypical symptoms, hyperphagia, hypersomnia, rejection sensitivity and leaden paralysis. In addition to the differential therapeutic response reported by various authors, these two types of depression can be differentiated by various biological measures including the dexamethasone suppression test, tyramine excretion following loading, REM latency, etc. A series of studies comparing phenelzine with imipramine and placebo in subgroups of atypical depressives showed better results with the tricyclic than with placebo; however phenelzine consistently gave the best results in this type of depression. The hypothesis is advanced that the difference between typical and atypical classes of depression could be accounted for by the loss of the ability to experience both “anticipatory” or “consummatory” pleasure in typical depression, but only anticipatory pleasure in atypical depression.

A novel theory on the pathophysiology of depression would be expected to resolve a contradiction between therapeutic time lag and monoamine hypothesis. On the basis of the fact that a subgroup of depression appears during or after stress, we exposed rats to a long-term (2 weeks) forced walking stress and produced depression-model rats in one group and spontaneous recovery rats in another. The density of axon terminals of the locus coeruleus (LC) neurons in the frontal cortex stained by dopamine β-hydroxylase antiserum was lower in the depression-model rats than in the spontaneous recovery rats and in the control rats without stress. The density was higher in the model rats daily treated with imipramine than in those treated with saline. Morphological projection (MP) index (a percentage of horseradish peroxidase-positive LC cells in total number of LC cells) and electrophysiological projection index (a percentage of LC neurons activated antidromically by electrical stimulation of the cerebral cortex) were lower in the depression-model rats than in the recovery and control rats. MP index was higher in the imipramine-treated rats than that in the saline-treated rats. Electron microscopic examination of the LC disclosed such degenerative changes as low-dense areas without structure, aggregation of intracellular organs, destroyed membranes around the rough endoplasmic reticulum (rER), a decreased number of deformed subsurface cisterns, glia invaginated into the LC neurons and prominent appearance of microglia containing increased number of lipofustin or lysosome in the model rats, but not in the spontaneous recovery rats. These findings suggest that the terminals and cell bodies of the LC noradrenergic neurons degenerate in the stress-induced depression-model rats and regenerate in the imipramine-treated model rats. This degenerative change may possibly contribute to the decrease in synthesis and metabolism of noradrenaline (NA), the slowing of axonal flow, the accumulation of NA in the neurons, the decrease in discharge rate of LC neurons without stress and the increase in release of NA in response to an additional stress. It may also explain the therapeutic time lag that is required to repair the noradrenergic neurons.

Réus GZ, Stringari RB, Ribeiro KF, Luft T, Abelaira HM, Fries GR, Aguiar BW, Kapczinski F, Hallak JE, Zuardi AW, Crippa JA, Quevedo J. Administration of cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala.

Objective: Cannabidiol is a chemical constituent from Cannabis sativa and it has multiple mechanisms of action, including antidepressant effects. The main objective of the present study was to evaluate behavioural and molecular effects induced by administration of cannabidiol and imipramine in rats.

Methods: In the present study, rats were acutely or chronically treated for 14 days once a day with saline, cannabidiol (15, 30 and 60 mg/kg) or imipramine (30 mg/kg) and the animals behaviour was assessed in forced swimming and open-field tests. Afterwards, the prefrontal cortex, hippocampus and amygdala brain-derived neurotrophic factor (BDNF) levels were assessed by enzyme-linked immunosorbent sandwich assay.

Results: We observed that both acute and chronic treatments with imipramine at the dose of 30 mg/kg and cannabidiol at the dose of 30 mg/kg reduced immobility time and increased swimming time; climbing time was increased only with imipramine at the dose of 30 mg/kg, without affecting locomotor activity. In addition, chronic treatment with cannabidiol at the dose of 15 mg/kg and imipramine at the dose of 30 mg/kg increased BDNF levels in the rat amygdala.

Conclusion: In conclusion, our results indicate that cannabidiol has an antidepressant-like profile and could be a new pharmacological target for the treatment of major depression.

Objective: The blood platelet has been proposed as a model of central neurons and may therefore be used as a peripheral marker of psychiatric illness. One method of investigating serotonin function in panic disorder has relied on the use of the platelet as a model of serotonergic neurons. This article reviews the studies of platelet function in panic disorder.

Method: A literature search and review of relevant papers was undertaken.

Result: Studies examining platelet serotonin uptake and concentration in panic disorder patients have to date yielded conflicting results, with some investigators reporting increased serotonin uptake, others reduced uptake. Similarly studies of platelet 3H-imipramine binding have also yielded conflicting results. Two studies of platelet 3H-paroxetine binding have shown a reduction in the density of binding sites (Bmax) in patients with panic disorder. Platelet monoamine oxidase activity in anxiety disorders has been reported to be increased by some investigators but decreased by others. Methodological considerations may have been responsible for these differences. Finally, studies of α2 adrenoceptor density have also produced contrasting findings.

Conclusion: The findings of these studies indicate that platelet function is altered in panic disorder. Such changes may allow an insight into the biochemical aetiology of the illness. Further studies are required to delineate the role of serotonin and non-adrenaline in panic disorder.

We studied the relationship of blood and brain levels of imipramine (IMI) and/or its active metabolite desipramine (DMI) to behavioural response, in the tail suspension test (TST). Compared to the control group, doses of 3.75, 7.5, 15, 30 and 60 mg/kg of IMI given intraperitoneally reduced immobility scores significantly. There were significant negative correlations between doses, brain levels of IMI, DMI, IMI + DMI, blood levels of IMI, DMI, IMI + DMI and the animal behaviour. Higher level of IMI and its metabolite in brain and in blood did not impair anti-immobility effect. These findings agree with most results found in men treated with IMI, and suggest a linear or sigmoid relationship between the antidepressant concentrations and its biological response.

Part I of this paper presents a comprehensive review of plasma level monitoring of tricyclic antidepressants (TCAs) and their relationship to clinical response to antidepressant therapy. Imipramine, nortriptyline, amitriptyline, clomipramine and desipramine are the most widely studied TCAs in this regard. Typical therapeutic plasma concentration ranges are suggested for some of these agents, although a consensus is lacking.