A calcium antagonist for the treatment of depressive episodes: Single case reports

doi:10.1016/0022-3956(94)00047-U

Journal of Psychiatric Research

Volume 29, Issue 1, January–February 1995, Pages 71-76

https://doi.org/10.1016/0022-3956(94)00047-U Get rights and content

Abstract

Preclinical studies indicate that a disturbed intracellular calcium ion homeostasis is involved in the pathophysiology of affective disorders. Therefore some calcium antagonists were investigated, especially in the treatment of the manic syndrome. In the present study the calcium antagonist nimodipine was used in 10 out-patients with single or recurrent depressive episodes. As a result the mean HAMD scores changed from 26.5 to 9.9 after the individual nimodipine administration. These single case reports suggest an effective new therapy strategy for the treatment of affective dysregulations and give rise to controlled clinical studies with calcium antagonists.

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Antidepressant-like and memory-enhancing effects of the N-type calcium channel blocker ziconotide in rats
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The influx of calcium into neurons and excessive glutamate release can exacerbate depressive symptoms [7]. Improved outcomes were observed when administering the calcium channel antagonists nimodipine and verapamil to patients suffering from major depression or bipolar manic-depressive disorders [8,9]. In addition, we previously reported that both single and long-term intrathecal administrations of ziconotide improved calcium-related neuropathological changes and attenuated memory impairments in a rat model of morphine withdrawal [10,11].
The lack of oral or injectable formulations of ziconotide (ω-conotoxin peptide), a novel analgesic agent, limits research on potential neurobehavioral protective properties of this substance, including antidepressant-like effects. Here we expose rats to a stress paradigm that induces depression and memory impairment to assess the effects of ziconotide treatment. Ziconotide was administered intracerebroventricular (i.c.v.) to rats undergoing stereotaxic surgery at a single dose (1 μg/rat) or in repeated long-term applications (dosage groups: 0.1, 0.3, and 1 μg/rat). The antidepressant activity and memory-enhancing effects of ziconotide were examined via the forced swimming test, the Morris water maze test, and the passive avoidance learning test. Behavioral results showed that long-term i.c.v. ziconotide administration significantly decreased the immobility time and delayed the latency period to immobility in a dose-dependent manner compared to controls. In the passive avoidance learning test, the latency period increased, and in the Morris water maze test, the platform location latency time decreased. A single dose of ziconotide (1 μg/rat) did not show a significant effect on memory function or depression parameters during the same tests. Animals were sacrificed immediately after behavioral testing, and both hippocampi were removed and prepared for BDNF evaluation. Hippocampal BDNF levels were significantly increased in rats receiving long-term i.c.v. ziconotide compared to controls. Our results suggest that long-term consumption of ziconotide may attenuate the severity of depression-like behavior and could be useful for preventing memory impairments in various learning models by elevating BDNF levels.
Dextromethorphan and Dextrorphan as Heuristic Rapid-Acting, Conventional, and Treatment-Resistant Antidepressants, with Substance Abuse Considerations
2016, Neuropathology of Drug Addictions and Substance Misuse Volume 3: General Processes and Mechanisms, Prescription Medications, Caffeine and Areca, Polydrug Misuse, Emerging Addictions and Non-Drug Addictions
Dextromethorphan (DM) and its metabolite dextrorphan (DO) are pharmacodynamically similar to the antidepressant ketamine and have been hypothesized to possess rapid-acting (RA), conventional (C), and treatment-resistant (TR) antidepressant properties (Lauterbach, 2011, Lauterbach, 2012). DM and DO share N-methyl-d-aspartate (NMDA) (RA, C, TR), phencyclidine (RA, C, TR), NMDA-2A (RA, C) receptor antagonism, sigma-1 (σ₁) stimulation (RA, C, TR), mu (μ) potentiation (RA, TR), serotonin-1b/d binding (C, TR), serotonin (RA, C, TR) and norepinephrine (C, TR) transporter inhibition, calcium channel antagonism (C, TR), activation of mammalian target of rapamycin, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, denditogenesis, and synaptogenesis (RA), while DM demonstrates NMDA-2B downregulation (RA, C, TR) and α₂ adrenergic receptor binding (C, TR), whereas DO shows μ antagonism (RA, C) and muscarinic and β-adrenergic receptor binding (RA, C, TR). Case reports of DM-induced mania and improved treatment-resistant depression exist. A clinical trial in treatment-resistant depression is in progress. Clinical considerations in administering DM or DO, including in substance disorders (e.g., alcohol, heroin), are discussed.
Dextromethorphan as a potential rapid-acting antidepressant
2011, Medical Hypotheses
Citation Excerpt :
The sigma-1 receptor is related to major depression pathophysiology [41,42], and to antidepressant response [41] in animal models of depression [43,44] and in psychotic major depression [45,46]. The only case series of calcium channel blocker treatment of major depression revealed a clinically substantial antidepressant activity of nimodipine, with a 63% decline in Hamilton depression scores; all 10 subjects improved, with half achieving full remission [47]. The relation between serotonin transporter blockade and antidepressant activity is well known, especially in regard to selective serotonin reuptake inhibitors.
Dextromethorphan shares pharmacological properties in common with antidepressants and, in particular, ketamine, a drug with demonstrated rapid-acting antidepressant activity. Pharmacodynamic similarities include actions on NMDA, μ opiate, sigma-1, calcium channel, serotonin transporter, and muscarinic sites. Additional unique properties potentially contributory to an antidepressant effect include actions at ß, alpha-2, and serotonin1b/d receptors. It is therefore, hypothesized that dextromethorphan may have antidepressant efficacy in bipolar, unipolar, major depression, psychotic, and treatment-resistant depressive disorders, and may display rapid-onset of antidepressant response. An antidepressant response may be associated with a positive family history of alcoholism, prediction of ketamine response, increased AMPA–to–NMDA receptor activity ratio, antidepressant properties in animal models of depression, reward system activation, enhanced erythrocyte magnesium concentration, and correlation with frontal μ receptor binding potential. Clinical trials of dextromethorphan in depressive disorders, especially treatment-resistant depression, now seem warranted.
Neurotransmitters and signal transduction processes in bipolar affective disorders: A synopsis
2001, Journal of Affective Disorders
New technologies have led to tremendous progress in understanding what today we call bipolar disorders, whose clinical diagnosis has been refined continuously since Kraepelin first described them. Molecular genetic studies have produced interesting findings, but to date have failed to identify specific genes that are so far responsible for the vulnerability to bipolar disorders. Biochemical studies in combination with pharmacotherapy give hints that the neurotransmitter function and the related signal transduction may be abnormally regulated. Since all the neurotransmitter circuits are interconnected, the dysregulation may occur on different levels and it is rather improbable that one single abnormality should account for the disorder. This paper reviews these promising developments.
Effects of (±)-kavain on voltage-activated inward currents of dorsal root ganglion cells from neonatal rats
1999, European Neuropsychopharmacology
Kava pyrones extracted from pepper Piper methysticum are pharmacologically active compounds. Since kava pyrones exhibit anticonvulsive, analgesic and centrally muscle relaxing properties, the influence of a synthetic kava pyrone, (±)-kavain, on voltage-dependent ion channel currents was studied. Effects of (±)-kavain on voltage-activated inward currents were analysed in cultured dorsal root ganglion cells derived from neonatal rats. Voltage-activated Ca²⁺ and Na⁺ currents were elicited in the whole-cell configuration of the patch clamp technique. Extracellularly applied (±)-kavain dissolved in hydrous salt solutions reduced voltage-activated Ca²⁺ and Na⁺ channel currents within 3–5 min. As the solubility of (±)-kavain in hydrous solutions is low, dimethyl sulfoxide (DMSO) was added to the saline as a solvent for the drug in most experiments. When (±)-kavain was dissolved in DMSO, the drug induced a fast and pronounced reduction of both Ca²⁺ and Na⁺ currents, which partly recovered within 2–5 min even in the presence of the drug. The present study indicates that (±)-kavain reduces currents through voltage-activated Na⁺ and Ca²⁺ channels.
Effects of the atypical antidepressant trimipramine on field potentials in the low Mg<sup>2+</sup> -model in guinea pig hippocampal slices
1998, European Neuropsychopharmacology
Trimipramine has been classified as an atypical tricyclic antidepressant, because only weak inhibitory effects on serotonin and/or noradrenaline reuptake have been found. Since some antidepressive drugs (e.g. imipramine) and other agents used in the treatment of affective disorders (e.g. carbamazepine) modulate neuronal calcium channels, trimipramine was tested on field potential changes (fp) in the low Mg²⁺-model of epilepsy which has been shown to be affected by calcium antagonists. Trimipramine reduced the frequency of occurrence of fp in a dose dependent manner (5–100 μM). The threshold concentration of trimipramine which did not decrease the firing rate was approximately 1 μM. Simultaneous application of subthreshold concentrations (2 μM) of the organic calcium antagonist verapamil with trimipramine decreased the firing rate to 37.0±22.7% (means±SEM, n=7) with respect to baseline values. In contrast, no additive effects of N-methyl-d-aspartate antagonists and trimipramine were observed. In conclusion, the data suggests that the antidepressive effects observed with trimipramine treatment may be due to its inhibitory action on neuronal calcium channels.

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Short reportA calcium antagonist for the treatment of depressive episodes: Single case reports

Abstract

Biological Psychiatry

Psychiatry Research

European Neuropsychopharmacology

Open trial of a calcium antagonist, nimodipine, in acute mania

Clinical Neuropharmacology

Imipramine's selective suppression of an L-type calcium channel in neurons of murine dorsal root ganglia involves G proteins

Journal of Pharmacology and Experimental Pheraperitics

Calcium antagonists in manic depressive illness

Neuropsychobiology

The pharmacology of verapamil V. Tissue distribution of verapamil and norverapamil in rat and dog

Pharmacology

Short report
A calcium antagonist for the treatment of depressive episodes: Single case reports