Serotonin toxicity: a short review of the literature and two case reports involving Citalopram

The serotonin toxicity (ST) is a potentially life-threatening adverse drug reaction results from therapeutic drug use, intentional self-poisoning, or inadvertent interactions between drugs. ST can be caused by a single or a combination of drugs with serotonergic activity due to excessive serotonergic agonism on central nervous system and peripheral serotonergic receptors (monoamine oxidase inhibitors, tricyclic antidepressants, SSRIs, opiate analgesics, over-the-counter cough medicines, antibiotics, weight-reduction agents, antiemetics, antimigraine agents, drugs of abuse, H2-antagonist and herbal products). The serotonin toxicity is often described as a clinical triad of mental-status changes (agitation and excitement with confusion), autonomic hyperactivity (diaphoresis, fever, tachycardia, and tachypnea), neuromuscular abnormalities (tremor, clonus, myoclonus, and hyperreflexia) and, in the advanced stage, spasticity; not all of these findings are consistently present. In this article, we describe two cases of ST due to interaction between Citalopram and two CYP2D6 inhibitors: Cimetidine and Topiramate and their clinical resolution after treatment discontinuation.     

The effects of serotonergic and antiserotonergic drugs on the flexor reflex of spinal rat: a proposed model to evaluate the action on the central serotonin receptor

Summary The effects of serotonergic and antiserotonergic drugs on the hind limb flexor reflex (measured as a contraction of musculus tibialis anterior or as a flexion of the paw) in the spinal rat was studied. All serotonergic drugs used (L-5-hydroxytryptophan, L-tryptophan, LSD, fenfluramine, p-chloro-amphetamine) stimulate the flexor reflex. Serotonin receptor blockers (cyproheptadine, WA-335, methergoline), which given alone are inactive, inhibit the stimulation induced by serotonergic drugs but do not influence that one caused by noradrenergic agents (amphetamine, clonidine). Both types of stimulation (serotonergic and noradrenergic) are antagonized by noradrenaline receptor blockers (phenoxybenzamine, clozapine). The anti-serotonergic action of serotonin antagonists used was confirmed on the basis of the antagonism to the head twitches induced by L-5-hydroxytryptophan.The flexor reflex in the spinal rat may be a good model to evaluate the effect on the central (spinal cord) serotonin receptor and to differantiate this effect from that on the noradrenaline system.     

Psychopharmacologic strategies for the prevention of suicidal behavior in bipolar patients

Current pharmacological strategies for the prevention of the suicide behavior in bipolar patients are reviewed. Additionally, these studies are discussed in the context of a stress–diathesis model, to explore whether this model explains the empirical fact that some drugs appear to have antisuicidal properties while others do not. A review of the relevant literature suggests that lithium and serotonin enhancing antidepressants reduce suicidal behavior in bipolar patients. A stress–diathesis model explains the differential effect of such medications compared to other antidepressants or mood stabilizers by proposing additional effects of these medications on the diathesis for suicidal behavior. This effect may be mediated by augmentation of serotonergic function, which is linked to suicidal behavior. Serotonergic enhancing drugs therefore can potentially reduce suicidal behavior.     

Pharmacologic safety concerns in Parkinson's disease: facts and insights

Knowledge and insight of pharmacologic safety issues and drug interactions are important for medical management of Parkinson's disease (PD). This review will discuss several topics, including apomorphine safety and interactions, impulsivity and excessive daytime somnolence associated with dopamine agonists (DAs), tolcapone hepatotoxicity, and monoamine oxidase type-B (MAO-B) inhibitor drug interactions. Initiation of apomorphine requires antiemetic prophylaxis to minimize nausea and orthostatic hypotension. Centrally acting antidopaminergic antiemetics will worsen parkinsonism and block the therapeutic effects of apomorphine and should be avoided. Additionally, serotonin 5-HT(3) receptor antagonist antiemetics should be avoided on the basis of limited clinical data suggesting lack of efficacy for apomorphine-induced nausea. Dopamine-agonist-induced impulsivity and daytime somnolence are not uncommon. When severe, these effects can be disabling and unsafe. Tolcapone-induced hepatotoxicity has been significantly minimized with routine monitoring of liver enzymes, especially during the initial 6 months of therapy. Early detection of abnormal results will allow tolcapone discontinuation before progression to fulminant hepatotoxicity. In patients treated with selective MAO-B inhibitors, the risk of serotonin toxicity (ST) due to a concomitant serotonergic agent (e.g., antidepressants, dextromethorphan, serotonergic analgesics) or hypertensive crisis due to dietary tyramine or sympathomimetic amines appears to be minimal and is based on isolated case reports and overgeneralizations from nonselective MAO inhibitor pharmacology. Concerns about ST or hypertensive crisis should not preclude or restrict clinicians from using MAO-B inhibitors in patients with PD.     

Serotonin syndrome due to duloxetine

Serotonin syndrome is a toxic condition due to serotoninergic hyperstimulation, which is caused mostly by serotonergic agents either in overdose or in combination. The diagnosis is purely clinical and poorly validated. We described a patient with tremor, mydriatic pupils, clonus, and ataxia after a single dose of duloxetine; on the dosage of admission. Duloxetine belongs to a large class of antidepressants called reuptake inhibitors. The case is presented to emphasize this possible toxicity due to increasing availability of serotonergic agents. It is a complex but easily preventable and recognizable condition. We believe this to be one of the rare reports of serotonin syndrome associated with duloxetine.     

Comparative study of fluoxetine, sibutramine, sertraline and dexfenfluramine on the morphology of serotonergic nerve terminals using serotonin immunohistochemistry

We compared the effects of treatment with high doses of fluoxetine, sibutramine, sertraline, and dexfenfluramine for 4 days on brain serotonergic nerve terminals in rats. Methylenedioxymethamphetamine (MDMA) and 5,7-dihydroxytryptamine (5,7-DHT) were used as positive controls because both compounds deplete brain serotonin. Food intake and body weight changes were also monitored and yoked, pair-fed animals were used to control for possible changes in morphology due to nutritional deficits. Fluoxetine, sibutramine, sertraline and dexfenfluramine all produced a significant reduction in body weight. Fluoxetine, sibutramine and sertraline treatment resulted in no depletion of brain serotonin but produced morphological abnormalities in the serotonergic immunoreactive nerve network. In contrast, dexfenfluramine and MDMA depleted brain serotonin and produced morphological changes in the serotonin nerve network. These results indicate that even though fluoxetine, sibutramine and sertraline do not deplete brain serotonin, they do produce morphological changes in several brain regions (as identified by serotonin immunohistochemistry). Dexfenfluramine and MDMA, on the other hand, markedly deplete brain serotonin and also produce morphological changes. Collectively, these results lend support to the concept that all compounds acting on brain serotonin systems, whether capable of producing serotonin depletion or not, could produce similar effects on the morphology of cerebral serotonin systems.     

Risk of Suicidality in Depression with Serotonergic Antidepressants

Since depression is a risk factor for suicidal thoughts and behaviors, and since suicidal behaviors are associated with low serotonin activity, are selective serotonin reuptake inhibitors (SSRIs) more effective than other antidepressants in treating suicidality in depressed patients? There is inconclusive evidence for and against this hypothesis. However, all studies suggest that antidepressants are effective treatments of suicidal ideations and behaviors, and SSRIs have been shown to have prophylactic effects in preventing suicidal behaviors. Although some reports suggest that SSRIs might increase suicidal ideations and behaviors, the results of large, double-blind studies do not suggest a causal relationship between pharmacotherapy and the emergence of suicidality. Undertreatment of depression and therapeutic failure are more significant problems with the use of antidepressants in suicidal patients than the risk of using antidepressants in overdose. Prescribing inadequate doses of antidepressants is therefore a source of overlooked risk.     

The serotonergic and noradrenergic effects of antidepressant drugs are anticonvulsant, not proconvulsant

Contrary to existing evidence, convulsant liability of the antidepressants has been attributed to noradrenergic and serotonergic increments. This is a classic case of confusing treatment effects with the manifestations of illness. In fact, the remarkable anticonvulsant effectiveness of antidepressant-induced noradrenergic and serotonergic activation has been ignored. Some antidepressant drugs such as the specific serotonin reuptake inhibitor (SSRI) fluoxetine may be devoid of convulsant liability entirely, while having distinct anticonvulsant properties. Some authorities advance the notion that the seizure predisposition of patients with epilepsy increases risks for antidepressant-induced seizures. However, evidence does not support this contention. Instead, data increasingly support the concept that noradrenergic and serotonergic deficiencies contribute to seizure predisposition. Indeed, the antidepressants have the potential to overcome seizure predisposition in epilepsy. Whereas therapeutic doses of antidepressants elevate noradrenergic and serotonergic transmission, larger doses can activate other biological processes that may be convulsant.     

The serotonergic and noradrenergic effects of antidepressant drugs are anticonvulsant,not proconvulsant

Contrary to existing evidence, convulsant liability of the antidepressants has been attributed to noradrenergic and serotonergic increments. This is a classic case of confusing treatment effects with the manifestations of illness. In fact, the remarkable anticonvulsant effectiveness of antidepressant-induced noradrenergic and serotonergic activation has been ignored. Some antidepressant drugs such as the specific serotonin reuptake inhibitor (SSRI) fluoxetine may be devoid of convulsant liability entirely, while having distinct anticonvulsant properties. Some authorities advance the notion that the seizure predisposition of patients with epilepsy increases risks for antidepressant-induced seizures. However, evidence does not support this contention. Instead, data increasingly support the concept that noradrenergic and serotonergic deficiencies contribute to seizure predisposition. Indeed, the antidepressants have the potential to overcome seizure predisposition in epilepsy. Whereas therapeutic doses of antidepressants elevate noradrenergic and serotonergic transmission, larger doses can activate other biological processes that may be convulsant.     

Functional polymorphism within the promotor of the serotonin transporter gene is associated with severe hyperkinetic disorders

In children and adolescents, hyperkinetic disorder (HD) with conduct disorder (CD) and without CD and attention-deficit/hyperactivity disorder (ADHD) is known to be comorbid with psychiatric disorders (anxiety, depression, aggression), some of which are related to disturbed serotonergic neurotransmission. The efficiency of serotonergic signalling relates to the concentration of the neurotransmitter in the synaptic cleft and is controlled by the serotonin transporter (5-HTT), which selectively removes serotonin out of the synaptic cleft.(1)The activity of serotonin transport itself has been shown to be also controlled by a 5-HTT-linked polymorphism in its promotor region with a L/L genotype yielding higher levels of 5-HTT function than do L/S or S/S genotypes.(2) Considering an association between 5-HTT polymorphism, serotonergic neurotransmission and HD +/- CD, we genotyped for 5-HTT polymorphism and compared patients with controls. In contrast to the distribution of L/L: L/S: S/S in controls (0.245: 0.509: 0.245), we found an enhanced expression of the L/L genotype in HD patients with CD (0.393: 0.304: 0.304; chi(2) = 7.603; P = 0.0211) and a significant overexpression of L/L in HD without CD (0.542: 0.333: 0.125; chi(2) = 9.127; P = 0.0092). To our knowledge, this is the first finding providing evidence for an association between the 5-HTT polymorphism and hyperkinetic disorder, implying that serotonergic neurotransmission might be affected in this desease. As a consequence, for a successful treatment of these patients one should now also consider drugs which specifically modulate serotonergic signalling such as selective serotonin reuptake inhibitors.     

Qualitative review of serotonin syndrome, ecstasy (MDMA) and the use of other serotonergic substances: hierarchy of risk

Growth of the antidepressant market and widespread use of the illicit drug ecstasy (methylenedioxymethamphetamine; MDMA) creates a need to delineate the potential harms associated with the concomitant use of ecstasy and serotonergic pharmaceutical drugs. One such harm is serotonin syndrome. The study aimed to synthesize the risk of serotonin syndrome associated with the concomitant use of ecstasy and other serotonergic substances in a clinically relevant hierarchy for psychiatrists and other medical practitioners. An extensive online database search was carried out of the literature on serotonin syndrome, in relation to illicit drugs and simultaneous use of other substances. Numerous licit and illicit substances implicated in serotonin syndrome, when used with ecstasy, have potential for increased toxicity and are presented in a resulting hierarchy of risk. Substances that inhibit serotonin re-uptake are less likely to lead to life-threatening elevations in serotonin when used with ecstasy. High doses or repeated use of stimulants such as methamphetamine and cocaine with ecstasy increase the risk of serotonin syndrome; as does the use of pharmaceutical amphetamine and ecstasy. Serotonin precursors also influence the course of serotonin syndrome when used with ecstasy. Substances that inhibit monoamine oxidase are most likely to lead to serious increases in serotonin when used with ecstasy. Findings highlight the importance of screening for the use of ecstasy and other serotonergic substances when prescribing antidepressant drugs.     

Neuroleptic malignant syndrome: Mechanisms,interactions, and causality

This review focuses on new data from recent publications concerning how compounding interactions between different thermoregulatory pathways influence the development of hyperthermia and/or neuroleptic malignant syndrome (NMS), and the fundamental issue of the presumed causal role of antipsychotic drugs. The formal criteria for substantiating cause‐effect relationships in medical science, established by Hill, are applied to NMS and, for comparison, also to malignant hyperthermia and serotonin toxicity. The risk of morbidities related to hyperthermia is reviewed from human and experimental data: temperatures in excess of 39.5°C cause physiological and cellular dysfunction and high mortality. The most temperature‐sensitive elements of neural cells are mitochondrial and plasma membranes, in which irreversible changes occur around 40°C. Temperatures of up to 39°C are “normal” in mammals, so, the term hyperthermia should be reserved for temperatures of 39.5°C or greater. The implicitly accepted presumption that NMS is a hypermetabolic and hyperthermic syndrome is questionable and does not explain the extensive morbidity in the majority of cases, where the temperature is less than 39°C. The thermoregulatory effects of dopamine and acetylcholine are outlined, especially because they are probably the main pathways by which neuroleptic drugs might affect thermoregulation. It is notable that even potent antagonism of these mechanisms rarely causes temperature elevation and that multiple mechanisms, including the acute phase response, stress‐induced hyperthermia, drugs effects, etc., involving compounding interactions, are required to precipitate hyperthermia. The application of the Hill criteria clearly supports causality for drugs inducing both MH and ST but do not support causality for NMS. © 2010 Movement Disorders Society     

Delayed pharmacological effects of antidepressants

Although antidepressants may not be primary mood stabilizers, they are efficacious in the prophylaxis of recurrent depressive illnesses, as well as in the treatment of acute episodes. Pharmacological effects that may contribute to the prophylactic effects of these drugs are not understood. Studies have been carried out in which antidepressants have been given to laboratory animals, such as rats, for periods of up to 3-4 weeks. Data obtained in such studies are thought to be important for their beneficial effects in depressive episodes, but also may be relevant to their prophylactic effects. Results are presented showing that when selective inhibitors of serotonin or norepinephrine uptake are given for such time periods, they still produce selective effects on serotonergic or noradrenergic parameters. For example, long-term administration of selective norepinephrine reuptake inhibitors causes a down-regulation of beta(1) adrenoceptors. Selective serotonin reuptake inhibitors do not produce this effect. Long-term administration of selective serotonin reuptake inhibitors causes down-regulation of the serotonin transporter, but not the norepinephrine transporter. In contrast, selective norepinephrine reuptake inhibitors down-regulate the norepinephrine transporter but not the serotonin transporter. Substantial loss of serotonin transporter binding sites takes 15 days to occur and is accompanied by a marked reduction of serotonin transporter function in vivo.     

Prevalence,clinical features and treatment of depression in Parkinson’s disease: An update

Parkinson’s disease (PD) is one of the most prevalent neurodegenerative diseases which typically affects individuals over 65 years. Although the symptomatology is predominantly motor, neuropsychiatric manifestations, e.g., depression, apathy, anxiety, and cognitive impairment occur in the course of the illness and can have a great impact on the quality of life in these patients. Parkinson’s disease is commonly comorbid with depression with prevalence rates of depression, generally higher than those reported in general population. Depression in PD is frequently underestimated and consequently undertreated, which have significant effects on the quality of life in these patients. The neurobiology of depression in PD is complex and involves alterations in dopaminergic, serotonergic, noradrenergic and possibly other neurotransmitter systems which are affected in the course of the disease. The tricyclic antidepressants and the selective serotonin reuptake inhibitors are the two classes of antidepressant drugs used for depressive symptoms in PD. Several published studies suggested that both classes are of comparable efficacy. Other serotonergic antidepressants, e.g., nefazodone and trazodone have also been of benefit. Meanwhile, there are limited data available on other drugs but these suggest a benefit from the serotonin and noradrenaline reuptake inhibitors such as mirtazapine, venlafaxine, atomoxetine and duloxetine. Some of the drugs used in symptomatic treatment of PD, e.g., the irreversible selective inhibitors of the enzyme monoamine oxidase-B, rasagiline and selegiline as well as the dopamine receptor agonist pramipexole are likely to have direct antidepressant activity independent of their motor improving action. This would make these drugs an attractive option in depressed subjects with PD. The aim of this review is to provide an updated data on the prevalence, clinical features of depression in subjects with PD. The effects of antiparkinsonian and antidepressant drugs on depressive symptoms in these patients are also discussed.     

Platelet 3H-paroxetine binding to the serotonin transporter is insensitive to changes in central serotonergic innervation in the rat.

The serotonin transporter labeled in platelets by 3H-imipramine or 3H-paroxetine binding has been suggested to be a peripheral marker for changes in serotonin uptake in the brain that may be related to depression. The present study was designed to determine whether major changes in central serotonergic innervation modify the platelet serotonin transporter as labeled by 3H-paroxetine binding. Fifteen days after the intracerebroventricular administration of 5,7-dihydroxytryptamine (250 micrograms/animal) to rats to lesion central serotonergic neurons, serotonergic innervation was reduced by 82% in the cortex and 98% in the hippocampus as determined by endogenous serotonin levels. The maximum binding of 3H-paroxetine was reduced by 55% in the cortex and was undetectable in the hippocampus. Serotonin levels and 3H-paroxetine binding in platelets were not, however, significantly modified in the same animals. Thus, following a major serotonergic lesion in the brain, changes in the platelet serotonin transporter do not parallel serotonergic changes in the brain. The hypothesis that binding to the platelet serotonin transporter is a state-dependent marker of brain serotonergic activity therefore appears to be unlikely.     

Noradrenergic approaches to antidepressant therapy

A decade of remarkable research in neuroscience has given us a much more complete picture of how the central nervous system works and, in some instances, how the brain does not work when patients develop depression. Preclinical and clinical studies have shown that stimulation of the serotonergic system leads to noradrenergic effects and vice versa, confirming that the serotonin and norepinephrine systems are intimately connected in the central nervous system. Although medications that target the serotonergic neurotransmitter system have recently dominated antidepressant therapy, atypical antidepressants--with either mixed serotonergic and noradrenergic effects or exclusively noradrenergic effects--have been shown to be clinically efficacious medications. This increased understanding of the interrelationship between neurotransmitter systems has renewed interest in the role of neurotransmitters other than serotonin in the treatment of depression. With the introduction of reboxetine, a very selective norepinephrine reuptake inhibitor, researchers have had an opportunity to study the unique effects of norepinephrine in the etiology and treatment of depression. Ultimately, differences in neurotransmitter profiles may influence therapeutic potentials of antidepressants. For example, influencing norepinephrine may affect the expression of energy and interest, while influencing serotonin may affect impulse control and influencing dopamine may affect drive. Clinicians now have a range of antidepressants with variable neurotransmitter effects, different side effect profiles, and some interesting differences in functional utility in their armamentarium for treating depression.     

Drug treatment of obsessive-compulsive disorder

Knowledge of pharmacotherapeutic treatment options in obsessive-compulsive disorder (OCD) has grown considerably over the past 40 years. Serotonergic antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and clomipramine, are the established pharmacologic first-line treatment of OCD. Medium to large dosages and acute treatment for at least 3 months are recommended until efficacy is assessed. In case of significant improvement, maintenance treatment is necessary. Unfortunately, about half of the patients do not respond sufficiently to oral serotonergic antidepressants; augmentation with atypical antipsychotics is an established second-line drug treatment strategy. Alternatives include intravenous serotonergic antidepressants and combination with or switch to cognitive behavioral psychotherapy. Remarkably, a considerable proportion of OCD patients still do not receive rational drug treatment. Novel research approaches, such as preliminary treatment studies with glutamatergic substances, and trials with further drugs, as well as needed aspects of future research, are reviewed.     

A review of olanzapine-associated toxicity and fatality in overdose

OBJECTIVE: Given the increasing use of atypical antipsychotics in psychiatric populations and the very limited data concerning the safety of such drugs, we examined the available data on olanzapine in untreated overdose situations. METHODS: Available toxicity data concerning olanzapine were obtained from the Offices of the Medical Examiners of Canada, the Canadian Adverse Drug Reaction Monitoring Program and a review of the literature. RESULTS: Despite the complexities and limitations of postmortem data analysis, 29 deaths were identified where an overdose of olanzapine was either the principal cause of toxicity or a significant contributor in combined toxicity. CONCLUSIONS: Olanzapine is associated with toxicity in certain overdose situations, but evidence of any relation is limited and likely influenced by the higher rates of cardiovascular disease and sudden death in subjects with schizophrenia. RECOMMENDATIONS: Similar toxicity data reviews should be conducted for all commonly prescribed psychotropics. Early signal detection and effective notification processes are crucial in the event that serious adverse effects do occur.     

Distribution of serotonin-immunoreactive cell bodies and processes in the abdominal ganglion of mature Aplysia

Sensitization of the gill withdrawal reflex in Aplysia californica is an elementary form of learning, in part resulting from presynaptic facilitation of the LE mechanoreceptor neurons of the abdominal ganglion. It has previously been established that either application of serotonin or direct stimulation of a group of facilitatory neurons, the L29 cells of the abdominal ganglion, can simulate the effect of physiological stimulation in producing presynaptic facilitation. Because the evidence that serotonin serves as a facilitatory transmitter was indirect, we examined the distribution of serotonin-immunoreactive fibers and cell bodies in the abdominal ganglion in order to answer two questions: (1) do the sensory neurons receive serotonergic innervation and (2) are the L29 cells serotonergic? We observed two distinctive patterns of serotonergic innervation within the ganglion, sparse and dense. The sparse pattern is correlated with a serotonin-stimulated increase in cAMP in identified target cells, while the dense innervation is not. We found a sparse distribution of serotonin-immunoreactive fibers with varicosities close to both cell bodies and processes of identified LE sensory cells. It therefore is likely that the sensory neurons do receive serotonergic innervation. We also mapped the population of serotonergic neuronal cell bodies in the ganglion, and found five clusters of neurons. Cells in one of these clusters, the identified RB neurons, had previously been shown to synthesize serotonin from tryptophan and to contain the neurotransmitter in high concentration. Identified L29 facilitator cells marked by injection with Lucifer Yellow do not contain serotonin immunoreactivity and therefore evidently are not a source of serotonergic input onto sensory cells.     

Acute iboga alkaloid effects on extracellular serotonin (5-HT) levels in nucleus accumbens and striatum in rats

The iboga alkaloid, ibogaine, its metabolite, noribogaine, and the congener, 18-methoxycoronaridine (18-MC) have all been claimed to have anti-addictive properties in animal models, but the mechanisms underlying these effects are unclear. Ibogaine and noribogaine were shown to have affinity for the serotonin transporter, and inhibition of serotonin reuptake has been proposed to be involved in their anti-addictive actions. It is not known yet if 18-MC also has this property. In vivo microdialysis and HPLC (microbore) were used to determine acute changes in extracellular serotonin levels in nucleus accumbens (NAC) and striatum (STR) after both i.p. (40 mg/kg for all drugs) and i.v. (1–10 mg/kg for ibogaine and noribogaine) drug administration in awake freely moving female Sprague–Dawley rats (250–275 g). After i.p. administration, ibogaine, noribogaine and 18-MC had very different effects on extracellular serotonin levels in both NAC and STR: ibogaine elicited large increases (up to 25-fold in NAC and 10- fold in STR), noribogaine produced moderate increases (up to 8-fold in NAC and 5-fold in STR), and 18-MC had no effect in either brain region. These and other data suggest that (1) the serotonergic system may not be an essential factor in the anti-addictive actions of these drugs; (2) ibogaine (or an unidentified metabolite) may release serotonin as well as inhibit its reuptake; (3) stimulation of the ascending serotonergic system may mediate ibogaine's hallucinogenic effect; and (4) 18-MC probably has no affinity for the serotonin transporter, and is unlikely to be a hallucinogen.