ORIGINAL ARTICLES

PSYCHIATRIC SEQUELÆ OF CHRONIC EXPOSURE TO ORGANOPHOSPHORUS INSECTICIDES

Intentional and accidental organophosphorus exposures pose a significant healthcare-related burden on South African communities. This study will review the demographics, characteristics and clinical course of patients presenting with features of acute organophosphorus toxicity to a regional Emergency Centre in Johannesburg, South Africa.

This was a retrospective chart review of all patients treated for possible acute organophosphorus toxicity from January 2020 to August 2021.

A total of 205 patients were identified of which 134 patients were included in the study. The median age was 26 years with a male predominance (male= 56%, female=44%). 109 patients (81.3%) survived, 18 patients (13.4%) demised and the outcome of 7 patients (5.2%) was unknown. The median hospital length of stay was 8 days, (IQR= 5-13 days), and the longest hospital stay was 37 days in ICU. Atropinisation dose was significantly higher for intubated patients (median=140.0mg; IQR=90mg-219.5mg) compared to patients who were not intubated (median=60mg; IQR=20.5mg-120mg, p < 0.05). The length of stay was significantly higher for intubated patients (median=11 days; IQR=7-15 days) compared to patients who were not intubated (median=5 days; IQR=3-8 days, p < 0.00). There was a moderate positive correlation between atropinisation dose and length of stay (Correlation coefficient = 0.37, p < 0.00). There was a moderate negative correlation between atropinisation dose and cholinesterase level (Correlation coefficient= - 0.39, p < 0.00). Of those reported to have adverse effects 78.6%, were related to atropine toxicity.

Our study shows a high mortality rate secondary to organophosphorus toxicity. Significant exposures and thus higher doses of atropine were associated with increased length of stay and need for intubation. We found a high incidence of atropine-related adverse effects. More studies are needed to further establish the balance between the therapeutic and adverse effects of high-dose atropine as a treatment modality for organophosphorus toxicity.

Increasing evidence has implicated the cholinergic system as a modulator of mood episodes, with possible involvement of nicotinic and/or muscarinic receptors. A number of randomized controlled trials (RCTs) have demonstrated a putative rapid antidepressant effect of the muscarinic antagonist scopolamine. Here, we review the clinical evidence regarding the three principal muscarinic-modulating agents administered in studies involving mood disorders: scopolamine, biperiden and physostigmine. We conduct a meta-analysis on RCTs where these agents were administered to participants experiencing a depressive episode.

A systematic bibliographic search of Medline, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies utilizing the above agents was conducted between January 1970 and December 2020. A meta-analysis was subsequently performed on 9 studies which satisfied inclusion criteria, including 322 participants.

Administration of scopolamine significantly reduced depressive symptoms compared to placebo, as measured by objective mood rating scales with SMD of -0.95 (95% CI -1.49, -0.42, p = 0.0005). This effect increased to -1.13 (95% CI -1.61, -0.66, p < 0.00001) when scopolamine was administered intravenously. Biperiden displayed no significant antidepressant effect. A systematic review noted anergia and an exacerbation of depressive symptomatology following physostigmine administration, but no obvious anti-manic effect.

There were a relatively small number of RCTs suitable for meta-analysis. 2 studies included patients enrolled in previous trials. Heterogeneity in study design examining physostigmine prevented meta-analysis for this agent.

This study suggests that scopolamine may be a potential rapid-acting and efficacious antidepressant agent. Further adequately statistically powered RCTs should be conducted in participants experiencing depressive episodes in the context of major depressive and bipolar disorder to further elucidate any potential treatment and side effects.

Approved pharmacological treatments for bipolar disorder (BD) include conventional mood stabilizers and antipsychotic medications. Pharmacological interventions remain the mainstay of BD treatment; however, clinical outcomes remain unacceptably poor with high rates of relapse, treatment resistance, persistent functional impairment, suicidality, and decreased life expectancy. Therefore novel pharmacological treatments are urgently needed. New interventions may target novel neurotransmitter systems (e.g., outside of serotonin, norepinephrine, dopamine, and GABA), such as glutamate, opioid, circadian rhythm, and cholinergic systems. Of these, modulation of the glutamate system has shown the most promise with ketamine demonstrating rapid and robust antidepressant effects in bipolar and unipolar depression. Nonneurotransmitter systems have also been targeted, with emerging and converging evidence implicating inflammation, oxidative stress, abnormal insulin signaling, and the gut-microbiota in the pathophysiology of BD. Antiinflammatory agents have been particularly promising; however, clinical trial results have been mixed. Subgrouping and sample stratification will likely be key strategies for effectively developing future novel interventions, matching the treatment target with underlying pathophysiology on an individual patient level.

Depression is extremely harmful to modern society. Despite its complex spectrum of symptoms, previous studies have mostly focused on the monaminergic system in search of pharmacological targets. However, other neurotransmitter systems have also been linked to the pathophysiology of depression. In this study, we provide evidence for a role of the cholinergic system in depressive-like behavior of female mice. We evaluated mice knockdown for the vesicular acetylcholine transporter (VAChT KD mice), which have been previously shown to exhibit reduced cholinergic transmission. Animals were subjected to the tail suspension and marble burying tests, classical paradigms to assess depressive-like behaviors and to screen for novel antidepressant drugs. In addition, brain levels of serotonin and dopamine were measured by high performance liquid chromatography. We found that female homozygous VAChT KD mice spent less time immobile during tail suspension and buried less marbles, indicating a less depressive phenotype. These differences in behavior were reverted by central, but not peripheral, acetylcholinesterase inhibition. Moreover, female homozygous VAChT KD mice exhibited higher levels of dopamine and serotonin in the striatum, and increased dopamine in the hippocampus. Our study thus shows a connection between depressive-like behaviors and the cholinergic system, and that the latter interacts with the monoaminergic system.

Psychiatry and psychology are beginning to recognize the importance of lead, mercury and heavy metals as causal partners in the development of mental disorders. Further, mental health researchers and clinicians are embracing the idea that the combined effects of genetics and environmental exposures can result in perturbations in brain neurochemistry leading to psychiatric disorders. The purpose of this review is to examine the biological foundations for the epidemiological observations previously identified by reviewing the toxicology literature and relating it to epidemiological studies addressing the role of poisoning with organophosphate pesticides (OPs) in neurobehavioral and neuropsychological disorders. The goal of this review is to raise awareness in the mental health community about the possibility that affective disorders might be the result of contributions from environmental and occupational pesticide poisoning.

Recent studies revealed a causal link between ventral tegmental area (VTA) phasic dopamine (DA) activity and pro-depressive and antidepressant-like behavioral responses in rodent models of depression. Cholinergic activity in the VTA has been demonstrated to regulate phasic DA activity, but the role of VTA cholinergic mechanisms in depression-related behavior is unclear. The goal of this study was to determine whether pharmacological manipulation of VTA cholinergic activity altered behavioral responding in the forced swim test (FST) in rats. Here, male Sprague-Dawley rats received systemic or VTA-specific administration of the acetylcholinesterase inhibitor, physostigmine (systemic; 0.06 or 0.125 mg/kg, intra-cranial; 1 or 2 μg/side), the muscarinic acetylcholine receptor (AChR) antagonist scopolamine (2.4 or 24 μg/side), or the nicotinic AChR antagonist mecamylamine (3 or 30 μg/side), prior to the FST test session. In control experiments, locomotor activity was also examined following systemic and intra-cranial administration of cholinergic drugs. Physostigmine administration, either systemically or directly into the VTA, significantly increased immobility time in FST, whereas physostigmine infusion into a dorsal control site did not alter immobility time. In contrast, VTA infusion of either scopolamine or mecamylamine decreased immobility time, consistent with an antidepressant-like effect. Finally, the VTA physostigmine-induced increase in immobility was blocked by co-administration with scopolamine, but unaltered by co-administration with mecamylamine. These data show that enhancing VTA cholinergic tone and blocking VTA AChRs has opposing effects in FST. Together, the findings provide evidence for a role of VTA cholinergic mechanisms in behavioral responses in FST.