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This article explores the clinical implications of withdrawal syndromes associated with antidepressant drugs. The author shares their own clinical observations and proposes an oppositional model of tolerance to explain the loss of treatment effectiveness and the occurrence of side effects over time. The article also discusses the phenomenon of withdrawal syndromes during the tapering and discontinuation of antidepressants, emphasizing the need for personalized approaches and the potential for severe and persistent symptoms. The author suggests the use of clonazepam, a medication with neuroprotective properties, to support patients during this phase, and highlights the importance of self-therapy and psychotherapeutic strategies in the discontinuation process. The author calls for further research on the behavioral toxicity of antidepressant medications and emphasizes the importance of individualized treatment approaches. [Extracted from the article]

The marijuana legalization trend in the U.S. will likely lead to increased use by younger adults during gestation and postpartum. The current study examined the hypothesis that delta-9-tetrahydrocannabinol (THC) would disrupt voluntary maternal care behaviors and negatively impact offspring development. Rat dams were gavaged with 0, 2, 5, or 10 mg/kg THC from the 1st day of gestation through the 21st postnatal day. Somatic growth and developmental milestones were measured in the offspring, and maternal pup retrieval tests were conducted on postnatal days 1, 3, and 5. THC did not affect body growth but produced transient delays in the righting reflex and eye opening in offspring. However, there was significant pup mortality due to impaired maternal care. Dams in all THC groups took significantly longer to retrieve their pups to the nest and often failed to retrieve any pups. Serum levels of THC and metabolites measured at this time were comparable to those in breastfeeding women who are chronic users. Benchmark doses associated with a 10% reduction of pup retrieval or increased pup mortality were 0.383 (BMDL 0.228) and 0.794 (BMDL 0.442) mg/kg THC, respectively. The current findings indicate that maternal care is an important and heretofore overlooked index of THC behavioral toxicity and should be included in future assessments of THC's health risks. [ABSTRACT FROM AUTHOR]

There is growing evidence of negative impacts of antidepressants on behavior of aquatic non-target organisms. Accurate environmental risk assessment requires an understanding of whether antidepressants with similar modes of action have consistent negative impacts. Here, we tested the effect of acute exposure to two antidepressants, fluoxetine and venlafaxine (0–50 µg/L), on the behavior of non-target organism, i.e., freshwater pond snail, Lymnaea stagnalis. As compounds interact with chemical cues in the aquatic ecosystems, we also tested whether the effects altered in the presence of bile extract containing 5α-cyprinol sulfate (5α-CPS), a characterized kairomone of a natural predator, common carp (Cyprinus carpio). Behavior was studied using automated tracking and analysis of various locomotion parameters of L. stagnalis. Our results suggest that there are differences in the effects on locomotion upon exposure to venlafaxine and fluoxetine. We found strong evidence for a non-monotonic dose response on venlafaxine exposure, whereas fluoxetine only showed weak evidence of altered locomotion for a specific concentration. Combined exposure to compounds and 5α-CPS reduced the intensity of effects observed in the absence of 5α-CPS, possibly due to reduced bioavailability of the compounds. The results highlight the need for acknowledging different mechanisms of action among antidepressants while investigating their environmental risks. In addition, our results underline the importance of reporting non-significant effects and acknowledging individual variation in behavior for environmental risk assessment. [ABSTRACT FROM AUTHOR]

Use of fish as biological early warning indicator for ecological hazards of water pollutants is efficient and fast. However, there is still a lack of attempts to apply fish shoaling behavior to biological early warning. Herein, cluster score was used to evaluate and quantify shoaling behavior of rare minnow ( Gobiocypris rarus) in their health state. Combined with the results of 24 h acute toxicity exposure experiment, the response of rare minnow shoaling behavior to Cd2+, MS222 and p-chloroaniline was tested by gradient exposure experiment and burst pollu- tion simulation experiment. The results showed that rare minnow had obvious shoaling behavior with a cluster score between 3 and 5, which changed significantly when exposed to chemicals. The LOEC values of shoaling behavior of rare minnow exposed to Cd2+, MS222 and p-chloroaniline for 1 h were 3, 11 and 10 mg·L-1, respective- ly. The shoaling behavior of rare minnow was sensitive to the chemical reaction and showed obvious response within 10 min after exposure to the three chemicals. Therefore, cluster score is an excellent quantitative parameter of fish shoaling score, and the shoaling behavior of rare minnow is a great indicator of biological early warning. [ABSTRACT FROM AUTHOR]

The present study examined the effects of environmentally realistic exposure to atrazine (ATZ) on the behavior of sailfin mollies, Poecilia latipinna. ATZ is one of the most commonly used pesticides in the US and a known endocrine disrupting chemical (EDC). The behavior of sailfin mollies is well documented in the scientific literature. Moreover, they are ecologically important indicators of environmental health, widely distributed among the mangroves along the Gulf Coast of the Southeastern US where significant amounts of ATZ are introduced via runoff and storm water drainage from coastal households, businesses, and farms. Four sets of experiments designed to assess ATZ's impact on various aspects of male and female reproductive behavior, aggression, anxiety, and boldness were conducted following 12 weeks of exposure to 1 or 15 ppb water-borne ATZ, along with a no-exposure control group. Results indicated that the behavior of ATZ-exposed individuals differed from those of controls: ATZ exposure affected which stimulus fish (a male vs. a female) subject females preferred to associate with while also affecting female strength of preference for males of larger body size and their sexual receptivity to conspecific males in general. ATZ-exposed males also showed reduced overall responsiveness to conspecific stimuli and directed significantly less aggression toward their mirror image compared with controls. Finally, ATZ exposure affected multiple aspects of male and female behavior that are often used as proxies for boldness and anxiety. Overall, ATZ exposure resulted in alterations across a variety of behaviors attributed to sexual receptivity, mate choice and motivation to mate, aggression, as well as boldness and anxiety. These ATZ-induced behavioral changes may adversely affect the long-term health of natural populations exposed to similar, environmentally realistic concentrations and add to a growing body of empirical data demonstrating substantial fitness consequences of exposure to sublethal concentrations of this known EDC. [ABSTRACT FROM AUTHOR]

Keywords: suicidality; Black Box; activation syndrome; behavioral toxicity; antidepressants EN suicidality Black Box activation syndrome behavioral toxicity antidepressants 1 3 3 05/05/20 20200430 NES 200430 In a recent issue of Frontiers in Psychiatry, Spielmans et al. ([1]) defend the 2004 decision of the Food and Drug Administration (FDA) to issue a Black Box warning on the potential risk of suicidality in youth being administered antidepressant medications. As various neural correlates (e.g., amygdala connectivity) have predicted attenuated antidepressant treatment response ([9], [10]), it is possible that such developmental alterations in brain maturation also relate to increased possibility of SSRI-induced behavioral side effects. [Extracted from the article]

Galantamine hydrobromide and (−)huperzine A, centrally active reversible acetylcholinesterase inhibitors, are potentially superior to the current standard, pyridostigmine bromide, as a pretreatment for organophosphorus chemical warfare nerve agent intoxication. Galantamine, huperzine, and pyridostigmine were compared for time course of acetylcholinesterase inhibition in 12 cynomolgus macaques. Although both galantamine and huperzine shared a similar time course profile for acetylcholinesterase inhibition, huperzine was 88 times more potent than galantamine. The dose for 50% acetylcholinesterase inhibition (ID) was 4.1 ug/kg for huperzine, 362 ug/kg for galantamine, and 30.9 ug/kg for pyridostigmine. In a safety assessment, galantamine, huperzine, and pyridostigmine were examined using an operant time-estimation task. Huperzine and pyridostigmine were devoid of behavioral toxicity, whereas galantamine was behaviorally toxic at doses producing peak acetylcholinesterase inhibition of about 50% and higher. Following pretreatment with galantamine, huperzine or pyridostigmine, monkeys were challenged with the median lethal dose of soman at the time of peak acetylcholinesterase inhibition and evaluated for overt signs of soman toxicity (cholinergic crisis, convulsions). Both huperzine and galantamine were equally effective at preventing overt signs of soman toxicity, but neither drug was capable of preventing soman-induced neurobehavioral disruption. In contrast, three of four pyridostigmine-pretreated animals exposed to soman exhibited convulsions and required therapy. Full functional recovery required 3-16 days. The degree of acetylcholinesterase inhibition was lower for pyridostigmine, but rates of recovery of acetylcholinesterase activity following soman challenge were comparable for all drug pretreatments. Huperzine may be the more promising centrally active reversible acetylcholinesterase inhibitor due to its greater potency and superior safety profile. [ABSTRACT FROM AUTHOR]

The aim of this critical review was to outline emerging trends and perspectives of clinical pharmacopsychology, an area of clinical psychology that is concerned with the psychological effects of medications. The historical development of clinical pharmacopsychology is outlined, with discussion of its most representative expressions and reference to current challenges of clinical research, with particular reference to clinimetrics. The domains of clinical pharmacopsychology encompass the clinical benefits of psychotropic drugs, the characteristics that predict responsiveness to treatment, the vulnerabilities induced by treatment (side effects, behavioral toxicity, iatrogenic comorbidity), and the interactions between drug treatment and psychological variables. Its aim is to provide a comprehensive assessment of the clinical important changes that are concerned with (a) wanted and expected treatment effects, (b) treatment-induced unwanted side effects, and (c) the patient's own personal experience of a change in terms of well-being and/or quality of life. Clinical pharmacopsychology offers a unifying framework for the understanding of clinical phenomena in medical and psychiatric settings. Research in this area deserves high priority. [ABSTRACT FROM AUTHOR]

ABSTRACT Fluoroquinolones (FQs) and tetracyclines (TCs), the two β-diketone antibiotics (DKAs), are two frequently detected pollutants in the environment; however, little data are available on their combined toxicity to zebrafish ( Danio rerio). This study reports that toxicologic effects of combined DKA (FQs-TCs) exposure on zebrafish were comparable with or slightly less than those of TCs alone, showing that TCs played a major toxicologic role in the mixtures. The effects of FQs, TCs, and DKAs on malformation rates of zebrafish were dose dependent, with EC50 values of 481.3, 16.4, and 135.1 mg/L, respectively. According to the combined effects of DKAs on zebrafish hatching, mortality, and malformation rates, the interaction between FQs and TCs was shown to be antagonistic based on three assessment methods: Toxic Unit, Additional Index, and Mixture Toxic Index. The 1.56 mg/L TC and 9.38 mg/L DKA treatments resulted in higher zebrafish basal swimming rate compared with the control group at 120 hours postfertilization (hpf). in both light and light-to-dark photoperiod experiments. Under conditions of no obvious abnormality in cardiac development, the heart beats were decreased significantly because of DKA exposure, such as decreasing by ∼20% at 150 mg/L DKAs. Transmission electron microscopy observation of myocytes from DKA-exposed hearts displayed prominent interruptions and myofibrillar disorganization of the normal parallel alignment of thick and thin filaments, and partial edematous and dissolved membranes of cell nuclear tissues. At 90 mg/L DKAs, the transcriptional levels of the acta1a, myl7, and gle1b genes, related to heart development and skeletal muscle formation, were significantly changed. This is consistent with the swimming behavior and histopathologic results obtained by transmission electron microscopy. In summary, the toxicity of the combined DKAs to zebrafish was comparable with or less than that of TCs alone and had the ability to impair individual behaviors that are of great importance in the assessment of their ecologic fitness. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 736-750, 2016. [ABSTRACT FROM AUTHOR]

Mercury (Hg) is a ubiquitous environmental contaminant and potent neurotoxin. In aquatic environments, Hg can be transformed into methylmercury (MeHg), which bioaccumulates in aquatic food webs, including fish. Methylmercury has been shown to transfer from female fish to developing eggs; however, relatively little is known regarding the effects of maternally transferred MeHg on fish embryos. The present study evaluated the effects of maternally transferred MeHg on fathead minnow ( Pimephales promelas) embryos. Embryos were collected from adult fatheads exposed for 30 d to 1 of 3 diets spiked with MeHg: a control diet (0.02 ppm Hg dry wt), a low diet (0.87 ppm Hg dry wt), or a high diet (5.5 ppm Hg dry wt). No effects on spawning frequency, clutch size, or total egg output were observed. In embryos, Hg concentration was a function of female diet and the duration (number of days) of female exposure. Compared with controls, embryos from the low-diet treatment displayed altered embryonic movement patterns (hyperactivity) and decreased time to hatch. Embryos from the high-diet treatment had delayed hatching and increased mortality compared with the other treatments. Collectively, these results suggest that maternally transferred Hg may impact survival, behavior, and developmental milestones of the embryo-larval stages of fish. Environ Toxicol Chem 2016;35:1436-1441. © 2015 SETAC [ABSTRACT FROM AUTHOR]

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BSTRACT Cadmium, a toxic heavy metal with various applications in technology, can affect people both by environmental (foodborne) and occupational (inhalation) exposure and can cause nervous system damage. To model this, rats were subacutely treated either with CdCl2 solution per os (3.0 mg kg−1 b.w.) or nanoparticulate CdO2 (particle size ca 65 nm) by intratracheal instillation (0.04 mg kg−1 b.w.) alone or in sequential combination. Nervous system effects were observed at different levels of function (open field behavior, cortical electrical activity, nerve action potential) and some general toxicological indicators were also measured. Three weeks of oral plus one week of intratracheal exposure caused significant reduction of body weight gain and open field motility. Lengthening of latency of sensory evoked potentials, observed in all treated rats, was also the most significant in the group receiving oral plus intratracheal treatment. Conduction velocity of the tail nerve was likewise decreased in all treated groups. Several of the effects pointed to a potentiating interaction between the two forms of Cd. Modeling environmental and occupational Cd exposure by oral and intratracheal application in rats was feasible, with results suggesting serious negative health effects in humans suffering such a combined exposure. [ABSTRACT FROM AUTHOR]

This study addressed the anticonvulsant effects of repeated administration of phenytoin, carbamazepine, phenobarbital, valproate, and ethosuximide in kindled guinea-pigs in order to further substantiate this novel model of partial seizures for the screening of future anticonvulsant drugs. Behavioral toxic effects were assessed at 30 min following drug administration using scores on a sedation/muscle relaxation rating index. In response to suprathreshold stimulation, the anticonvulsant efficacy of the drugs were evaluated from measurements of afterdischarge duration (ADD) and behavioral seizure severity (SS) during a repeated drug treatment schedule in kindled guinea-pigs. All drugs exerted slight to moderate sedative effects in guinea-pigs on our rating index. We found that phenytoin, carbamazepine, and phenobarbital exhibited effective anticonvulsant properties in kindled guinea-pigs by reducing both ADD and SS. We found that valproate consistently reduced ADD throughout the treatment schedule but failed to significantly reduce SS. Lastly, ethosuximide failed to exhibit effective anticonvulsant properties. Our results indicate that the guinea-pig kindling model correctly predicted the actions of these common anticonvulsant drugs in the treatment of partial seizures. Guinea-pig amygdala kindling appears to serve as a useful and valid model for partial epilepsy. [ABSTRACT FROM AUTHOR]

This study addressed the anticonvulsant effects of phenobarbital, valproate, and ethosuximide in the amygdala of kindled guinea pigs to further validate this model for the screening of anticonvulsant drugs. Behavioral toxic effects were assessed at 30 min following drug administration using quantitative locomotor tests, as well as scores on a sedation and muscle relaxation rating index. The anticonvulsant efficacy of the drugs were evaluated from measurements of afterdischarge threshold (ADT), afterdischarge duration (ADD), and behavioral seizure severity (SS) during early and late phases of kindling acquisition, and in kindled guinea pigs. ADD and SS were also measured in response to both threshold and suprathreshold kindling stimulation. All drugs exerted slight to moderate sedative effects in guinea pigs on both the behavioral tests and rating index. We found that phenobarbital exhibited effective anticonvulsant properties in guinea pigs by consistently reducing ADD and SS in response to both threshold and suprathreshold kindling stimulation. Valproate exhibited effective anticonvulsant properties at threshold stimulation and less effective properties at suprathreshold stimulation. Lastly, we found that ethosuximide lacked effective anticonvulsant action at either threshold or suprathreshold kindling stimulation. Our results indicate that the guinea pig kindling model correctly predicted the actions of phenobarbital, valproate, and ethosuximide in the treatment of partial seizures. Guinea pig amygdala kindling appears to serve as a useful and valid model for partial epilepsy. [ABSTRACT FROM AUTHOR]

The potential for neurotoxic effects was evaluated in rat offspring after exposure in utero and/or during the neonatal period to a recombinant subunit vaccine of gp120 prepared from the MN strain of HIV-1 (MN rgp120/HIV-1). Thirty pregnant female rats were given MN rgp120/HIV-1 with alum adjuvant, and 30 rats were given vehicle, once every 3 days from Day 1 of presumed gestation until parturition. One pup/sex/litter from treated and control group dams were given a daily subcutaneous injection, from Day 1 through Day 22 postpartum (PP) of vehicle, MN rgp120/HIV-1, MN rgp120/HIV-1 with alum, or MN rgp120/HIV-1 with OS-21 adjuvant. Neurobehavioral and physical development were evaluated (preweaning reflex and development, sexual maturation, motor activity, acoustic startle, passive avoidance, functional observational battery, and water M-maze testing), and tissues were processed for anatomical examination (whole and regional brain weights, and neuropathology). Administration of MN rgp120/HIV-1, with or without adjuvant, to pups did not cause any persistent effect on any parameter evaluated. Neurohistological examination did not reveal any pathological effects related to treatment. Thus, MN rgp120/HIV-1 alone or formulated as a vaccine does not cause neurotoxicity or developmental toxicity in neonatal rats after exposure in utero and/or during the neonatal period. [ABSTRACT FROM PUBLISHER]

A multiple behavioral schedule with food reinforcement was designed to measure the drug-induced performance enhancement and non-effective activity in rats. The schedule, 20 min in duration, had CRF components in the 33 trials and extinction components in the inter-trial periods. During each trial, food reinforcement was present in the limited period (8 sec each) which was preceded by a discriminative stimulus (1 sec, either a light or a footshock). The rats generated a high rate of lever pressing during the limited period and a low rate of lever pressing during the inter-trial period. The drugs studied were d-amphetamine, methylphenidate, pipradrol and phenindamine. At low dosages, these drugs increased further the high rate of lever pressing. This was considered to be the performance enhancement effect. At higher doses, the drugs increased the low rate of lever pressing, decreased the high rate of lever pressing, and decreased responding of the rats to the discriminative stimulus. This latter pattern was considered to be the non-effective activity caused by the drugs. As expected, d-amphetamine was the most potent. Minor differences in drug effects were seen between the group of rats having light and that group having footshock as discriminative stimulus. [ABSTRACT FROM AUTHOR]

Some investigators have used evidence that a drug may induce conditioned taste aversion to dismiss other behavioral effects of the drug as due to general toxicity rather than specific pharmacological action. To test the validity of this position, behaviorally relevant doses of alcohol, chlordiazepoxide, and morphine were studied in an aversive taste conditioning paradigm. Drug injections were paired with exposure to saccharin solution on repeated trials. Each drug produced saccharin aversion at one or more doses. Since comparable doses are known to facilitate rather than impair behavior in some situations, the taste aversion test is insufficient to establish the general behavioral toxicity of particular drug doses. [ABSTRACT FROM AUTHOR]