Newer generation antidepressants and withdrawal effects: reconsidering the role of antidepressants and helping patients to stop

In England, the prescribing of antidepressants, primarily the newer generation antidepressant classes, has steadily increased over recent years. There is ongoing debate about how the efficacy of these drugs is viewed, their place in therapy and the harms associated with stopping them. Much of the evidence of their efficacy comes from short-term placebo-controlled trials which tend not to include outcomes that are of greatest relevance to patients, such as social functioning or quality of life, but rather restrict outcomes narrowly to symptom measures. On such measures these studies do not demonstrate clinically significant differences from placebo for depression. A range of adverse effects are also recognised, often greater in naturalistic studies of long-term antidepressants users than those measured in short-term efficacy studies, including emotional numbing, sexual difficulties, fatigue and weight gain. There is increasing recognition that withdrawal symptoms from antidepressants are common and that these symptoms can be severe and long-lasting in some patients. Recent guidance on how to stop antidepressants in a tolerable way has been presented by the Royal College of Psychiatrists. We believe that increasing awareness about the difficulty that some patients have in stopping antidepressants should lead to more cautious prescribing practice, with antidepressants given to fewer patients and for shorter periods of time. This article discusses the perceived benefits and harms of antidepressant use.

Clinically relevant doses of methylphenidate elicit behavioral sensitization and impair cognition on drug withdrawal in normal adult rats

Methylphenidate (MPD), a psychostimulant, is the first line drug for improving cognitive performance in attention deficit hyperactivity disorder (ADHD). A non-prescription use of this drug for improving performance is also becoming increasingly known. A growing rise in its medical and nonmedical use suggests that the drug is addictive.The present study was designed to ascertain the reinforcing and withdrawal effects of clinically relevant doses of methylphenidate on cognitive behavior of normal adult rats. Potential addictive effects and withdrawal effects on cognition were also determined.Effects of MPD in improving cognition were monitored after drug administration as well as withdrawal using Morris Water Maze test. Taking behavioral sensitization as an important contributing factor of drug addiction; addictive effects of MPD were also determined. Data analysis was done on SPSS version 13 by one-way and two-way ANOVA (repeated measure design) where applicable; post hoc comparisons were done by Tukey’s test. Repeated oral administration of MPD (0.5 and 1mg/kg) for six days produced behavioral sensitization and reduced daily food intake. After six days of treatment rats were repeatedly administered/withdrawal from repeated administration of MPD to investigate effects of MPD on cognitive behaviors. Results showed an improvement in cognition in rats repeatedly administered with MPD (0.5 and 1 mg/kg). Whereas, withdrawal from repeated administration of MPD impaired short term memory, long term memory and memory retention. Doses of MPD which improve learning and memory are potentially addictive and elicit behavioral sensitization. Use of drug in healthy subjects can impair performance below basal levels particularly in drug withdrawal conditions.

Later is not necessarily better: limitations of survival analysis in studies of long-term drug treatment of psychiatric conditions

Survival analysis is routinely used to assess differences between groups in relapse prevention and treatment discontinuation studies involving people with long-term psychiatric conditions. The actual outcome in survival analysis is ‘time to event’, yet, in the mental health field, there has been little consideration of whether a temporary delay to relapse is clinically relevant in a condition that can last for decades. Moreover, in psychiatric drug trials, a pattern of elevated early relapses following randomisation to placebo or no treatment is common. This may be the result of the withdrawal of previous treatment leading to physiological withdrawal effects, which may be mistaken for relapse, or genuine relapse precipitated by the process of withdrawal. Such withdrawal effects typically produce converging survival curves eventually. They inevitably lead to differences in time to relapse, even when there is little or no difference in the cumulative risk of relapse at final follow-up. Therefore, statistical tests based on survival analyses can be misleading because they obscure these withdrawal effects. We illustrate these difficulties in a trial of antipsychotic reduction versus maintenance, and a trial of prophylactic esketamine in people with treatment-resistant depression. Both illustrate withdrawal-related effects that underline the importance of long-term follow-up and question the use of tests based on time to event. Further discussion of the most relevant outcome and appropriate approach to analysis, and research on patient and carer preferences is important to inform the design of future trials and interpretation of existing ones.

Methadone, Buprenorphine, and Clonidine Attenuate Mitragynine Withdrawal in Rats

Background: Kratom or Mitragyna speciosa Korth has been widely used to relieve the severity of opioid withdrawal in natural settings. However, several studies have reported that kratom may by itself cause dependence following chronic consumption. Yet, there is currently no formal treatment for kratom dependence. Mitragynine, is the major psychoactive alkaloid in kratom. Chronic mitragynine treatment can cause addiction-like symptoms in rodent models including withdrawal behaviour. In this study we assessed whether the prescription drugs, methadone, buprenorphine and clonidine, could mitigate mitragynine withdrawal effects. In order to assess treatment safety, we also evaluated hematological, biochemical and histopathological treatment effects.Methods: We induced mitragynine withdrawal behaviour in a chronic treatment paradigm in rats. Methadone (1.0 mg/kg), buprenorphine (0.8 mg/kg) and clonidine (0.1 mg/kg) were i.p. administered over four days during mitragynine withdrawal. These treatments were stopped and withdrawal sign assessment continued. Thereafter, toxicological profiles of the treatments were evaluated in the blood and in organs.Results: Chronic mitragynine treatment caused significant withdrawal behaviour lasting at least 5 days. Methadone, buprenorphine, as well as clonidine treatments significantly attenuated these withdrawal signs. No major effects on blood or organ toxicity were observed.Conclusion: These data suggest that the already available prescription medications methadone, buprenorphine, and clonidine are capable to alleviate mitragynine withdrawal signs rats. This may suggest them as treatment options also for problematic mitragynine/kratom use in humans.

Multifactorial Etiology of Adolescent Nicotine Addiction: A Review of the Neurobiology of Nicotine Addiction and Its Implications for Smoking Cessation Pharmacotherapy

Nicotine is the primary pharmacologic component of tobacco, and its highly addictive nature is responsible for its widespread use and significant withdrawal effects that result in challenges to smoking cessation therapeutics. Nicotine addiction often begins in adolescence and this is at least partially attributed to the fact that adolescent brain is most susceptible to the neuro-inflammatory effects of nicotine. There is increasing evidence for the involvement of microglial cells, which are the brain's primary homeostatic sensor, in drug dependence and its associated behavioral manifestations particularly in the adolescent brain. A hallmark of neuro-inflammation is microglial activation and activation of microglia by nicotine during adolescent development, which may result in long-term addiction to nicotine. This non-systematic review examines multifactorial etiology of adolescent nicotine addiction, neurobiology of nicotine addiction and the potential mechanisms that underlie the effects of nicotine on inflammatory signaling in the microglia, understanding how nicotine affects the adolescent brain. We speculate, that modulating homeostatic balance in microglia, could have promising therapeutic potential in withdrawal, tolerance, and abstinence-related neural adaptations in nicotine addiction, in the adolescent brain. Further, we discuss nicotine addiction in the context of the sensitization-homeostasis model which provides a theoretical framework for addressing the potential role of microglial homeostasis in neural adaptations underlying nicotine abuse.

Irreversible effects of anticholinergic withdrawal in the elderly: a case report

Anticholinergics, such as benztropine and trihexyphenidyl, are a class of medications that have been used to treat several different conditions including antipsychotic-induced extrapyramidal side effects (EPS) that are most often associated with first-generation antipsychotics (FGAs), such as haloperidol and fluphenazine. Many other medications, including antimuscarinics, antipsychotics, and antidepressants, also have anticholinergic effects. In this report, we review the case of an 80-year-old male who experiences irreversible anticholinergic withdrawal effects following the discontinuation of trihexyphenidyl and trospium secondary to side effects. Discontinuation of anticholinergics must be approached with care as abrupt withdrawal can lead to cholinergic rebound and muscular rigidity, and in some cases can lead to acute hospitalization and an inability to return to baseline functioning, as seen in our elderly patient. Keywords: Anticholinergic withdrawal, trihexyphenidyl, trihexyphenidyl withdrawal, trospium, anticholinergic drugs, cholinergic rebound

N-Oleoylglycine and N-Oleoylalanine Do Not Modify Tolerance to Nociception, Hyperthermia, and Suppression of Activity Produced by Morphine

The endogenous amide N-Oleoylglycine (OlGly) and its analog N-Oleoylalanine (OlAla), have been shown to interfere with the affective and somatic responses to acute naloxone-precipitated MWD in male rats. Here we evaluated the potential of a single dose (5 mg/kg, ip) which alleviates withdrawal of these endogenous fatty acid amides to modify tolerance to anti-nociception, hyperthermia, and suppression of locomotion produced by morphine in male Sprague-Dawley rats. Although rats did develop tolerance to the hypolocomotor and analgesic effects of morphine, they did not develop tolerance to the hyperthermic effects of this substance. Administration of neither OlGly nor OlAla interfered with the establishment of morphine tolerance, nor did they modify behavioral responses elicited by morphine on any trial. These results suggest that the effects of OlGly and OlAla on opiate dependence may be limited to naloxone-precipitated withdrawal effects.

Functional observation after morphine withdrawal: effects of SJP-005

Rationale and objective SJP-005 (ketotifen and ibuprofen) is being developed as a potential new treatment for opioid withdrawal. Three studies were conducted to evaluate the early phase (acute, day 1) and late phase (days 2–12) effects of SJP-005 on discontinuation-induced morphine withdrawal. Methods Sprague-Dawley rats received subcutaneous morphine twice daily for 18 days and ceased on day 19. Twice daily, oral dosages of placebo or SJP-005 (1 mg/kg ketotifen and 15 mg/kg ibuprofen) were administered starting 4 days before (study 1), 2 days before (study 2), or immediately after (study 3) morphine cessation. Functional observations were made up to 12 h after treatment cessation on day 19 (early phase), and immediately after treatment on days 20–30 (late phase). Treatment effects (mean overall score, and individual symptoms) were compared with placebo using ANOVA, and Tukey’s tests in case of multiple comparisons. Results Across the studies, the number of withdrawal signs on day 19 (early phase) and days 20–30 (late phase) was lower with SJP-005 compared with placebo. The effects of SJP-005 when treatment was initiated 2 days before morphine cessation by discontinuation were most pronounced and statistically significant in the late phase (F(1,18) = 14.10, p = 0.001). In particular, a significant reduction was observed in hypersensitivity to touch (F(1,18) = 13.65, p = 0.002). A 50% reduction in withdrawal symptoms was observed 9.0 days after placebo versus 4.5 days after SJP-005. After 9.0 days, all withdrawal symptoms were absent in the SJP-005 group, while symptoms in the placebo group were still evident on day 18. Conclusion Compared to placebo, SJP-005 significantly reduced the incidence and duration of discontinuation-induced morphine withdrawal symptoms when treatment was initiated 2 days before morphine cessation.