Psychiatric Annals August 2016 - Volume 46 · Issue 8: 466-472 August 12, 2016
Catastrophic Complications Related to Psychopharmacologic Drug Withdrawal
James Jenkins, MD; Sean Glass, MD
James Jenkins, MD, is a Postgraduate Year-4 Resident, Massachusetts General Hospital/McLean Hospital Adult Psychiatry Residency Program; and a Clinical Fellow in Psychiatry, Harvard Medical School. Sean Glass, MD, is an Instructor in Psychiatry, Harvard Medical School and Massachusetts General Hospital.
Disclosure: The authors have no relevant financial relationships to disclose.
Abstract at http://www.healio.co...drug-withdrawal
Numerous physical and psychiatric effects can be attributed to the cessation of psychotropic medications, similar to those agents with abuse potential. In addition, drug withdrawal can exacerbate underlying psychiatric conditions and alter disease course and long-term outcomes. This article discusses specific withdrawal syndromes associated with several classes of psychotropic medications to increase prescriber awareness when tapering and discontinuing psychotropic medications, thereby facilitating discussions with patients about the risks of withdrawal. [ Psychiatr Ann . 2016;46(8):466-472.]
A group of symptoms of variable clustering and degree of severity which occur on cessation or reduction of use of a psychoactive substance that has been taken repeatedly, usually for a prolonged period and/or in high doses. The syndrome may be accompanied by signs of physiological disturbance. 1
These syndromes are presumed to relate to the physiologic adaptations that include, but are not limited to, receptor density, sensitivity, and autoregulation, as well as to changes in neuro-connectivity that appear with prolonged exposure to a centrally acting drug. 2 The manifestations of withdrawal syndromes are thought to result from disruption of homeostasis created when a drug is removed and a new equilibrium needs to be achieved.
Given this relationship between changes in receptor levels and withdrawal symptoms, the withdrawal symptoms that are associated with specific classes of medications are predictable when placed in the context of their pharmacodynamics. In this article, we discuss the withdrawal symptoms associated with three major classes of psychotropic medications and address how knowledge of these drugs' mechanism of action can inform clinicians' predictions of withdrawal symptoms for those agents with less clearly researched withdrawal syndromes.
Because of their direct agonist effects, sedative-hypnotics most clearly show the interactions between drugs and receptors in the central nervous system (CNS) that lead to the emergence of withdrawal phenomenon. They also support the homeostasis disruption hypothesis for the genesis of drug-withdrawal syndromes.
Sedative-hypnotics exert their effects by modulating the brain's major neuroexcitatory pathway-the glutamate system. The excitatory effects of glutamate are balanced in the CNS by the inhibitory effects of the neurotransmitter gamma-amino butyric acid (GABA). GABA works by binding to GABA receptors on neurons and ultimately by decreasing the neuronal firing rate. 3 Despite subtle differences in where and how they activate receptors, sedative-hypnotics all function as GABA analogues. Like GABA, these drugs reduce neuronal firing, either by altering chloride ion influx (GABA-A receptor subtype) or via secondary messenger systems (GABA-B receptor subtype). It is this decrease in the neuronal firing rate that results in the anxiolytic, sedative, hypnotic, and anti-convulsant effects of these drugs. 3 Many therapeutic agents and illicit drugs interact with GABA receptors, but the most commonly prescribed ones in psychiatry are the benzodiazepines, "z-drugs" (eg, zolpidem), and barbiturates. Of these, benzodiazepines are, by far, the most prescribed and best-studied agents.
Prolonged use of benzodiazepines induces down-regulation of GABA-A receptors while triggering an increase in N-methyl-D-aspartate (NMDA) glutamate receptors in a regulatory feedback mechanism. This presumably occurs to "balance" excitatory and inhibitory neurotransmission systems. A new ratio of excitatory to inhibitory neural transmission is thus created to account for the addition of the GABA-ergic drug. Clinically, this process results in the tolerance to the effects of the medication that are observed with protracted use. When this balance is disrupted via rapid tapering or an abrupt discontinuation of medication, an excitatory neuronal surge results from excess glutamate acting on NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid receptors. Left unchecked, this results in the mild to severe glutamate- and hyperadrenergic-driven symptoms associated with benzodiazepine withdrawal. 4 Similar mechanisms and symptoms have been demonstrated for most other sedative-hypnotic drugs.
The most common symptom associated with discontinuation of a benzodiazepine is insomnia. 5,6 Other common symptoms of withdrawal include anxiety, restlessness, agitation, irritability, muscle tension, muscle aches, poor concentration, and impaired memory. 5-8 Less commonly, there may be an increased sensitivity to sound, light, touch, smell, and pain, as well as tremulousness, diaphoresis, palpitations, psychosis, confusion, and seizures. 6-8
Dreaded complications of benzodiazepine withdrawal (eg, psychosis, delirium, and seizures) are uncommon, occurring primarily in those with predisposing conditions (such as prior complicated withdrawal syndromes, seizures, or CNS pathology); these often arise after an abrupt discontinuation of high daily doses of benzodiazepines (>40 mg of diazepam-equivalents per day) 9,10 ( Table 1 ).
The timing of withdrawal symptoms is related to the individual pharmacokinetics of each of the benzodiazepines, with particular correlation to the half-life of the drug. After the abrupt discontinuation or dose reduction of short-acting benzodiazepines such as alprazolam, withdrawal symptoms typically begin within 12 to 24 hours and peak within 1 to 3 days; for longer-acting agents, such as diazepam, withdrawal symptoms may not emerge for 2 to 7 days, may not peak until 4 to 7 days, and may continue for 2 to 8 weeks or longer. 5,8,10
Of note, most benzodiazepines are metabolized in hepatocytes via the cytochrome P450 3A4 system. 9 In those with hepatic insufficiency, renal insufficiency, or dysfunction of other organs, metabolism of benzodiazepines may be reduced and their half-life increased. Clinicians should be aware that this may drastically delay the timing and course of withdrawal symptoms and the susceptibility to dreaded events such as seizures and delirium. In those with liver disease, oxazepam, temazepam, and lorazepam are preferred agents as they are metabolized by direct glucuronidation and not by oxidative metabolism (as are the remaining benzodiazepines), and thus their pharmacokinetics are less likely to become unpredictable.
Traditionally, short-acting benzodiazepines, such as alprazolam, have been associated with the most frequent and intense withdrawal syndromes. 7,8,10 However, a 2006 Cochrane review suggested that there is little direct support for this commonly held belief, as withdrawal symptom scores were similar in patients withdrawing from short-acting and long-acting agents. 11
Current guidelines for the pharmacologic management of benzodiazepine withdrawal in otherwise healthy adults typically include use (and then taper) of a long-acting benzodiazepine regardless of half-life of the initially prescribed medication. 5,11 However, key comparison studies with other agents are lacking, 12 and multiple strategies such as various benzodiazepine tapers, 5,10 phenobarbital taper, 12 and use of adjunctive carbamazepine 11,13 have been employed effectively. These studies suggest that, given the cross-tolerance and similar mechanism of action of drugs in the broader sedative-hypnotic class, treatment recommendations for benzodiazepine withdrawal can be extrapolated to other agents such as the barbiturates and z-drugs.
The WHO's 2009 Guidelines for the treatment of sedative-hypnotic withdrawal includes use of low doses (for patients taking <40 mg of diazepam-equivalents per day) and high doses (>40 mg of diazepam-equivalents per day). 5 In both strategies, patients are first stabilized on diazepam by converting their current sedative-hypnotic dose to diazepam-equivalents. The patient is continued on this dose in thrice daily doses for 4 to 7 days, and after that a gradual tapering strategy is initiated. 5
A retrospective analysis of benzodiazepine withdrawal (studying 310 patients treated over a 5-year period) showed that the use of a phenobarbital taper had significant efficacy and minimal adverse effects (the most common being sedation). 12 The recommended dosing schedule involved a 3-day oral taper of phenobarbital starting with a one-time dose of 200 mg, then 100 mg every 4 hours for 5 doses, then 60 mg every 4 hours for 4 doses, then 60 mg every 8 hours for 3 doses. Some patients received extra doses if they manifested persistent symptoms of withdrawal. This study supports the common clinical practice of substitution of various sedativehypnotics in the treatment of withdrawal.
Ultimately, the strategy used for treating withdrawal will depend on the patient's clinical status, including comorbid conditions, the clinical setting (eg, outpatient clinic, general hospital ward, intensive care unit), and other financial, institutional, and provider-specific considerations.
Withdrawal syndromes have been documented for all classes of antidepressants. Case reports of antidepressant withdrawal first appeared in the psychiatric literature in 1959, shortly after the introduction of the first tricyclic-imipramine. 14 Antidepressant withdrawal syndromes are believed to result from a combination of decreased monoamine availability in synaptic clefts, changes in density of receptor types in different regions of the brain, and alterations in receptor sensitivity to available neurotransmitters (especially with muscarinic, histaminergic, and adrenergic receptors). 15 The mechanism for how withdrawal symptoms are produced is much less well-defined than with the sedative-hypnotics, because these drugs have a mix of indirect (via reuptake inhibition) and direct (via receptor agonism/antagonism) effects on CNS homesostasis. Nevertheless, it is the re-establishing of homeostasis that is thought to account for symptom production.
Although the exact prevalence rates are difficult to determine, prospective studies using the Discontinuation-Emergent Signs and Symptoms scale, a validated measurement of withdrawal symptoms, have found that at least one withdrawal symptom, across all antidepressants (ie, selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], monoamine oxidase inhibitors [MAOIs], and tricyclic antidepressants [TCAs]), is present in approximately one-third of patients. 16 As with sedativehypnotics, the prevalence and severity of withdrawal syndromes has also been shown to correlate with the drug's half-life ( Table 2 ). In a prospective, blinded study where antidepressant treatment was discontinued abruptly for 1 week, the prevalence of paroxetine-associated withdrawal symptoms was 55%, whereas it was only 30% for fluoxetine. 17
In observational studies, symptoms of antidepressant withdrawal emerged within 4 days of stopping the medication in 86% of patients and in 93% within the first 7 days. 18 As might be expected, withdrawal symptoms emerge sooner with drugs that have a shorter half-life. The duration of withdrawal symptoms is typically 1 to 3 weeks, with a median duration of 8 days. 18
There is significant overlap between the observed withdrawal symptoms associated with SSRIs and SNRIs. 19 Symptoms include nausea, lethargy, headache, electric shock-like sensations, dizziness with eye movement, ataxia, irritability, low mood, and sleep disturbance (usually insomnia and vivid dreams). 20 Dysequilibirum and sensory disturbances appear to be more common from SSRI/SNRI withdrawal than from withdrawal of other classes of antidepressants.
TCA withdrawal syndromes are driven primarily by a "cholinergic rebound syndrome." Symptoms of cholinergic rebound result from alterations in the muscarinic receptors after prolonged antagonism. Symptoms of cholinergic rebound and TCA withdrawal include nausea, vomiting, diarrhea, diaphoresis, insomnia, anxiety, and "flu-like" sensations. 21 TCAs are also unique among the antidepressants for their risk of inducing arrhythmias upon discontinuation.
Withdrawal from MAOIs is usually more impairing than seen with SSRIs, SNRIs, and TCAs. Although there is substantial overlap between withdrawal symptoms seen with MAOIs and all other classes of antidepressants, MAOI withdrawal has the added risk of being associated with delirium, paranoia, hallucinations, and severe depressive symptoms. 22
Less common reactions to antidepressant withdrawal include sudden-onset hypomania/mania, akathisia, and parkonsinism.
Guidelines for the management of antidepressant withdrawal are controversial. Schatzberg et al. 23 proposed guidelines that involved a gradual taper over abrupt discontinuation, reassurance when mild symptoms arose, and restarting the antidepressant at the lowest effective dose to ameliorate symptoms and then using a slow taper. Meta-analyses looking at gradual versus abrupt discontinuation failed to reliably demonstrate reduction of withdrawal symptoms with gradual reduction. Approaches to the management of more distressing withdrawal symptoms have included use of fluoxetine substitution (similar rationale to the use of diazepam for sedative-hypnotic withdrawal), benzodiazepines, and anticholinergic medications to reduce symptoms. Evidence for best practices for treatment of antidepressant withdrawal syndromes is lacking and treatment protocols remain pragmatic.
Similar to withdrawal from antidepressants, the withdrawal symptoms associated with antipsychotics appear to result from monoamine and receptor adaptations to drug exposure. Antipsychotics as a group, however, are more heterogeneous and complex in their pharmacodynamics. As a result, there are no similarly current or proposed diagnostic criteria for a unified antipsychotic withdrawal syndrome, and its prevalence rates are unknown. Most of what is known about antipsychotic withdrawal symptoms comes from retrospective reanalyses of trials like the Clinical Antipsychotic Trials of Intervention Effectiveness. 24
Each antipsychotic has varying degrees with which they interact with serotonergic, muscarinic, histaminergic, adrenergic, and dopaminergic receptors. Basic knowledge about relative affinities for each of these receptor types help clinicians predict a specific medication's side effects and, similarly, can be used to predict withdrawal symptoms ( Table 3 ). This type of approach is supported by both theoretical background and observational studies. 25
In general, the earliest withdrawal symptoms from antipsychotic discontinuation typically emerge within 1 to 4 days of abrupt discontinuation and tend to resolve within 2 to 3 weeks. 26 Early withdrawal symptoms are usually somatic and are related to rebound phenomena of previously antagonized receptors. For example, cessation of low-potency, highly anticholinergic, and antihistaminergic antipsychotics may result in rebound cholinergic symptoms and insomnia, respectively. As with withdrawal from TCAs, withdrawal symptoms associated with antipsychotics include myalgias, diaphoresis, malaise, rhinitis, nausea, vomiting, headaches, and increased anxiety. 26 These symptoms have been best described with chlorpromazine, but may also be expected with other lowpotency agents and the atypical antipsychotics (eg, olanzapine, quetiapine). 25,27
High-potency antipsychotics, characterized by their propensity for dopamine receptor blockade, best exemplify withdrawal symptoms unique to antipsychotics. Dopamine receptor blockade in the CNS has been shown to result in a post-synaptic "supersensitivity" of the receptor, particularly in the nigrostriatal and mesolimbic pathways. When antipsychotics are discontinued there is an abrupt increase in stimulation of these receptors by available dopamine that is thought to be responsible for rebound motor and psychotic symptoms. Motor symptoms include akathisia, dystonias, parkinsonism, and paradoxical worsening of tardive dyskinesia. 24,25,28 These motor disturbances can be transient or persistent, reversible or irreversible, and are also the best predictor of rebound psychosis. 24,25
"Supersensitivity" or rebound psychosis is defined by psychosis that emerges within the first 6 weeks after stopping an orally administered antipsychotic. 28 Rebound psychotic symptoms may also differ from those of prior psychotic episodes and respond more rapidly when the discontinued antipsychotic has been restarted. One meta-analysis found a prevalence of 25% in the first 6 weeks after abruptly stopping a typical antipsychotic, nearly double the rate when the antipsychotic was tapered gradually. 28
Clozapine is also associated with a withdrawal psychosis involving motor symptoms, despite its low affinity for dopamine D2 receptors. Clozapine is thought to induce these effects because, although it has a low D2 binding affinity, it rapidly dissociates and can repeatedly antagonize the receptor and therefore sensitize it. 29 Moreover, clozapine's strong muscarinic receptor antagonism is thought to potentiate the risk of rebound psychosis. Rates of psychosis in the first 7 days after abrupt clozapine discontinuation are as high as 13%. 28 Clozapine withdrawal is also associated with more significant symptoms of cholinergic withdrawal and it has been reported to lead to neuroleptic malignant syndrome, catatonia, and hyperthermia. 30 Withdrawal from olanzapine and quetiapine have many of the same manifestations as clozapine withdrawal, although the prevalence and severity seem to be much lower.
Little is known about the relationship between serotonin receptor subtypes and withdrawal symptoms. This makes it difficult to predict withdrawal syndromes for drugs with little effect on dopamine, histamine, and cholinergic receptors (eg, aripriprazole, lurasidone, and ziprasidone).
Given the heterogeneity of antipsychotic binding profiles, clinicians should be vigilant for the emergence of withdrawal symptoms (including psychosis) when switching from one antipsychotic to another, particularly when the agents used differ dramatically in their binding profile. There is a high risk of misattribution of these symptoms to the new medication.
As with antidepressants, there are no clear guidelines for management of antipsychotic-associated withdrawal symptoms. In general, the same approach is taken as with treating antidepressant withdrawal (provide a gradual taper schedule and supportive care). Some preliminary research has looked at the use of the anticonvulsants (eg, valproic acid, lamotrigine, gabapentin) for the treatment of severe supersensitivity motor and psychotic symptoms; however, definitive recommendations are lacking. 31
Although the specific nature of withdrawal symptoms differs based on the class of medication and receptor binding profiles, common principles apply across classes. Withdrawal symptoms can involve physical, neurologic, and psychologic features; they tend to be time-limited; and in almost all cases they appear to improve with slowing of the taper or with reintroduction of the discontinued medication. Patients should be warned about these symptoms and the clinician should be aware of their potential to emerge. The lack of clear guidelines for treatment of withdrawal symptoms is evidence for the need for further research in this area.
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