Despite the lack of guidance available for practitioners, extensive polypharmacy has become the primary method of treating patients with severe and chronic mood, anxiety, psychotic or behavioral disorders. This ground-breaking new book provides an overview of psychopharmacology knowledge and decision-making strategies, integrating findings from evidence-based trials with real-world clinical presentations. It adopts the approach and mind-set of a clinical investigator and reveals how prescribers can practice 'bespoke psychopharmacology', tailoring care to the individualized needs of patients.
Cross-tapering and the Logistics of Drug Discontinuation
It is a bad plan that admits of no modification.
▢ Recognize clinical situations that warrant stopping an existing psychotropic medication, either abruptly or gradually
▢ Identify clinical situations in which it is more appropriate to switch from one drug to another via direct substitution versus cross-tapers, and the pros and cons of each approach
▢ Describe risks for rebound effects caused by abrupt cessation of some psychotropic drugs
▢ Know how to convert dosages from oral to long-acting injectable antipsychotics, from one benzodiazepine to another, and from one psychostimulant formulation to another
▢ Understand the probabilities and timeframes of relapse from randomized drug discontinuation trials in mood and psychotic disorders
“Necessary clinical adjustments,” as noted in Chapter 1, come with the pharmacological territory for most patients with complex psychiatric disorders – partly because symptoms often can be protean and nonstatic, partly because illness severity can wax and wane, partly because of the impact of cotherapies, and partly from other factors such as pharmacokinetic interactions, treatment nonadherence, loss of efficacy, or other events in the natural evolution of illness. The mechanics and logistics of changing from one pharmacotherapy to another, or deciding when and how to deprescribe an ineffective or otherwise unhelpful medication, are seldom discussed in textbooks or practice guidelines. From an evidence-based perspective, there are few controlled trials designed to compare tolerability and outcomes across various methods and timeframes for stopping and starting or cross-tapering one drug in exchange for another. In this chapter we hope to shed light on how to make decisions about starting, stopping, or replacing drugs within an existing pharmacotherapy regimen safely, effectively, and logically.
Medications become discontinued for innumerable reasons: deliberately or accidentally, unilaterally or by doctor–patient agreement, because they are inadequately helpful or an alternative agent seems more compelling, or their side effects outweigh benefits, or they are thought to no longer be necessary, or because of acute toxicities, or manufacturing unavailabilities, or cost, or inconvenience, or sheer curiosity about what might happen off medication. We would contrast the mechanics of stopping a drug altogether with replacing it with an alternative agent. There are a handful of scenarios or general situations where a medication is purposefully discontinued without particular thought about its possible future reinitiation or replacement, such as those described in Box 9.1.
Pre-pregnancy: Drugs such as divalproex or carbamazepine have strong relative contraindications in pregnancy (see Chapter 12) and when feasible, taper-offs should be completed by a week before anticipated conception.
Toxicity/Overdose: Particularly for drugs with narrow therapeutic indices, clearance after acute toxicity often necessitates a lengthy period before a drug can safely be reintroduced, if its eventual resumption is deemed appropriate. In the case of lithium, where brain and bone concentrations can remain high after toxicity, long after serum lithium levels are undetectable, many weeks may need to elapse before lithium can be safely reintroduced (guided in part by cognitive and neurological status).
Serious or persistent adverse effects: Adverse drug effects can be benign and annoying or medically hazardous; they are sometimes transient and self-limited (e.g., nausea or headache when starting an SSRI) or manageable by dosage reductions or antidote strategies (see Chapter 10). The latter of these scenarios is especially relevant when few if any viable and effective alternative medication options may exist for a particularly difficult condition (e.g., clozapine for refractory schizophrenia; an MAOI for multidrug-resistant major depression).
Hypersensitivity reactions: Severe reactions may include anaphylaxis (immediate hypersensitivity (Type I) reactions), angioedema, cutaneous reactions such as purpura, vasculitis, or thrombocytopenia, and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms, usually arising in an idiosyncratic fashion two to eight weeks after initiation of the causal agent). Laryngeal angioedema can be life-threatening due to airway obstruction and is a medical emergency managed with antihistamines, possible corticosteroids, and sometimes intubation for airway protection.
Good pharmacological hygiene, as noted in Chapter 6, means retaining drugs that provide unambiguous benefit while jettisoning those which lack demonstrated efficacy for a given patient. One must obviously assure that adequate medication trials (adequate dosages for adequate durations for appropriate disorders) have occurred before concluding that a drug is ineffective and should be stopped. Sometimes, particularly if several or more medication trials have yielded no compelling value, one or more stakeholders (patient, clinician, family member) may be inclined to cling to a drug nevertheless, because it “ought” to work (e.g., because it is generally associated with efficacy for a particular diagnosis), even if by all measures it confers no usefulness. Such situations can also foster the idea that, while a patient may remain highly symptomatic despite taking a given medication, their plight might become even worse were they to stop it. Stopping ineffective drugs that “ought” to work for a suspected diagnosis also makes more tangible the possibility that the presumptive diagnosis may simply be wrong. Consider Clinical Vignette 9.1.
Angie was a 27-year-old single female whose “ultra-ultra-rapid cycling bipolar II disorder” failed to respond to multiple adequate trials of lithium, divalproex, lamotrigine, carbamazepine, SSRIs, SNRIs, bupropion, levothyroxine, and several SGAs. Her symptoms consisted mainly of chronic affective instability and easily provoked anger outbursts, as well as chronic insomnia, feelings of boredom and emptiness, low motivation, and low self-worth. During a second-opinion consultation it was noted that her symptoms never coalesced as a distinct constellation to define either hypomania or a major depressive episode, and the psychiatrist wondered if she had been misdiagnosed with bipolar disorder rather than borderline personality disorder. Rather than add more medications, the suggestion was made to consider sequentially removing current medications to gauge their relevance, without replacement, and instead redirect the focus of her care more toward psychotherapy as the cornerstone of her treatment.
More often than not, the intentional decision to continue or stop a medication due to an adverse event becomes a risk–benefit decision without clear or absolute guidelines. Besides the general situations noted above, and apart from judged lack of efficacy after an adequate trial, other specific situations that may necessitate drug discontinuation are summarized in Table 9.1. (See Chapter 10 for further detail on management of adverse effects described.)
|Anticonvulsants||Hypersensitivity/severe cutaneous reactions||Abruptly stop. In principle, sudden discontinuation can lower the seizure threshold, increasing seizure risk; in practice this is unlikely unless there is an existing seizure disorder|
|Hepatic dysfunction||Major increases in liver enzymes (AST, ALT>3–4× the upper limit of normal) warrant drug cessation|
|Myelosuppression||Generally discontinue if WBCs fall to <3000 mm3 or ANC <1500 mm3, if persistent or accompanied by infection, or in thrombocytopenia when platelet counts are <100 000 per mm3|
|Antidepressants||Emergence of mania/hypomania||As a rule, antidepressants should be stopped in the setting of acute mania or hypomania, although, as noted in Chapter 13, this is often easier said than done; short half-life antidepressants may require modified tapers to minimize discontinuation effects|
|Hyponatremia/SIADH||Serotonergic antidepressants should be discontinued when hyponatremia/SIADH occurs without other more likely causes; mirtazapine and tricyclics may be less risky (De Picker et al., 2014)|
|Serotonin syndrome||Characterized by clonus, tremor, hyper-reflexia (see Chapter 6), usually within 24 hours of starting or raising the dose of a serotonergic agent. 5HT2A antagonists may be protective|
|Worsening of suicidal features||Assess overall clinical picture to gauge likelihood that exacerbations of suicidal thoughts or behaviors reflect iatrogenic causes versus worsening of an underlying disorder|
|Antipsychotics||Neuroleptic malignant syndrome||Abruptly stop; most often occurs in first 10–14 days after start of treatment; case reports of cautious rechallenges with alternative antipsychotics more than five days after symptom resolution, although recurrence rates up to 40% (Caroff and Mann, 1993); mortality=5%|
|Myelosuppression||FGAs or SGAs other than clozapine carry a class warning for rarely causing leukopenia, neutropenia, or agranulocytosis; specific criteria for monitoring or drug discontinuation are not established but discontinuation would seem logical in the setting of apparent infection or if WBCs fall to <3000 mm3 or ANC <1500 mm3|
|Myocarditis (clozapine)||Abruptly stop and generally do not rechallenge, due to high chance for recurrence|
|QTc prolongation on ECG||Not an absolute contraindication to continued antipsychotic use; must consider magnitude of QTc, underlying correctable factors, concomitant medications, overall risk–benefit analysis|
|Tardive dyskinesia||Do not discontinue antipsychotic if benefit exceeds risk, particularly given option of VMAT2 inhibitors (see Chapter 10)|
|Lithium||Acute toxicity||Abruptly stop. After significant toxicity (e.g., serum [Li+] >1.5 mEq/L; renal consequences; mental status changes) do not reinstitute (even when serum levels are zero) until mental status changes clear and neurological exam is nonfocal|
||Typically reduce lithium dose, dose once daily, re-estimate eGFR via cystatin C (Shlipak et al., 2013), increase frequency of renal function monitoring (e.g., every three months); anticipate and attempt eventual need to cross-taper to an alternative agent when feasible|
|Stimulants||Tolerance; misuse||Can be abruptly stopped without adverse physiological effects|
Abbreviations: ALT = alanine transaminase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; FGA = first-generation antipsychotic; SGA = second-generation antipsychotic; SIADH = syndrome of inappropriate antidiuretic hormone secretion; VMAT2 = vesicular monoamine transporter 2; WBC = white blood cell