Journal of Psychosocial Nursing and Mental Health Services

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Psychopharmacology 

Potential Adverse Effects of Discontinuing Psychotropic Drugs--Part 3: Antipsychotic, Dopaminergic, and Mood-Stabilizing Drugs

Robert H. Howland, MD

Abstract

Abrupt discontinuation of antipsychotic drugs in patients with schizophrenia is associated with earlier, and often more severe, illness episodes than are seen with gradual discontinuation. Antipsychotic drugs can cause various abnormal motor syndromes, but abruptly stopping them has been associated with the seemingly paradoxical development of similar motor syndromes, such as withdrawal dyskinesias, parkinsonian symptoms, dystonias, and neuroleptic malignant syndrome. Dopamine-releasing and dopamine-agonist drugs are used to treat some of the motor syndromes caused by antipsychotic drugs, but their abrupt discontinuation can also be associated with abnormal syndromes. When antipsychotic drugs, lithium, or certain anticonvulsant drugs are used for treatment of bipolar disorder, rapid versus gradual discontinuation is more likely to lead to greater mood instability and manic relapse. If necessary, these medications should be gradually tapered to minimize all types of adverse discontinuation effects. Patients should be educated about the possible adverse effects of abrupt medication discontinuation.

Abstract

Abrupt discontinuation of antipsychotic drugs in patients with schizophrenia is associated with earlier, and often more severe, illness episodes than are seen with gradual discontinuation. Antipsychotic drugs can cause various abnormal motor syndromes, but abruptly stopping them has been associated with the seemingly paradoxical development of similar motor syndromes, such as withdrawal dyskinesias, parkinsonian symptoms, dystonias, and neuroleptic malignant syndrome. Dopamine-releasing and dopamine-agonist drugs are used to treat some of the motor syndromes caused by antipsychotic drugs, but their abrupt discontinuation can also be associated with abnormal syndromes. When antipsychotic drugs, lithium, or certain anticonvulsant drugs are used for treatment of bipolar disorder, rapid versus gradual discontinuation is more likely to lead to greater mood instability and manic relapse. If necessary, these medications should be gradually tapered to minimize all types of adverse discontinuation effects. Patients should be educated about the possible adverse effects of abrupt medication discontinuation.

Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.

Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.

Posted Online: July 22, 2010

Knowledge about the pharmacology of a drug is necessary for nurses to understand its therapeutic use and side effect profile, as well as any potential adverse effects when the drug is stopped. This four-part article series provides a general overview of the potential adverse effects associated with the discontinuation of various psychotropic drugs. In this month’s article, I will cover antipsychotic, dopamine-releasing, dopamine-agonist, and mood-stabilizing drugs.

Dopamine Receptor-Blocking (Antipsychotic) Drugs

Dopamine (DA) receptor-blocking drugs are usually referred to as antipsychotic drugs because their initial and most common use is for the treatment of psychotic symptoms in schizophrenia, but they are also used to treat other psychiatric, neurological, and medical conditions. The two main antipsychotic drug classes are now referred to as first-generation (typical) antipsychotic (FGA) drugs and second-generation (atypical) antipsychotic (SGA) drugs. Abrupt discontinuation of antipsychotic drugs in patients with schizophrenia is associated with earlier, and often more severe, illness episodes than are seen with gradual drug discontinuation (Chouinard & Chouinard, 2008; Viguera, Baldessarini, Hegarty, van Kammen, & Tohen, 1997). When antipsychotic drugs are used for treatment of bipolar disorder, rapid versus gradual discontinuation is also more likely to lead to greater mood instability and manic relapse.

The primary effect of FGA drugs is blockade of DA-2 receptors (a DA receptor subtype) in the brain, but their potency in doing so varies from drug to drug. As such, they are often grouped according to low potency (chlorpromazine [Thorazine®], thioridazine [Mellaril®], and mesoridazine [Serentil®]), mid potency (trifluoperazine [Stelazine®], loxapine [Loxitane®], and molindone [Moban®]), and high potency (fluphenazine [Prolixin®], haloperidol [Haldol®], perphenazine [Trilafon®], pimozide [Orap®], prochlorperazine [Compazine®], and thiothixene [Navane®]).

In addition to their DA-2 receptor blocking effects, FGA drugs have variable blocking effects on alpha-adrenergic, cholinergic, and histamine receptors. In general, FGA drugs demonstrate an inverse relationship between their DA-2 receptor potency and their potency at blocking these other receptors. In other words, high potency DA-2 blockers have relatively weaker effects on blocking alpha-adrenergic, cholinergic, and histamine receptors, whereas low potency DA-2 blockers have relatively stronger blocking effects on these other receptors. This inverse relationship helps explain the different side effect profile of FGA drugs, as well as possible discontinuation effects.

The most important adverse effects of FGA drugs relate to their DA receptor blockade in the basal ganglia (i.e., the involuntary motor system of the brain). Blocking DA receptors in the basal ganglia can cause five types of motor syndromes: (a) extrapyramidal (parkinsonian) symptoms, (b) acute dystonia, (c) akathisia, (d) tardive dyskinesia (TD), and (e) neuroleptic malignant syndrome (NMS). Extrapyramidal symptoms are similar to Parkinson’s disease: resting tremor, muscle rigidity, shuffling gait, stooped posture, blunted facial expression, and drooling. Acute dystonia is a sudden severe prolonged muscle contraction, usually involving an isolated muscle or group of muscles. Akathisia is characterized by a subjective and objective sense of restlessness, anxiety, and mild motor agitation. TD is characterized by abnormal, involuntary, irregular motor movements involving muscles of the head, limbs, or trunk. NMS is a rare, serious, and potentially fatal reaction to DA-blocking drugs that can occur at any time. Its motor and behavioral symptoms include muscular rigidity and dystonia, akinesia (immobility), mutism, obtundation, and agitation. Autonomic symptoms include high fever, sweating, tachycardia, and hypertension. Patients can develop increases in muscle and liver enzymes, and kidney failure.

Although DA receptor blockade in the basal ganglia causes these five motor syndromes, abrupt antipsychotic drug discontinuation has been associated with the seemingly paradoxical development of similar motor syndromes. Antipsychotic drug withdrawal dyskinesias (appearing similar to TD) are not uncommon (Amore & Zazzeri, 1995; Dixon et al., 1993). Parkinsonian symptoms, dystonias, and NMS are also possible but less common (Amore & Zazzeri, 1995). These drug discontinuation-related syndromes may be due to changes in DA receptor sensitivity or imbalances in dopamine-cholinergic counter-regulatory systems (Amore & Zazzeri, 1995; Chouinard & Chouinard, 2008).

Other important side effects of FGA drugs relate to their effects on alpha-adrenergic, cholinergic, and histamine receptors, which are more likely to be seen with the low potency drugs. Alpha-receptor blockade can result in dizziness, orthostatic hypotension, and reflex tachycardia. Conversely, abruptly stopping these drugs can cause rebound anxiety, restlessness, sweating, tremors, abdominal pain, heart palpitations, headache, and hypertension.

Dry mouth, constipation, blurred vision, and urinary retention are due to the anticholinergic effects of these drugs, and stopping them can be associated with an anticholinergic discontinuation syndrome characterized by cholinergic rebound. Symptoms include nausea, vomiting, abdominal cramping, sweating, headache, and muscle spasms.

The pharmacology of SGA drugs is relatively more complicated than that of FGA drugs. Because they share the DA-2 receptor blocking effects of FGA drugs, they are classified as antipsychotic drugs and are all approved for the treatment of schizophrenia. However, SGA drugs have significantly greater effects on blocking 5HT-2 receptors (a serotonin receptor subtype) compared with FGA drugs. Also in contrast to FGA drugs, SGA drugs have effects on other neurotransmitters and receptors, especially alpha-adrenergic receptors, although these pharmacological effects vary among each of the SGA drugs. These unique SGA pharmacological properties have two important clinical implications: They are generally less likely to be associated with adverse motor syndromes, and they have antidepressant-like effects.

Because DA-blocking drugs have antimanic effects, FGA and SGA drugs are all effective for the acute treatment of mania. However, the additional antidepressant effect of SGA drugs imparts mood-stabilizing qualities on these drugs. Although SGA drugs are less commonly associated with the basal ganglia motor syndromes, abrupt discontinuation can still be associated with withdrawal dyskinesias and a risk of developing NMS (Ahmed et al., 1998; Chouinard & Chouinard, 2008; Michaelides, Thakore-James, & Durso, 2005; Urbano, Spiegel, & Rai, 2007). Because of their alpha-adrenergic receptor effects, abruptly stopping SGA drugs can cause rebound anxiety, restlessness, sweating, tremors, abdominal pain, heart palpitations, headache, and hypertension.

Dopamine-Releasing and Dopamine-Agonist Drugs

Amantadine (Symmetrel®) is an approved treatment for influenza (type A), Parkinson’s disease, and drug-induced extrapyramidal effects (e.g., associated with antipsychotic drugs). It increases DA activity by facilitating the presynaptic release of DA and possibly blocking the presynaptic reuptake of DA. Bromocriptine (Parlodel®) is a postsynaptic DA receptor agonist approved for the treatment of hyperprolactinemia and Parkinson’s disease. It is sometimes used to treat increased prolactin secretion (from the pituitary gland) and the parkinsonian effects of antipsychotic drugs. Pramipexole (Mirapex®) and ropinirole (Requip®) are also postsynaptic DA receptor agonist drugs, although their chemical structures and mechanism is not the same as bromocriptine. Both are approved for treating Parkinson’s disease and restless legs syndrome. They are sometimes used in psychiatry when these syndromes are caused by psychotropic drugs. With prolonged use, dopamine-releasing and dopamine-agonist drugs can cause motor dyskinesias (similar to TD), which can be worsened with abrupt discontinuation. Rarely, abrupt discontinuation can be associated with NMS (Simpson & Davis, 1984).

Lithium

Lithium works via second-messenger signal transduction systems, rather than neurotransmitters, receptors, or reuptake transporters. Lithium is an approved mood-stabilizing agent for the treatment of bipolar disorder. Sudden discontinuation of lithium can be associated with significant mood instability and an increased risk of mood episode relapses compared with gradual discontinuation (Baldessarini, Tondo, & Viguera, 1999; Faedda, Tondo, Baldessarini, Suppes, & Tohen, 1993). Restarting lithium, even at the same previously therapeutic dosage, might not easily or quickly lead to restabilization.

Anticonvulsant Drugs

Anticonvulsant drugs are approved for seizure disorders (epilepsy) and are often used for the treatment of migraine headaches and chronic pain syndromes. They are very commonly used in psychiatry, especially as mood-stabilizing drugs for the treatment of bipolar disorder (some are approved for this indication), but also for the treatment of some anxiety disorders, behavioral dys-control syndromes, and alcohol and benzodiazepine withdrawal.

Anticonvulsant drugs are not pharmacologically similar. Their presumed mechanism of action in epilepsy or bipolar disorder is not clearly known, but they probably influence second-messenger signal transduction systems. The adverse effects of anticonvulsants vary from drug to drug. The most commonly used anticonvulsant drugs in psychiatry are valproic acid (Depakene®, Stavzor®), divalproex sodium (Depakote®, Depakote® ER, Depakote® DR, Depakote® Sprinkle Capsules), carbamazapine (Tegretol®, Tegretol® XR, Carbatrol®, Equetro®), lamotrigine (Lamictal®), gabapentin (Neurontin®), and topiramate (Topamax®).

When anticonvulsant drugs are used for the treatment of bipolar disorder, their abrupt discontinuation can be associated with a significant mood-destabilizing effect not unlike that seen with discontinuing antipsychotic drugs or lithium. For psychiatric patients without a history of seizures, abrupt discontinuation of anticonvulsant drugs is not likely to precipitate seizures (Callaghan, Garrett, & Goggin, 1988; Wallis, 1987). Depending on the clinical use, discontinuation can also be associated with increased anxiety, agitation, and sleep disturbances. Carbamazepine potently increases the metabolism of many drugs through the liver. Carbamazepine discontinuation can therefore result in decreased metabolism and increased serum concentrations of concurrently prescribed medications, leading to adverse effects or toxicity. By contrast, valproic acid and divalproex sodium can decrease the hepatic metabolism of some drugs, and their discontinuation can lead to increased metabolism and lower concentrations of co-prescribed medications. Topiramate is used to treat weight gain associated with other psychotropic drugs, and its discontinuation will usually result in regaining lost weight.

Conclusion

Adverse effects, often serious, are likely to occur after abrupt discontinuation of antipsychotic, dopamine-releasing, dopamine-agonist, and mood-stabilizing drugs. As a general practice, these medications should be gradually tapered (if it is necessary to stop them) to minimize all types of adverse discontinuation effects. Nurses should be familiar with these discontinuation effects, as they are important not only for patient monitoring but also for counseling patients and families about the importance of consistent medication adherence during treatment. Next month’s article, the last of this series, will cover benzodiazepine, glutamate, opioid, and stimulant drugs.

References

  • Ahmed, S., Chengappa, K.N., Naidu, V.R., Baker, R.W., Parepally, H. & Schooler, N.R. (1998). Clozapine withdrawal-emergent dystonias and dyskinesias: A case series. Journal of Clinical Psychiatry, 59, 472–477.
  • Amore, M. & Zazzeri, N. (1995). Neuroleptic malignant syndrome after neuroleptic discontinuation. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 19, 1323–1334. doi:10.1016/0278-5846(95)00269-3 [CrossRef]
  • Baldessarini, R.J., Tondo, L. & Viguera, A.C. (1999). Discontinuing lithium maintenance treatment in bipolar disorders: Risks and implications. Bipolar Disorders, 1, 17–24. doi:10.1034/j.1399-5618.1999.10106.x [CrossRef]
  • Callaghan, N., Garrett, A. & Goggin, T. (1988). Withdrawal of anticonvulsant drugs in patients free of seizures for two years: A prospective study. New England Journal of Medicine, 318, 942–946. doi:10.1056/NEJM198804143181502 [CrossRef]
  • Chouinard, G. & Chouinard, V.A. (2008). Atypical antipsychotics: CATIE study, drug-induced movement disorder and resulting iatrogenic psychiatric-like symptoms, supersensitivity rebound psychosis and withdrawal discontinuation syndromes. Psychotherapy and Psychosomatics, 77, 69–77. doi:10.1159/000112883 [CrossRef]
  • Dixon, L., Thaker, G., Conley, R., Ross, D., Cascella, N. & Tamminga, C. (1993). Changes in psychopathology and dyskinesia after neuroleptic withdrawal in a double-blind design. Schizophrenia Research, 10, 267–271. doi:10.1016/0920-9964(93)90061-M [CrossRef]
  • Faedda, G.L., Tondo, L., Baldessarini, R.J., Suppes, T. & Tohen, M. (1993). Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders. Archives of General Psychiatry, 50, 448–455.
  • Michaelides, C., Thakore-James, M. & Durso, R. (2005). Reversible withdrawal dyskinesia associated with quetiapine. Movement Disorders, 20, 769–770. doi:10.1002/mds.20427 [CrossRef]
  • Simpson, D.M. & Davis, G.C. (1984). Case report of neuroleptic malignant syndrome associated with withdrawal from amantadine. American Journal of Psychiatry, 141, 796–797.
  • Urbano, M., Spiegel, D. & Rai, A. (2007). Atypical antipsychotic withdrawal dyskinesia in 4 patients with mood disorders. Journal of Clinical Psychopharmacology, 27, 705–707. doi:10.1097/JCP.0b013e31815a5870 [CrossRef]
  • Viguera, A.C., Baldessarini, R.J., Hegarty, J.M., van Kammen, D. & Tohen, M. (1997). Clinical risk following abrupt and gradual withdrawal of maintenance neuroleptic treatment. Archives of General Psychiatry, 54, 49–55.
  • Wallis, W.E. (1987). Withdrawal of anticonvulsant drugs in seizure-free epileptic patients. Clinical Neuropharmacology, 10, 423–433. doi:10.1097/00002826-198710000-00004 [CrossRef]
Authors

Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.

Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: .HowlandRH@upmc.edu

10.3928/02793695-20100708-01

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