by Emily Wheeler
Editor’s note: We know that our reviews of the withdrawal
literature are incomplete, and we urge readers to help us add to
them. Please send study citations that are relevant to the
withdrawal literature for mood stabilizers to rwhitaker@madinamerica.com.
1) Balon R, Yeragani VK, Pohl RB, Gershon S. Lithium discontinuation: withdrawal or relapse? Compr Psychiatry 1988;29:330-4. PubMed link
8) Ahluwalia P, Singhal R. Effect of low-dose lithium administration and subsequent withdrawal on biogenic amines in rat brain. Br J Pharmacol 1980;71(2):601-607. PubMed link
23) Rifkin A, Quitkin F, Howard A, Klein D. A study of abrupt lithium withdrawal. Psychopharmacologia 1975;44(2):157-158. PubMed link
53) Baastrup P, Poulsen J, Schou M, Thomsen K, Amdisen A. Prophylactic lithium: double blind discontinuation in manic-depressive and recurrent-depressive disorders. Lancet 1970;2(7668):326-330. PubMed link
83) Baldessarini R, Tondo L, Faedda G, Suppes T, Floris G, Rudas N. Effects of the rate of discontinuing lithium maintenance treatment in bipolar disorders. J Clin Psychiatry 1996;57(10):441-448. PubMed link
Introduction
The class of drugs known as “mood stabilizers” is a disparate group of medications with different theorized mechanisms of action and effects. The classification of mood stabilizer is itself contested, with no standardized definition. This document will review the drugs lithium and the “antiepileptic” or “anticonvulsant” medications carbamazepine, lamotrigine, and valproate/divalproex/sodium valproate. As the longest prescribed drug in the class, lithium is the most thoroughly researched, although areas of needed research exist across this class of drugs as a whole.Mechanism of Action
Various theories of the mechanisms of action of lithium and other mood stabilizers have been proposed, but no prevailing or unifying theory has been established. Thus is it unknown how the neurochemical effects of these drugs result in any therapeutic effects, nor how their withdrawal might affect users.1) Balon R, Yeragani VK, Pohl RB, Gershon S. Lithium discontinuation: withdrawal or relapse? Compr Psychiatry 1988;29:330-4. PubMed link
Balon et al. review
animal and human studies of lithium discontinuation, including the
possible pathophysiological explanation for rebound phenomena. The
authors conclude that the research is mixed, and that no research has
specifically addressed the neurochemical basis of withdrawal from
lithium.
2) Williams R, Cheng L, Mudge A, Harwood A. A common mechanism of action for three mood-stabilizing drugs. Nature 2002;417(6886):292-295. PubMed link
In this article, the
authors propose that a common mechanism of action in which lithium,
carbamazepine, and valproic acid “inhibit the collapse of sensory neuron
growth cones and increase growth cone area.”
3) Harwood A, Agam G. Search for a common mechanism of mood stabilizers. Biochem Pharmacol 2003;66(2):179-189. PubMed link
Authors review the search for a common
mechanism of action among mood stabilizers, as a means of understanding
their therapeutic effects and justification for being a unified class of
drugs. While reviewing some possibilities, the authors conclude that no
common mechanism has been established, nor theory of common action.
4) Post R. Kindling and sensitization as models for affective episode recurrence, cyclicity, and tolerance phenomena. Neurosci Biobehav Rev 2007;31(6):858-873. PubMed link
In this article, Post outlines his
kindling hypothesis of treatment of bipolar disorder, including the
hypothesis and supporting research that discontinuation of lithium
treatment can lead to a refractory period. In the refractory period,
Post proposes that outcomes may be worse than before the introduction of
treatment and that reintroduction may not achieve the same effects,
although this phenomenon only occurs in 10-15% of patients.
5) Moncrieff J. The Myth of the Chemical Cure: A Critique of Psychiatric Drug Treatment. 2009; New York: Palgrave Macmillan. Publisher link
Moncrieff’s critical text on psychiatric
drugs includes two chapters on drugs used to treat bipolar disorder.
Moncrieff discusses the lack of consensus on a biological theory or
animal model of bipolar disorder that would explain or justify the
effects of mood stabilizers. She proposes that theoretically the
withdrawal effects of lithium could be accounted for by a rebound from
its toxic effects, resulting in excitability of the nervous system. She
also reviews research on effectiveness of lithium and other mood
stabilizers.
6) Schloesser RJ, Martinowich K, Maji HK. Mood stabilizing drugs: mechanisms of action. Trends Neurosci 2012;35:36-46. PubMed link
The authors discuss recent research on
the effect of mood stabilizing drugs and that, “at least some of the
therapeutic effects of mood-stabilizing drugs appear to be induced by
activating neurotrophic and neuroprotective pathways, and related
intracellular signaling pathways.” The reason for their therapeutic
effects, or how to identify more effective drugs, are unknown.
7) Malhi GS, Tanious M, Das P, Coulston CM, Berk M. Potential mechanisms of action of lithium in bipolar disorder. CNS Drugs 2013;27:135-153. PubMed link
The authors review research on the
various theories of mechanisms of action of lithium from microscopic to
macroscopic levels, including that lithium affects enzymes involved in
second messenger systems that then modulate neurotransmission, resulting
in generally inhibitory effects, and that lithium may also be
neuroprotective. However, it is unknown why or how lithium’s varied
neurochemical effects are implicated in the treatment of mania and
depression.
Animal Studies
Animal studies have attempted to explain treatment efficacy of mood stabilizers, as well as account for any “rebound” effects of withdrawal from these drugs. In many cases, withdrawal rat studies suggest that some effects of these medications are reversible whereas others persist after discontinuation.8) Ahluwalia P, Singhal R. Effect of low-dose lithium administration and subsequent withdrawal on biogenic amines in rat brain. Br J Pharmacol 1980;71(2):601-607. PubMed link
The authors found that lithium
administration and withdrawal affected levels of tyrosine, tryptophan,
noradrenaline, dopamine, 3-Methoxy-4-hydroxyphenylglycol,
3,4-dihydroxyphenylacetic, and 5-Hydroxytryptamine. Effects varied
across different brain regions. Two days of withdrawal of lithium did
not result in a straightforward return to baseline levels.
9) Ahluwalia P, Singhal R. Monoamine uptake into synaptosomes from
various regions of rat brain following lithium administration and
withdrawal. Neuropharmacology 1981;20(5):483-487. PubMed link
The authors examined noradrenaline,
dopamine, and 5-hydroxytryptamine (5-HT) uptake across different brain
regions during lithium administration and 2 days of withdrawal. Lithium
administration resulted in variable effects on uptake across different
regions; withdrawal resulted in return to control levels in all regions
except the dopamine and 5-HT uptake in the striatum and 5-HT uptake in
the midbrain. The authors propose that “rebound” mania following lithium
withdrawal may be a result of this persistent effect on monoamine
uptake.
10) Ahluwalia P, Singhal R. Effect of lithium treatment and
withdrawal on uptake of noradrenaline into rat brain synaptosomes: a
kinetic study. Prog Neuropsychopharmacol Biol Psychiatry 1982;6(4-6):339-342. PubMed link
The authors report on a rebound
phenomenon related to noradrenaline uptake following lithium withdrawal.
In control animals, two different uptake mechanisms for noradrenaline
were found, one low-capacity mechanism and one high-capacity mechanism.
Following withdrawal of lithium, uptake returned to control levels in
the low-capacity mechanism but further increased uptake in the
high-capacity mechanism. The authors posit that the noradrenaline uptake
increase seen in the high-capacity mechanism may help explain “rebound”
mania seen after lithium withdrawal.
11) Christensen S, Hansen B, Faarup P. Functional and structural changes in the rat kidney by long-term lithium treatment. Ren Physiol 1982;5(2):95-104. PubMed link
The authors observed renal concentrating
ability is impaired during long-term (21 week) administration of lithium
in rats and that these effects were completely reversed upon drug
withdrawal, despite reports that impairment can persist in humans.
12) Ahluwalia P, Singhal R. Comparison of the changes in central
catecholamine systems following short- and long-term lithium treatment
and the consequences of lithium withdrawal. Neuropsychobiology 1984;12(4):217-223. PubMed link
This study provides support that
withdrawal of lithium, in this case following either short-term or
long-term treatment, does not lead to a return to normal states in
central catecholamine systems in the rat brain.
13) Lerer B, Globus M, Brik E, Hamburger R, Belmaker R. Effect of
treatment and withdrawal from chronic lithium in rats on
stimulant-induced responses. Neuropsychobiology 1984;11(1):28-32. PubMed link
The authors found inhibition of
hyperactivity induced by a lower dose of stimulants but not by a higher
dose during administration of lithium. After withdrawal from lithium,
rats showed a subsensitivity to this hyperactivity response; the authors
theorize a relationship between this subsensitivity and reports of
psychotic symptoms in humans following withdrawal.
14) Ahluwalia P, Singhal R. Kinetics of the uptake of monoamines into
synaptosomes from rat brain. Consequences of lithium treatment and
withdrawal. Neuropharmacology 1985;24(8):713-720. PubMed link
Results of this study suggest increased
uptake of dopamine during lithium treatment across observed brain
regions, whereas withdrawal resulted in decreased uptake below control
levels.
15) Berggren U. The effect of chronic lithium administration and
withdrawal on locomotor activity and apomorphine-induced locomotor
stimulation in rats. J Neur Transm 1988;71(1):65-72. PubMed link
Berggren observed no change in in
apomorphine-induced locomotor stimulation in rats following
administration of lithium, but reported an increase in stimulation
following withdrawal. This effect was short-term, with no difference
found 4 days after withdrawal, suggesting a temporary increased
sensitivity of dopamine receptors.
16) Barros H, Tannhauser S, Tannhauser M, Tannhauser M. Effect of sodium valproate on the open-field behavior of rats. Braz J Med Biol Res 1992;25(3):281-287. PubMed link
Rats were observed for 14 days following interruption of sodium valproate treatment, with no changes in behavior observed.
17) Carli M, Morissette M, Hébert C, Di Paolo T, Reader T. Effects of
a chronic lithium treatment on central dopamine neurotransporters. Biochem Pharmacol 1997;54(3):391-397. PubMed link
The authors found some effects of lithium
on dopamine systems, supporting the role of dopamine in affective
disorders, but did not find any prolonged effects following 48 hours of
lithium withdrawal.
18) Miki M, Hamamura T, Kuroda S, et al. Effects of subchronic
lithium chloride treatment on G-protein subunits (Golf, Ggamma7) and
adenylyl cyclase expressed specifically in the rat striatum. Eur J Pharmacol 2001;428(3):303-309. PubMed link
The authors found an increase in
G-protein after 2 weeks of lithium administration, and that levels did
not return to baseline levels until 1 week after withdrawal. The authors
discuss the possible relationship between these results and “rebound”
mania phenomena after lithium withdrawal.
19) Sattin A, Senanayake S, Pekary A. Lithium modulates expression of TRH receptors and TRH-related peptides in rat brain. Neuroscience 2002;115(1):263-273. PubMed Link
The authors report the observed effects
of acute and chronic lithium administration and its withdrawal on
Thyrotropin-releasing hormone (TRH) receptors and TRH-related peptides.
Lithium administration resulted in varied effects (both increases and
decreases) in different brain regions, and opposite effects in the
48-hours of observed withdrawal. Observed withdrawal effects were not
equivalent to a return to baseline levels.
20) Pekary A, Sattin A, Meyerhoff J, Chilingar M. Valproate modulates
TRH receptor, TRH and TRH-like peptide levels in rat brain. Peptides 2004;25(4):647-658. PubMed link
The authors report on the effects of
valproate on TRH levels, finding that TRH levels increased with
valproate administration and persisted after two days of withdrawal from
treatment. The authors discuss these results in light of theories of
this drug’s mood regulating potential.
21) Ferrie L, Young A, McQuade R. Effect of chronic lithium and
withdrawal from chronic lithium on presynaptic dopamine function in the
rat. J Psychopharmacol 2005;19(3):229-234. PubMed link
The authors found in this study that
lithium administration decreased presynaptic dopamine release in rats
and that dopamine release levels returned to normal once lithium was
withdrawn. The authors conclude that lithium’s effects on dopamine
release are not related to rebound mania phenomena.
22) Ferrie L, Young A, McQuade R. Effect of lithium and lithium
withdrawal on potassium-evoked dopamine release and tyrosine hydroxylase
expression in the rat. Int J Neuropsychopharmacol 2006;9(6):729-735. PubMed link
The authors found that lithium treatment
attenuated release of dopamine in treated rats and that this effect
persisted 3 days after withdrawal of lithium. Thus, these results do not
suggest a “rebound” effect of withdrawal on dopamine release, as has
been theorized due to recurrent mania in humans.
Withdrawal Symptoms
The main concern in withdrawal of mood stabilizing drugs is potential “relapse,” principally in the form of manic episodes. Research related to relapse is discussed in the “Discontinuation Success Rate” section below, although some researchers have suggested that the experience of mania after withdrawal from mood stabilizers is a withdrawal reaction rather than relapse. Reports of other withdrawal symptoms are mixed, from no effects to more typical drug- withdrawal symptoms such as anxiety and irritability to kidney-related effects related to lithiumwithdrawal. Some research suggests that mood stabilizers are protective against suicidality, such that withdrawal may increase this risk.23) Rifkin A, Quitkin F, Howard A, Klein D. A study of abrupt lithium withdrawal. Psychopharmacologia 1975;44(2):157-158. PubMed link
Twelve participants were prescribed
lithium for 6 weeks and then abruptly withdrawn to placebo. The authors
compared reported side effects in the last week of lithium and the first
week on placebo. Reported symptoms were similar, leading the authors to
conclude that lithium does not produce withdrawal effects.
24) Rabin E, Garston R, Weir R, Posen G. Persistent nephrogenic
diabetes insipidus associated with long-term lithium carbonate
treatment. Can Med Assoc J 1979;121(2):194-198. PubMed link
This case report describes persistent
urine concentration ability of the kidneys of a woman for 4 years
following discontinuation of lithium. The authors conclude that the
persistent renal effects were likely related to lithium administration.
25) Christodoulou G N, Lykouras E P. Abrupt lithium discontinuation in manic-depressive patients. Acta Psychiatr Scand 1982:65:310-314. PubMed link
Eighteen patients were discontinued from
lithium and followed for 15 days. The authors found reduced side effects
and no withdrawal symptoms in their sample, although 3 individuals
relapsed within the first four days of discontinuation.
26) King JR, Hullin RP. Withdrawal symptoms from lithium: four case reports and a questionnaire study. Br J Psychiatry 1983;143:30-5. PubMed link
This questionnaire study surveyed lithium
users about withdrawal symptoms. Users reported short-term anxiety as a
symptom, as well as longer-term effects such as increased emotional
responsiveness, improved concentration, and decreased thirst.
27) Bendz H. Kidney function in a selected lithium population. A prospective, controlled, lithium-withdrawal study. Acta Psychiatr Scand 1985;72(5):451-463. PubMed link
By studying withdrawal effect, the author
found that long-term use of lithium effects kidney functioning in both
reversible and irreversible ways.
28) Goodnick P. Clinical and laboratory effects of discontinuation of lithium prophylaxis. Acta Psychiatr Scand 1985;71(6):608-614. PubMed link
Twelve patients who had been taking
lithium for at least a year and were in remission discontinued lithium
for three weeks and completed weekly rating scales regarding mood
symptoms and side effects. No significant changes in mood symptoms or
relapses were found. Side effects decreased after two weeks of
discontinuation, particularly renal functioning improvement.
29) Balon R, Yeragani VK, Pohl RB, Gershon S. Lithium discontinuation: withdrawal or relapse? Compr Psychiatry 1988;29:330-4. PubMed link
The authors conclude that little evidence
documents “true” withdrawal (i.e., symptoms not attributable to
relapse) but that its existence is probable, with symptoms of anxiety,
irritability, and disturbed sleep.
30) Duncan J, Shorvon S, Trimble M. Withdrawal symptoms from phenytoin, carbamazepine and sodium valproate. J Neurol Neurosurg Psychiatry 1988;51(7):924-928. PubMed link
This withdrawal study was conducted in
order to determine withdrawal symptoms from these medications in the
treatment of seizures and seizure disorders. Faster and slower rates of
withdrawal were compared to a control group that maintained the
medications. No significant differences in symptoms were found between
groups.
31) Souza F, Mander A, Foggo M, Dick H, Shearing C, Goodwin G. The
effects of lithium discontinuation and the non-effect of oral inositol
upon thyroid hormones and cortisol in patients with bipolar affective
disorder. J Affect Disord July 1991;22(3):165-170. PubMed link
The authors monitored hormone levels in
14 individuals who were withdrawn from lithium treatment. Significant
changes in hormones were found among the participants, which the authors
related to the research supporting decreased thyroid functioning during
lithium treatment. Seven of the participants relapsed following
withdrawal, and relapse was not associated with changes in hormones.
32) Suppes, T, Baldessarini, RJ, Fredda, GL, Tohen, M. Risk of
recurrence following discontinuation of lithium treatment in bipolar
disorder. Arch Gen Psychiatry 1991;48:1082–1088. PubMed link
This article reviews research on the
risks to users following discontinuation from lithium, first and
foremost the risk of relapse. The possibility of a risk of users
becoming refractory to lithium after discontinuing and then
reintroducing it, as well as increased suicide risk, are discussed in
terms of a being areas of concern that require further research.
33) Post R, Leverich G, Altshuler L, Mikalauskas K. Lithium-discontinuation-induced refractoriness: preliminary observations. Am J Psychiatry 1992;149(12):1727-1729. PubMed link
The authors present a case study of four
individuals diagnosed with bipolar disorder who experienced relapses
following discontinuation of long-term treatment, followed by
ineffectiveness of the treatment once reinstated. The authors suggest
that this refractoriness may be a withdrawal effect.
34) Schou M. Is there a lithium withdrawal syndrome? An examination of the evidence. Br J Psychiatry 1993;163:514-518. PubMed link
After reviewing research evidence, the
author concludes that little quality evidence of a withdrawal syndrome
for lithium had been produced to date. In the review, Schou explores
other interpretations of reported symptoms and methodological weaknesses
of studies that have led to inconclusive results.
35) Ketter T, Malow B, Flamini R, White S, Post R, Theodore W. Anticonvulsant withdrawal-emergent psychopathology. Neurology 1994;44(1):55-61. PubMed link
The authors studied psychopathology
symptoms that occurred during withdrawal of anticonvulsant
(carbamazepine, valproic acid, or phenytoin) drugs used to treat
seizures among 32 participants. Tapering ranged between 5 and 45 days.
The authors found increases in reported symptoms in the final week of
tapering, followed by dramatic increases once the drugs were
discontinued. Moderate to severe pathology was documented in 12
participants, including 2 with psychotic symptoms. The authors conclude
that this symptomatology may have been due in part to withdrawal
effects.
36) Swartz C, Dolinar L. Encephalopathy associated with rapid decrease of high levels of lithium. Ann Clin Psychiatry 1995;7(4):207-209. PubMed link
This case study documents neurotoxicity
following rapid withdrawal from high doses of lithium, which the authors
distinguish from toxicity resulting from high doses of lithium alone.
37) Bendz H, Sjödin I, Aurell M. Renal function on and off lithium in
patients treated with lithium for 15 years or more. A controlled,
prospective lithium-withdrawal study. Nephrol Dial Transplant 1996;11(3):457-460. PubMed link
Results supported decreased kidney functioning in long-term lithium patients that persisted for 9 weeks after withdrawal.
38) Darbar D, Connachie A, Jones A, Newton R. Acute psychosis
associated with abrupt withdrawal of carbamazepine following
intoxication. Br J Clin Pract 1996;50(6):350-351. PubMed link
This case study discusses the incidence
of psychotic symptoms, including agitation and paranoid delusions, after
withdrawal from a toxic dose of carbamazepine in a patient with no
history of psychosis.
39) Tondo L, Baldessarini R, Floris G, Rudas N. Effectiveness of
restarting lithium treatment after its discontinuation in bipolar I and
bipolar II disorders. Am J Psychiatry 1997;154(4):548-550. PubMed link
The authors studied the effects of
withdrawing and restarting lithium treatment, finding no evidence to
support any “refractoriness” after interruption of treatment.
40) Tondo L, Jamison K, Baldessarini R. Effect of lithium maintenance on suicidal behavior in major mood disorders. Ann N Y Acad Sci 1997;836:339-351. PubMed link
In this review, the authors discuss the evidence of an increased risk of suicidality following discontinuation of lithium.
41) Tondo, L, Baldessarini RJ, Hennen J, et al.: Lithium treatment and risk of suicidal behavior in bipolar disorder patients. J Clin Psychiatry 1998, 59:405–414. PubMed link
This article found an increased risk of
suicidality in the year following discontinuation of lithium when
compared to those who maintained treatment.
42) Baldessarini R, Tondo L, Hennen J. Effects of lithium treatment
and its discontinuation on suicidal behavior in bipolar manic-depressive
disorders. J Clin Psychiatry 1999;60 Suppl 2:77-84. PubMed link
From their review, the authors conclude
that lithium discontinuation, and particularly abrupt discontinuation,
is associated with increased risk of suicidal ideation and death by
suicide.
43) Bowden C. The ability of lithium and other mood stabilizers to decrease suicide risk and prevent relapse. Curr Psychiatry Rep 2000;2(6):490-494. PubMed link
In this review article, the author
discusses evidence of suicide risk reduction via use of lithium,
divalproex, and carbamazepine. Evidence for lithium’s effects were
mostly drawn from naturalistic studies and suggest that length of
lithium use may be a factor in the lower rates of suicidality found. The
author also discusses two trials that compared lithium to other mood
stabilizers, and that it remains unclear the extent to which any
medication reduces suicide risk versus other psychosocial interventions
delivered in the course of medication management.
44) Faedda G, Tondo L, Baldessarini R. Lithium discontinuation: uncovering latent bipolar disorder? Am J Psychiatry 2001;158(8):1337-1339. PubMed link
In this letter to the editor, the authors
comment on a recent study of discontinuation of adjunctive lithium
treatment among individuals with unipolar depression. The authors point
out that the incidence of manic episodes after lithium withdrawal, and
thus rediagnosis to bipolar disorder, is greater than would be expected
than would be expected statistically. These results suggest that manic
episodes experienced after discontinuation are withdrawal-related rather
than relapse.
45) Gelisse P, Kissani N, Crespel A, Jafari H, Baldy-Moulinier M. Is there a lamotrigine withdrawal syndrome? Acta Neurol Scand 2002;105(3):232-234. PubMed link
This case reports describes the
development of psychomotor inhibition in a patient withdrawn from
lamotrigine abruptly. The authors discuss the possibility of a
withdrawal syndrome, with typically minor and less typically severe
reactions.
46) Carmaciu C, Anderson C, Lawton C. Thyrotoxicosis after complete
or partial lithium withdrawal in two patients with bipolar affective
disorder. Bipolar Disord 2003;5(5):381-384. PubMed link
In this case study the authors describe
the emergence of thyrotoxicosis in two patients following withdrawal
from lithium, one having been withdrawn fully and the other partially.
The authors discuss possible explanations for the relationship between
withdrawal and this condition and the need for further research.
47) Yerevanian B, Koek R, Mintz J. Bipolar pharmacotherapy and
suicidal behavior. Part I: Lithium, divalproex and carbamazepine. J Affect Disord 2007;103(1-3):5-11. PubMed link
The authors compared individuals
maintained on lithium, divalproex, and carbamazepine to those withdrawn
in rates of suicidality. For all three medications, rates of suicidality
were higher after withdrawal of the medication than with treatment.
48) Frey L, Strom L, Shrestha A, Spitz M. End-of-dose emergent
psychopathology in ambulatory patients with epilepsy on stable-dose
lamotrigine monotherapy: a case series of six patients. Epilepsy Behav 2009;15(4):521-523. PubMed link
The authors identified six individuals
via retrospective chart review who experienced distressing psychiatric
symptoms during late-dose withdrawal from lamotrigine. The principal
symptoms reported were anxiety and irritability.
49) Grünfeld J, Rossier B. Lithium nephrotoxicity revisited. Nat Rev Nephrol 2009;5(5):270-276. PubMed link
This article reviews literature on the
effects of lithium use on renal functioning. The authors discuss the
costs and benefits of discontinuing lithium treatment, especially given
that discontinuation can sometimes but not always improve renal
functioning.
50) Howland R. Potential adverse effects of discontinuing
psychotropic drugs. Part 3: Antipsychotic, dopaminergic, and
mood-stabilizing drugs. J Psychosoc Nurs 2010;48(8):11-14. PubMed link
Howland reviews research on potential
withdrawal symptoms of mood instability and risk of mood episode
relapse, with the highest risk associated with more sudden
discontinuation. The anticonvulsants have different side effects, but
generally discontinuation is also associated with mood instability, as
well as anxiety, agitation, and sleep disturbance. These drugs, and thus
their discontinuation, also affect metabolism of other medications.
51) Werneke U, Ott M, Renberg E, Taylor D, Stegmayr B. A decision
analysis of long-term lithium treatment and the risk of renal failure. Acta Psychiatr Scand 2012;126(3):186-197. PubMed link
The authors discuss relative risks and
benefits of lithium continuation and discontinuation in response to
kidney disease. The authors conclude that lithium continuation is still
recommended in most cases given risk of relapse and suicide upon
discontinuation.
52) Chen M, Zhang W, Guo Z, Zhang W, Chai Y, Li Y. Withdrawal
reaction of carbamazepine after neurovascular decompression for
trigeminal neuralgia: a preliminary study. J Neurol Sci 2014;338(1-2):43-45. PubMed link
Ninety patients were followed after
carbamazepine withdrawal; 26 patients reported withdrawal symptoms
within 4 days of withdrawal. Symptoms included insomnia, dysphoria,
hallucination, hand fremitus, and headaches, and symptoms alleviated
within 1 week.
Discontinuation Success Rates
The incidence of withdrawal-related relapses is fairly well-established for lithium, although less is known about discontinuation of other drugs in this class. Differentiation of symptoms that result from drug withdrawal from a recurrence of illness is not systematic in the research literature, making it difficult to assess withdrawal (see Peter Breggin’s book Psychiatric Drug Withdrawal: A Guide for Prescribers, Therapists, Patients, and Their Families and Guy Chouinard’s article “Issues in the clinical use of benzodiazepines: potency, withdrawal and rebound” in the Journal of Clinical Psychiatry for further discussion of this issue). Dropouts from clinical studies also complicate this research. Shorter term studies favor drug-treated groups over those taking placebo in terms of risk of relapse, but longer term studies suggest that the risk of relapse is comparable for those who maintain drug treatment and those who withdraw. In addition, the time spent withdrawing the drug treatment may affect the risk of relapse, with abrupt withdrawal increasing that risk. (See “tapering speed” section below.”)53) Baastrup P, Poulsen J, Schou M, Thomsen K, Amdisen A. Prophylactic lithium: double blind discontinuation in manic-depressive and recurrent-depressive disorders. Lancet 1970;2(7668):326-330. PubMed link
The authors found that 21 of 39 patients
discontinued from lithium relapsed during the trial, whereas none of the
patients who continued taking lithium relapsed. The authors reported
that the relapses were distributed across the period of the trial (5
months) and did not indicate “rebound” effects.
54) Small JC, Small IF, Moore DF. Experimental withdrawal of lithium in recovered manic-depressive patients. Am J Psychiatry 1971:127:1555-1558. PubMed link
In this case study five patients were
withdrawn from lithium; the authors found that 4 of the 5 patients
relapsed within seven weeks of withdrawing from the drug.
55) Lapierre Y D, Gagnon A, Kokkinidis L. Rapid recurrence of mania following lithium withdrawal. Biol Psychiatry 1980:15:859-864. PubMed link
In this study of 20 patients who were
withdrawn from lithium after a long period of mood stability, 4 were
found to relapse within one week. The authors suggest that the manic
relapses were rebound phenomena, reflecting a reaction to lithium
withdrawal.
56) Klein H, Broucek B, Greil W. Lithium withdrawal triggers psychotic states. Br J Psychiatry 1981;139:255-256. PubMed link
In this study of lithium withdrawal of 21
patients, 11 patients relapsed within two weeks of discontinuation.
Among the other 10 participants, discontinuation symptoms of anxiety,
irritability, disturbed sleep, and some mood lability were reported.
57) Margo A, McMahon P. Lithium withdrawal triggers psychosis. Br J Psychiatry 1982:141:407-410. PubMed link
The authors of this case study of lithium
withdrawal concluded that all 4 of 4 patients relapsed with manic
episodes within 2 weeks of discontinuation.
58) Christodoulou G N, Lykouras E P. Abrupt lithium discontinuation in manic-depressive patients. Acta Psychiatr Scand 1982:65:310-314. PubMed link
Eighteen patients were discontinued from
lithium and followed for 15 days. The authors found reduced side effects
and no withdrawal symptoms in their sample, although 3 individuals
relapsed within the first four days of discontinuation.
59) Sashidharan S, McGuire R. Recurrence of affective illness after withdrawal of long-term lithium treatment. Acta Psychiatr Scand 1983;68(2):126-133. PubMed link
The authors followed 22 patients who had
discontinued lithium in this observational study and found that 16
experienced mood episode recurrence within 67 months of discontinuation.
The observed that manic episodes seemed to occur closer to
discontinuation than depressive episodes, and 4 of the 16 experienced a
mood episode within 3 months of discontinuation.
60) Mander A. Is there a lithium withdrawal syndrome? Br J Psychiatry 1986;149:498-501. PubMed link
The author compared a control group of
participants who had never taken lithium, or had taken it for less than
three months, to those who were treated with lithium. All participants
had been discharged from care and had been stable for three months
afterward. Mander found that the risk of recurrence was higher for those
who had taken lithium and discontinued use than in those who had never
taken lithium, concluding that these results support the existence of a
lithium withdrawal syndrome. Most relapses within the first three months
of discontinuation were manic rather than depressive episodes.
61) Heh C, Sramek J, Herrera J, Costa J. Exacerbation of psychosis after discontinuation of carbamazepine treatment. Am J Psychiatry 1988;145(7):878-879. PubMed link
Twenty individuals diagnosed with
schizophrenia were discontinued abruptly, with an exacerbation of
psychotic symptoms for two individuals. The authors review several
hypotheses that could account for the increase in symptoms following
discontinuation.
62) Suppes T, Baldessarini R, Faedda G, Tohen M. Risk of recurrence
following discontinuation of lithium treatment in bipolar disorder. Arch Gen Psychiatry 1991;48(12):1082-1088. PubMed link
The authors analyzed risk of recurrence
from 14 studies in which participants were discontinued from lithium.
They found that 50% of mood episodes that occurred following
discontinuation occurred within the first 10 weeks after treatment was
stopped.
63) Suppes T, Baldessarini R, Faedda G, Tondo L, Tohen M.
Discontinuation of maintenance treatment in bipolar disorder: risks and
implications. Harv Rev Psychiatry 1993;1(3):131-144. PubMed link
This review article discusses recurrence
risk following discontinuation, as well as other potential risks such as
treatment refractoriness and suicidality.
64) Scull D, Trimble MR. Mania precipitated by carbamazepine withdrawal. Br J Psychiatry 1995; 167:698. PubMed link
This case study of a woman being treated
for epilepsy with carbamazepine describes the appearance of symptoms of
mania following withdrawal, suggesting a possible relationship between
withdrawal and “rebound” mania.
65) Johnson R, McFarland B. Lithium use and discontinuation in a health maintenance organization. Am J Psychiatry 1996;153(8):993-1000. PubMed link
The authors compared rate of mental
health service use among patients who maintained lithium treatment and
those who discontinued it, finding that those who discontinued had
higher rates of psychiatric hospitalization and emergency services.
66) Coryell W, Winokur G, Solomon D, Shea T, Leon A, Keller M.
Lithium and recurrence in a long-term follow-up of bipolar affective
disorder. Psychol Med 1997;27(2):281-289. PubMed link
In this study, patients with bipolar
disorder were followed for 5 years, with one group of patients
continuing lithium prophylaxis and another group discontinuing and
patients taking lithium were compared to those who were not. The authors
suggest that lithium prophylaxis may be helpful in preventing relapse
but not recurrence, as there was no significant difference between the
two groups in rates of recurrence in the long term.
67) Kennebäck G, Ericson M, Tomson T, Bergfeldt L. Changes in
arrhythmia profile and heart rate variability during abrupt withdrawal
of antiepileptic drugs. Implications for sudden death. Seizure 1997;6(5):369-375. PubMed link
The authors studied cardiac symptoms in
ten patients following abrupt withdrawal from carbamazepine and
phenytoin in the last day of treatment and four days following
withdrawal. The authors conclude that the cardiac symptoms associated
with abrupt withdrawal may contribute to sudden unexpected deaths among
patients with epilepsy.
68) Baldessarini R, Tondo L. Recurrence risk in bipolar
manic-depressive disorders after discontinuing lithium maintenance
treatment: an overview. Clin Drug Investig 1998;15(4):337-351. PubMed link
In this review, the authors conclude that
discontinuation carries a risk of recurrence of mood symptoms,
particularly within the first year of discontinuation, but that gradual
discontinuation attenuates this risk. The authors also conclude that
individuals risk only minor loss of effectiveness of lithium if it is
reintroduced after discontinuation.
69) Baldessarini R, Tondo L, Viguera A. Discontinuing lithium
maintenance treatment in bipolar disorders: risks and implications. Bipolar Disord 1999;1(1):17-24. PubMed link
This review of the research evidence
highlights the increased risk of recurrence and suicidality after
lithium discontinuation, particularly abrupt discontinuation, and the
authors’ hypothesis that this phenomenon reflects a reaction the body’s
adaptations to long-term treatment. The authors caution interpretation
of discontinuation studies and any conclusion that the heightened
recurrence risk resulting from discontinuation in placebo arms is
comparable to non-treatment.
70) Davis J, Janicak P, Hogan D. Mood stabilizers in the prevention of recurrent affective disorders: a meta-analysis. Acta Psychiatr Scand 1999;100(6):406-417. PubMed link
In this meta-analysis, Davis et al.
conclude that maintenance lithium reduces relapses when compared to no
treatment, and they present their argument against evidence of lithium
withdrawal-related relapse.
71) Bowden C. The ability of lithium and other mood stabilizers to decrease suicide risk and prevent relapse. Curr Psychiatry Rep 2000;2(6):490-494. PubMed link
The author discusses evidence of reduced
risk of relapse when patients are maintained with lithium or divalproex
when compared to placebo, while also discussed the limitations of the
designs of earlier studies from the 1970s that overinflated the apparent
risk of relapse upon discontinuation.
72) Calabrese J, Suppes T, Monaghan E, et al. A double-blind,
placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling
bipolar disorder. Lamictal 614 Study Group. J Clin Psychiatry 2000;61(11):841-850. PubMed link
This withdrawal study found that 23 of 89
participants who withdrew to placebo had not relapsed after the 26-week
study period. Forty-nine required some intervention, and the remaining
participants withdrew before the end of the study. The authors did not
find a significant difference in the time to additional intervention
between those withdrawn to placebo and those maintained on lamotrigine.
73) Macritchie K, Hunt N. Does ‘rebound mania’ occur after stopping carbamazepine? A pilot study. J Psychopharmacol 2000;14(3):266-268. PubMed link
This pilot study followed 6 individuals
who had withdrawn carbamazepine treatment and did not support a
“rebound” effect as has been reported with lithium discontinuation.
74) Bowden C, Calabrese J, DeVeaugh-Geiss J, et al. A
placebo-controlled 18-month trial of lamotrigine and lithium maintenance
treatment in recently manic or hypomanic patients with bipolar I
disorder. Arch Gen Psychiatry 2003;60(4):392-400. PubMed link
This study compared patients who were all
treated with lamotrigine before being maintained on lamotrigine,
lithium, or placebo. Participants in the two maintenance treatment
groups had significantly longer time to a subsequent mood episode than
those who had discontinued.
75) Calabrese J, Bowden C, DeVeaugh-Geiss J, et al. A
placebo-controlled 18-month trial of lamotrigine and lithium maintenance
treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry 2003;64(9):1013-1024. PubMed link
Participants in this study were
stabilized on lamotrigine in an open-label phase and then maintained on
lamotrigine, lithium, or placebo. For those participants stabilized on
lamotrigine and then withdrawn to placebo, the median time to treatment
was significantly shorter than for those maintained on lithium or
lamotrigine. Adverse events reported by placebo participants were
headache, nausea, dizziness, tremor, rash, somnolence, diarrhea,
insomnia, and infection or influenza.
76) Jess G, Smith D, Mackenzie C, Crawford C. Carbamazepine and rebound mania. Am J Psychiatry 2004;161(11):2132-2133. PubMed link
The authors describe a case study of
patient with no history of mood disorders who experienced manic symptoms
after withdrawing from carbamazepine.
77) Biel M, Peselow E, Mulcare L, Case B, Fieve R. Continuation
versus discontinuation of lithium in recurrent bipolar illness: a
naturalistic study. Bipolar Disord 2007;9(5):435-442. PubMed link
This 2-year study followed 159
individuals who maintained treatment and 54 patients who discontinued
lithium. Illness recurrence occurred in both groups, with higher odds of
recurrence among the discontinued group.
78) Viguera A, Whitfield T, Cohen L, et al. Risk of recurrence in
women with bipolar disorder during pregnancy: prospective study of mood
stabilizer discontinuation. Am J Psychiatry 2007;164(12):1817-1824. PubMed link
Pregnant female participants who had
discontinued mood stabilizer treatment were compared to women who
maintained drug treatment up to a year postpartum. Most participants
were also taking adjunctive antidepressants. The authors reported higher
risk of recurrence of bipolar symptoms among those who had discontinued
medication, as well as longer duration of episodes. Postpartum findings
were not reported.
79) Franks M, Macritchie K, Mahmood T, Young A. Bouncing back: is the
bipolar rebound phenomenon peculiar to lithium? A retrospective
naturalistic study. J Psychopharmacol 2008;22(4):452-456. PubMed link
This study found that the “rebound” of
bipolar disorder symptoms after discontinuation of medication occurred
in the majority (74%) of cases reviewed and included those discontinuing
all medications in this class. Rates of relapse were highest among
those who had withdrawn from lithium and anticonvulsants versus those
discontinuing antidepressants or antipsychotics.
80) Moncrieff J. The myth of the chemical cure: a critique of psychiatric drug treatment. 2009; New York: Palgrave Macmillan. Publisher link
Moncrieff critically reviews clinical
trials on prophylactic treatment with lithium and other mood stabilizing
drugs, noting the many methodological issues in this research that make
it difficult to determine if long-term treatment does in fact reduce
the risk of mania and/or depression in comparison to no treatment.
81) Sharma P, Kongasseri S, Praharaj S. Outcome of mood stabilizer
discontinuation in bipolar disorder after 5 years of euthymia. J Clin Psychopharmacol 2014;34(4):504-507. PubMed link
This study followed 23 individuals
withdrawing from lithium, valproate, or carbamazepine after at least 5
years of prophylactic treatment. Discontinuation was planned over 3 to
12 months. Twenty individuals had a recurrent manic episode following
discontinuation; the time to the recurrent episode was a median of 10
months.
82) Simhandl C, König B, Amann B. A prospective 4-year naturalistic
follow-up of treatment and outcome of 300 bipolar I and II patients. J Clin Psychiatry 2014;75(3):254-262. PubMed link
The authors followed 300 patients over 4
years and found that stopping medication, either by the patient or the
prescribing psychiatrist, decreased the time to relapse in comparison to
those who maintained medication, including those who reduced their
dosage. No differences in risk to relapse were found in relation to
various demographic and clinical variables or bipolar I versus bipolar
II diagnoses.
Tapering Speed
Most researchers agree that gradual tapering (2 weeks or longer) of lithium is safer than abrupt tapering (less than two weeks). This conclusion has been broadened to other mood stabilizers, although less research supports the superiority of a particular tapering speed among the anticonvulsant drugs.83) Baldessarini R, Tondo L, Faedda G, Suppes T, Floris G, Rudas N. Effects of the rate of discontinuing lithium maintenance treatment in bipolar disorders. J Clin Psychiatry 1996;57(10):441-448. PubMed link
In this trial comparing of rapid (1-14
days) and gradual (15-30 days) discontinuation of lithium, the time to
recurrence was 5 times faster with rapid discontinuation and
specifically in the first year after discontinuation. Participants were
20 times more likely to be stable 3 years post-discontinuation following
a gradual versus rapid taper.
84) Darbar D, Connachie A, Jones A, Newton R. Acute psychosis
associated with abrupt withdrawal of carbamazepine following
intoxication. Br J Clin Pract 1996;50(6):350-351. PubMed link
Due to the incidence of psychotic
symptoms following withdrawal from a toxic dose of carbamazepine, the
authors suggested slow tapering of carbamazepine treatment given the
risk of these symptoms after abrupt withdrawal.
85) Faedda G, Tondo L, Baldessarini R, Suppes T, Tohen M. Outcome
after rapid vs gradual discontinuation of lithium treatment in bipolar
disorders. Arch Gen Psychiatry 1993;50(6):448-455. PubMed link
In comparing gradual versus rapid
discontinuation, the authors found that risk of recurrence was higher
among those who had discontinued rapidly, and that this risk was highest
within the first year of discontinuation. Beyond the first year,
recurrence rates were not significantly different between groups.
86) Baldessarini R, Tondo L, Floris G, Rudas N. Reduced morbidity
after gradual discontinuation of lithium treatment for bipolar I and II
disorders: a replication study. Am J Psychiatry 1997;154(4):551-553. PubMed link
This replication study (Faedda et al.,
1993) included a 2-year follow-up of participants withdrawn rapidly
(less than 2 weeks) or gradually (2+ weeks) from lithium. Slower
discontinuation was associated with increased latency to first relapse;
in addition, significantly more of the gradual taper group had remained
stable at the 2-year follow-up than the rapid taper group. Thus, the
authors conclude that gradual discontinuation could reduce recurrent
episodes as well as delaying them.
87) Baldessarini R, Tondo L. Recurrence risk in bipolar
manic-depressive disorders after discontinuing lithium maintenance
treatment: an overview. Clin Drug Investig 1998;15(4):337-351. PubMed link
In this review of studies on lithium
discontinuation, the authors provide support for their hypothesis that
gradual discontinuation (over 2-4 weeks) reduces risk of relapse versus
more abrupt discontinuation (2 weeks or less). The authors propose that
the brain’s need to adapt gradually to the withdrawal of lithium
accounts for this reduced risk.
88) Baldessarini R, Tondo L, Viguera A. Discontinuing lithium
maintenance treatment in bipolar disorders: risks and implications. Bipolar Disord 1999;1(1):17-24. PubMed link
In this study, the authors reviewed
research on clinical effects of lithium discontinuation, concluding that
a) discontinuation increases suicide risk and risk of relapse and b)
gradual tapering is associated with less risk.
89) Gelisse P, Kissani N, Crespel A, Jafari H, Baldy-Moulinier M. Is there a lamotrigine withdrawal syndrome? Acta Neurol Scand 2002;105(3):232-234. PubMed link
This case reports describes the
development of psychomotor inhibition in a patient withdrawn from
lamotrigine abruptly. The authors recommend withdrawal of lamotrigine
over two weeks whenever possible to reduce risk.
90) Perlis R, Sachs G, Rosenbaum J, et al. Effect of abrupt change
from standard to low serum levels of lithium: a reanalysis of
double-blind lithium maintenance data. Am J Psychiatry 2002;159(7):1155-1159. PubMed link
Ninety-four patients were followed for up
to 182 weeks after maintaining their dose of lithium or dose reduction.
The authors conclude that the abrupt change in lithium serum levels is a
stronger predictor of illness recurrence than dosage, and thus that
abrupt dose changes should be avoided.
91) Cavanagh J, Smyth R, Goodwin G. Relapse into mania or depression following lithium discontinuation: a 7-year follow-up. Acta Psychiatr Scand 2004;109(2):91-95. PubMed link
Through long-term follow-up after
discontinuation of lithium, the results of this study support that the
risk of relapse is highest immediately after acute discontinuation. The
authors did not find evidence of significantly increased risk of relapse
after the increased period of risk immediately after discontinuation.
Thank You Ms Wheeler and Mia.
