Mood Stabilizers in Prophylaxis:

Should we ever Discontinue?

E. Timuçin Oral, MD

Bakırköy Prof Mazhar Osman Research and Training Hospital

for Psychiatric & Neurological Diseases
İstanbul / Turkey
 Treatment of Bipolar Disorder

Cross
sectional

Longitudinal

Cross
sectional
 Targets of Prophylactic Treatment in
Bipolar Disorder

• Reducing mortality
• Reducing the duration of “sick period”
• Preventing relapse & recurrence
• Improving functioning & QoL
 The Consequences of Suddenly Stopping
Psychotropic Medication in Bipolar Disorder

• Li discontinuation increases the risk of mania

• Abrupt discontinuation (<2 wk) carries greater
risk than gradual (2–4 wk), no optimal period
• Discontinuation with all major ADs: hypomania
has also been reported
• Further research in BP is required for the
discontinuation effects of AC & AP drugs
• Discontinuation clinically important in choosing
treatment for non-compliant, pregnancy and in
stopping treatment after a long remission
 Defining Discontinuation

Discontinuation syndrome ?
Rebound phenomenon ?
Withdrawal effect ?

– withdrawal implies dependence (tolerance ?

Addiction ?)
– rebound requires a temporary rise in symptom
frequency to a higher level than previously
experienced

“The concept remained unproven”

Schou,1993
 Treatment Guidelines for BPD of TPD
Algorithm for “Maintenance Treatment”
E.T.Oral, 2003 (Vahip S, Yazici O: Eds)

1st episode 2nd or later episodes

Taking MS
Not taking MS
Severity of the episode
Quality of life
Positive family history
Cont. MS started at
The choice of the patient Start MS (Li) acute episode
or
Change MS
Decision: YES

Decision: NO
Full remission Recurrence or
partial/minimal response

Taper down MS and STOP Decision

Combine 2 MSs

Continue treatment
Alternatives
 Lithium Maintenance Therapy
Recommended Ranges
Schou & Baastrup,1967 0.6 to 1.5 mEq/L
APA Task Force, 1975, 0.7 to 1.2 mEq/L
Prien & Caffey, 1977 0.6 to 0.8 mEq/L
Schou, 1984 0.6 to 0.8 mEq/L < 0.4 mEq/L, risk of
relapse
NIH Consensus Panel, 1985
Schou, 1997 0.6 to 0.8 mEq/L
Recommends 0.5 to 0.8 mEq/L, but
< 0.5 mEq/L in elderly
0.8 mEq/L in younger
“Changes in serum lithium levels as small
as 0.1 to 0.2 mmol/L, upward and
downward may improve patients’ quality of
life
 Retrospective Studies that Found a
Relationship Between Lithium Level and
Response
Study N Comments
Baastrup & Schou 1967 88 80% responded at1.0
0.5mEq/L

Prien & Caffey 1976 32 > 0.1 mEq/L were no more effective1.0 than
mEq/L
0.8
0.7 mEq/L were no more effective than
Venkoba Rao & 28 12 had good
placebo. responses at >0.8 mEq/L. 6 were at
Hariharasubramanian1978 low levels,”
“very
James et al. 1980 100 Respondersmean level: 0.69 mEq/L
Nonresponders mean level: 0.58mEq/L
Sarantidis & Waters 1981 46 Fair response (n=6)
0.63 Excellent response (n=31)
0.74 mEq/L No respo
nse (n=9)0.79 mEq/L
Jann et al. 1982 30 12 switched (once = 0.66 mEq/L, twice=0.48 mE
did not switch (0.77 mEq/L).
Peselow et al. 1982 116 Significantly higher lithium level during
euthymia.
Sashidharan et al. 198253 (41 BP, good outcom
e < 0.9 mEq/L than >0.9 mEq/L.
12 UP)
Yang 1985 101 2% responded at0.490.4 mEq/L, 78% at0.790.5
mEq/L, and 20% at1.090.8 mEq/L.
 Retrospective Studies that Did Not
Find a Lithium Level-Response
Relationship
Study N Levels (mEq/L) Comment
Coppen et al. 1971 65 0.73-1.23 No relationship

Persson 1973 53 (23BP, 30 UP) average, 0.7 No significant difference in relapse

rate between <0.6 and>0.6
Dunner & Fieve 1974 55 0.7 - 1.2 No differen
cebetween responders&
nonresponders
Vinarova & Vinar 1984 39 responders 0.76
17 nonresponders 0.73
Goodnick & Fieve 1985 44 0.58vs0.87 No signifcant difference in mood
symptoms or side effects
Lokkegaard et al. 1985 153 0.73, 0.77, 0.80 No significant difference among 3
groups
Maj et al. 1985 43 responders mean: 0.65
25 nonresponders mean: 0.66
Smigan 1985 49 responders mean: 0.63
23 nonresponders mean: 0.61
Standard vs. Low Lithium Levels

• Lower range associated with a 2.6-times

increased risk of relapse
• Cycling episodes - 11 patients on low
level vs 2 on standard level
• Three or more episodes means ? effect
of lithium at either level
• Median lithium levels: 0.54 + 0.12
mEq/L (low range) and 0.83 + 0.11
mEq/L (standard range)
Patients receiving lithium doses that
achieved standard serum levels (0.8 to 1.0
mEq/L) had better psychosocial functioning
than those receiving doses that achieved
low serum levels (0.4 to 0.6 mEq/L); this
effect was partially but not wholly
mediated through relapse prevention.
Solomon et al. Am J Psychiatry
1996;153:1301-1307
• Relapse rate 50% within 5 months
90% within 1.5 year
Suppes 1991

• 10-15% of patients, well for sustained periods of

time, who chose to discontinue Li and
experienced relapse, failed to re-respond

Post 1992; Bauer 1994; Koukopulos 1995; Maj 1995; Tondo 1997

• Abrupt decreases in Li (even in therapeutic

range) were a powerful predictor of relapse
Perlis 2002
 QUESTION?
• After what duration of Li treatment do its benefits
outweigh the possible risk of recurrence on
withdrawal?

• In discontinuing Li after 6 months, the risk was

brought forward by 20 months, after 18 months
it was brought forward by ~7 months.

ANSWER:
• “Li should not be used for <2 years”

GM Goodwin, Br J Psychiatry 1994

The risk of relapse post-Li discontinuation after (A) 6 months and (B) 18 months. The control
risk in first-episode bipolar patients not treated with Li is from Mander (© The Royal College of
Psychiatrists, 1994)
 • BP women discontinued Li maintenance

• 42 pregnant X 59 nongravid followed during

pregnancy + postpartum 24 wk & equivalent
times

• Discontinuation: Rapid (<14) X Gradual (15 - 30)

• First 40 wk → little difference in recurrence

(overall 55.4 %)

• Postpartum → Pregnant : Nonpregnant = 2.9

Viguera AC, et al. Risk of recurrence of bipolar disorder in pregnant and nonpregnant women
after discontinuing lithium maintenance. Am J Psychiatry February 2000;157: 179-84
 • 3/9 women receiving Li during pregnancy had
recurrence in two weeks after delivery

• In 64-wk after Li discontinuation, recurrences

were common (85.7 % in pregnant/postpartum vs
67.8 % in nonpregnant)

• 30% of 20 pregnant X 76% of 25 nonpregnant

women remained stable 6 months more

• During first 40 wk recurrence risk was 2.5 times

shorter in rapid discontinuation.

Viguera AC, et al. Risk of recurrence of bipolar disorder in pregnant and nonpregnant women
after discontinuing lithium maintenance. Am J Psychiatry February 2000;157: 179-84
 P<0.0001
AD
Patient (%)

Viguera et al. 2001

 • Postpartum period brings great risk for women

• Postpartum recurrence can be reduced by Li

maintenance during pregnancy

• Gradually discontinuing lithium limits the

recurrence risk during the first 40 wk

Viguera AC, et al. Risk of recurrence of bipolar disorder in pregnant and nonpregnant women
after discontinuing lithium maintenance. Am J Psychiatry February 2000;157: 179-84
• 78 BPs Rapid Li discontinuation (<14 days)
Gradual discontinuation (15-30 days)
• Time to recurrence x 5.6 gradual (14 m) > rapid
discontinuation (2.5 m)

Baldessarini RJ et al, reduced morbidity after gradual discontinuation of lityum treatment

for bipolar I and II disorder: a replication study.Am J Psychiatry1997;154)

• Rapid discontinuation (<7) = 47% recurrence risk

• Special attention in rapid discontinuation needed
Baldessarini RJ, Tondo L: Recurrence risk in bipolar manic-depressive disorders after
discontinuing lithium maintenance treatment: an overview. Clin Drug Investigation 1998;
15:337-351
 Controlled Lithium Discontinuation in
Bipolar Patients with Good Response to
Long-term Lithium Prophylaxis.

O Yazıcı, K Kora, A Polat, M Şaylan

Istanbul Faculty of Medicine, University of Istanbul

J Affect Disord. 2004 Jun;80(2-3):269-71

 Discontinuation of Long-term Treatment

• BP-I (DSM-IV)
• Discontinuation of a >5 year successful,
long-term lithium prophylaxis
• Definite good response
• Controlled cessation
• Prospective follow-up
• 32 patients (16 M, 16 F)
 Discontinuation of Short-term Treatment

• BP-I (DSM-IV)
• Discontinuation of a <5 (1,5 -4,5) year
successful, long-term lithium
prophylaxis
• Definite good response
• Cessation
• Retrospective evaluation
• 30 patients (11 M, 19 F)
 Clinical Characteristics During
Discontinuation
LT ST p
Duration of illness (yr) 15 9 <0.002
Total episodes 10 5 <0.005
Li usage (yr) 6.2 2.7 <0.0001
Hospitalizations 2 1.4 NS
Age of Li use 35 33 NS
First episode ratio (%)
Mania 59 80 NS
Depression 41 20
Psychotic episodes (%) 25 33 NS
 Clinical Characteristics During
Discontinuation
LT ST p
Age of Discontinuation 41 36 NS
Psychiatrists approval (%) 100 37 <0.0001
Feeling well enough (%) 88 78 NS
Rate of Discontinuation (%) NS
Rapid 72 73
Slow 28 27
 Recurrence Rates (%)
LT ST
One Week 7 10
6 Months 32 26 NS

One Year 62 66

30% of the patients had recurrence in one

week, 50% in 6 months and more than 60%
at the end of first year.
 Results

• No differences between two groups by

means of sociodemographic variables
• There were no BP-II patients in the short-
term treatment group
• Total duration of illness, number of
episodes, duration of lithium usage and
approval of discontinuation by physician is
hisgher in LT group
 Results

• Episode type, severity latency and rate of

recurrence are equal in both groups
• Being in prophylactic treatment more than
5 years did not make any difference in
recurrence rate when Li was discontinued
•
Discontinuation of Valproate in BP Maintenance:
One-year follow-up

Toksoy OM, Erten E, Verimli A, Oral ET

Bakırköy State Teaching and Research Hospital

for Psychiatry & Neurology / Istanbul

European Neuropsychopharmacology 12-S212

Suppl. 3 2002
Objective

The risk of a new episode and predictors

of treatment were investigated in BP
patients being in remission at least for 6
months after the discontinuation of VPA
which was started as an adjuvant agent
to Lithium during the acute episode and
continued during the maintenance period
of treatment.
INCLUSION CRITERIA EXCLUSION CRITERIA

DSM-IV BP I Abnormal EEG

6 m remission Epilepsia
Li+VPA in prevention Hx Org. Brain Disease
Age 18-65 y Not responded sole Li

66 remitted BP (34 female 32 male) in age 18-65

VPA discontinued abruptly (3 days) or slowly (15 days)

33 patients in each group
Followed for 1 year
 Li (VPA tapered in 3 d.)

Follow-up period
Li + VPA + AP Li + VPA After VPA Discontinuation

Li (VPA tapered in 15 d.)

Acute Period Main.Period

2-12 weeks 6 months 12 months

Mean age: 32.44 ±9.92 (18-58)
Male 32 (48.5%) Female 34 (51.5%)

BP history in first degree relatives 40.9 %

No correlation between life events, occupation,
marital status and episodes

Duration of Treatment
Li ONLY Li+VPA
27 (42.9%) < 2 yrs 33 (54.5 %) <1 yr
17 (27 %) 2 –5 yrs 17 (25.8 %) 1-2 yr
19 (30.2%) 5 > yrs 13 (19.7 %) >2 yr
 Ilness Characteristics
• Age of onset 24,05 ± 8,4 (14-49)
• Total # of episodes 4,24 ± 4,2 (1-20)
• Type of first episode
•Manic 75,8 %
•Depression 22,7 %
• Mixed 1,5 %
 Ilness Characteristics II
• Psychotic features 75%
•Mood Congruent 53%
•Mood Incongruent 22%

• Rapid-cycling 3%
• Seasonality 37,9%
• Premenstruel onset 5,8%
• Postpartum onset 5,8%
 Results I

Episode in the first year :28 patients (43.1%)

(11 female, 17 male)

Duration of a new episode:149 ± 91.5 (8-300 dy)

Type of the new episode:

Hypomania-mania
27.7%
Depression
13.8%
Mixed
 Results II
Type of Discontinuation / New Episode

Abruptly new episode 40.6 %

Gradual new episode 45.5 % * NS

Patients hospitalized: 17.8 % *** (All in abrupt group)

# of manic patients: 4
# of depressive patients: 1
 Blood Levels at Discontinuation

• Lithium
• 6% 0.6 mEq / lt >
•79.8 % 0.6 – 0.8 mEq / It
•14.2 % 0.8 mEq / It <

• Valproate
•54 % 45 – 60 mg / lt
•46 % 60 – 80 mg / lt
 Results
Risk of a new episode is similar between slow
and abrupt discontinuation groups. In the second
group, episodes seemed to be more severe.

Predictors of Relapse

– Prior history of suicide (p<0.01)

– Alcohol abuse (p<0.01)
– Male gender (p<0.05)
– Subsyndromal symptoms (p<0.01)
 Results
• After VPA discontinuation 56.9 % of the patients
were still in remission.

• Episodes were seen in the first 6 month of

discontinuation in 22 / 28.

• In abrupt discontinuation group, episodes were

more severe and lasted longer. (Duration of the illness
was higher in this group which may also be a reason for severity )
 Li Rebound Phenomena ?
• 2 retrospective, 4 RCT-DB, 2 RCT-CO,
1 meta-analysis
• 29 rapid Li stoppers had 51.7% recurrence in
3 months

Franks et al. The consequnces of suddenly stopping Psychotropic Medication in

Bipolar Disorder, Clinical Approaches in Bipolar Disorders 2005; 4:3)
• Meta-analysis on 14 Li discontinuation studies (n=257)
• Time to 50% relapse was 2.5 months.
Mania (med: 2.5 month) > Depression (med: 6 month)
• New episodes / month = X 27.9 between patients
continuing and discontinuing Li.
Suppes et al, Arch Gen Psychiatry 1991

• Li discontinuation may increase the risk of suicide

• 185/310 BP on long-term Li, discontinued treatment
• Risk of suicidal acts was X 7.5 greater

Tondo,L. Acta Psychiatr Scand, 2001

 Anticonvulsant Discontinuation

• AC & AP are now widely used to treat BP

• Few studies investigated the discontinuation

• One retrospective study of 6 BP discontinued

CBZ did not demonstrate a rebound effect.
Following 3 months
none of them experienced a manic episode, one
developed depression

Macritchie KA, J Psychopharmacol 2000

 Antipsychotic Discontinuation

BP patients in remission with OLZ

Continuing patients (n=225)
X
Rapid stoppers (n=136)

Recurrence OLZ PBO

Rate 46.7% 80.1%
Time 174 days 22 days

Tohen, Arch Gen Psychiatry 2005