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FORUM – IS THE RISK-BENEFIT RATIO OF LONG-TERM ANTIPSYCHOTIC TREATMENT FAVORABLE

FOR MOST PEOPLE WITH SCHIZOPHRENIA, AND WHAT CAN WE DO TO IMPROVE IT?

What is the risk-benefit ratio of long-term antipsychotic treatment in


people with schizophrenia?
Christoph U. Correll1-4, Jose M. Rubio1-3, John M. Kane1-3
1
Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA; 2Hofstra Northwell School of Medicine, Hempstead, NY, USA; 3Feinstein Institute for
Medical Research, Manhasset, NY, USA; 4Department of Child and Adolescent Psychiatry, Charite Universit€atsmedizin, Berlin, Germany

The long-term benefit-to-risk ratio of sustained antipsychotic treatment for schizophrenia has recently been questioned. In this paper, we critically
examine the literature on the long-term efficacy and effectiveness of this treatment. We also review the evidence on the undesired effects, the impact
on physical morbidity and mortality, as well as the neurobiological correlates of chronic exposure to antipsychotics. Finally, we summarize factors
that affect the risk-benefit ratio. There is consistent evidence supporting the efficacy of antipsychotics in the short term and mid term following sta-
bilization of acute psychotic symptoms. There is insufficient evidence supporting the notion that this effect changes in the long term. Most, but not
all, of the long-term cohort studies find a decrease in efficacy during chronic treatment with antipsychotics. However, these results are inconclusive,
given the extensive risk of bias, including increasing non-adherence. On the other hand, long-term studies based on national registries, which
have lower risk of bias, find an advantage in terms of effectiveness during sustained antipsychotic treatment. Sustained antipsychotic treatment
has been also consistently associated with lower mortality in people with schizophrenia compared to no antipsychotic treatment. Nevertheless,
chronic antipsychotic use is associated with metabolic disturbance and tardive dyskinesia. The latter is the clearest undesired clinical consequence
of brain functioning as a potential result of chronic antipsychotic exposure, likely from dopaminergic hypersensitivity, without otherwise clear evi-
dence of other irreversible neurobiological changes. Adjunctive psychosocial interventions seem critical for achieving recovery. However, overall, the
current literature does not support the safe reduction of antipsychotic dosages by 50% or more in stabilized individuals receiving adjunctive psy-
chosocial interventions. In conclusion, the critical appraisal of the literature indicates that, although chronic antipsychotic use can be associated
with undesirable neurologic and metabolic side effects, the evidence supporting its long-term efficacy and effectiveness, including impact on life
expectancy, outweighs the evidence against this practice, overall indicating a favorable benefit-to-risk ratio. However, the finding that a minority
of individuals diagnosed initially with schizophrenia appear to be relapse free for long periods, despite absence of sustained antipsychotic treat-
ment, calls for further research on patient-level predictors of positive outcomes in people with an initial psychotic presentation.

Key words: Long-term antipsychotic treatment, schizophrenia, benefit-to-risk ratio, efficacy, effectiveness, physical morbidity, mortality,
metabolic disturbance, tardive dyskinesia, psychosocial interventions, non-adherence, dopaminergic hypersensitivity

(World Psychiatry 2018;17:149–160)

Schizophrenia is a disorder character- during the first 1-2 years following an effects18. Such debate, and the uncer-
ized by acute episodes often followed by acute psychotic episode2-5,11. tainty in the interpretation of long-term
symptom improvement1. Most guidelines Clinical guidelines do not provide sys- studies, with inherent biases12,19, results in
recommend at least 1-2 years of antipsy- tematic recommendations for treatment unclear recommendations for clinicians.
chotic treatment after symptom remis- continuation or discontinuation beyond In this paper, we review the literature
sion of an acute episode2-5. Of those dis- 1-2 years, yet they warn about the risks on the potential risks and benefits of long-
continuing antipsychotic treatment, up of relapse associated with treatment dis- term antipsychotic treatment, summa-
to 75% have a relapse within 12 to 18 continuation2-5,11. The effects of antipsy- rizing the evidence of efficacy, effective-
months6,7. Meta-analyses of 26 to 52 chotic treatment beyond the first 2 years ness, tolerability, physical morbidity and
week studies comparing second-genera- of treatment are not well understood, mortality, as well as functional and struc-
tion antipsychotics vs. placebo in the given the lack of double-blind, placebo- tural brain changes associated with that
prevention of relapse found a very fa- controlled randomized trials (RCTs)9. treatment. Additionally, we review the role
vorable number-needed-to-treat (NNT) There has been an emerging body of of interventions to optimize such risk-
of 3-58,9. literature on the long-term effects of anti- benefit ratio.
Risks of acute antipsychotic treatment, psychotics questioning their necessity12-15.
compared with placebo, mostly include Long-term animal studies of antipsycho-
weight gain, metabolic disturbance, QTc tic exposure16, naturalistic cohorts14,15,
prolongation, neurologic adverse effects and treatment discontinuation studies13 EFFICACY, EFFECTIVENESS AND
and sedation10. It is generally accepted have been cited by some authors who TOLERABILITY
that, given the usually moderate magni- claim that antipsychotics do not improve
tude of these potential side effects and outcomes in the long term, and that there The longer the study, the more likely
the availability of strategies to manage may even be iatrogenic adverse conse- that systematic error accumulates over
them, as well as the efficacy of antipsy- quences of long-term antipsychotic treat- time and biases the results. Measurements
chotics in preventing relapse, antipsycho- ment17. Others suggest that there is in- tend to prioritize feasibility over reliability;
tics have a favorable risk-benefit balance sufficient evidence supporting iatrogenic the intervention is less controlled due to

World Psychiatry 17:2 - June 2018 149


greater influence of environmental fac- with a 2% greater likelihood of being the top eight antipsychotic monothera-
tors; and there is greater chance of sys- non-adherent for each point of increase pies that were significantly superior re-
tematic or non-random drop-outs differ- in body mass index, and a 25% greater garding hospitalization risk compared to
ing between the arms of the trial. likelihood of being adherent in individu- not receiving any antipsychotic (hazard
Hence, the interpretation of the re- als living independently. In this study, ratios, HRs50.51-0.64) were LAIs (with
sults should consider how each one of no other undesired outcomes were asso- the two oral antipsychotics being cloza-
these potential biases affects the study. ciated with adherence status30. pine and olanzapine)37.
Interpretation should also consider the Long-acting injectable (LAI) formula- In a meta-analysis that compared ad-
literature, not isolated studies. Here, we tions have also provided meaningful data. verse effects with LAIs vs. the same oral
summarize the available data separately When LAIs and oral formulations were antipsychotics across sixteen RCTs with a
for different methodological approaches, compared in RCTs, no overall difference mean duration of one year, those prepara-
as all have their own strengths and limi- was found regarding relapse prevention tions did not differ regarding 115 (96.6%)
tations20-22. in the mid term after stabilization31. This of the 119 reported adverse effects38.
is not surprising, given that the control LAIs were more likely to present with
groups taking oral medication in these akinesia, low-density lipoprotein cho-
Treatment adherence and long- RCTs tend to include patients with better lesterol change and anxiety, whereas
acting injectable antipsychotic treatment adherence and lower illness se- oral antipsychotics were associated with
studies verity. Non-adherence levels did not dif- greater hyperprolactinemia. Furthermore,
fer across ten meta-analyzed trials with there were no differences regarding treat-
The longer the treatment, the greater adherence data (p50.27)31. ment discontinuation due to side effects
the chance of insufficient adherence9,23,24. When the same question was address- and mortality38. Little is known, how-
Data from administrative claims in the ed by meta-analyzing mirror-image stud- ever, about differences in adverse events
US suggest that, in clinical practice, pa- ies, where each research participant acts beyond one year of treatment.
tients with psychosis treated in an out- as his/her own control, LAI treatment Overall, assuming that the main advan-
patient setting fill their prescriptions an phases, compared to those with oral an- tage of LAI over oral antipsychotics is
average of 40-60% of the days prescrib- tipsychotics, were associated with a sig- lower risk of non-adherence, this litera-
ed25. Adherence studies find that poor nificantly 57% lower risk of a next hos- ture supports the relationship between
mid-term adherence ranges from 11.6% pitalization and a 62% reduced risk of suboptimal adherence in the long term
based on self-report to 58.4% in studies number of hospitalizations32. This is not and greater risk of relapse27,39, while dif-
using serum concentration23. In addition simply the result of the order of the oral ferences in adverse effects are small within
to high rates of insufficient adherence24, and LAI phases, as two trials confirmed the time span of one year.
we lack practical/reliable measures of that the reverse switch (i.e. from an LAI
exposure26. to an oral antipsychotic) was associ-
In a systematic review and meta- ated with poorer outcomes for the oral Placebo-controlled antipsychotic
analysis of longitudinal studies examin- phase33,34. maintenance treatment studies
ing relapse and its risk factors in patients The finding of greater effectiveness of
following stabilization after a first psy- LAIs in mirror image studies was repli- Methodologically, placebo-controlled
chotic episode, non-adherence was found cated in a meta-analysis of cohort stud- maintenance RCTs have the advantage
to be the greatest predictor of relapse ies, where the number of hospitalizations of minimizing systematic differences be-
among twenty variables in seven long- was reduced by 15% (14 studies; 60,260 tween groups, yet their time frame is
term studies, increasing the chance of re- person-years), despite greater illness se- only mid-term (i.e., 1-3 years following
lapse by 400%27. Individuals in another verity in the LAI cohorts than the oral an- stabilization), and their results assume
study with non-adherence for >1 month tipsychotic treatment cohorts (p50.014)35. full long-term adherence with antipsycho-
of an 18-month follow-up had a five- Results were particularly apparent in tics (which is known to decrease over
fold greater chance of relapse than indi- Scandinavian registries, that have fully time24). Increasing non-adherence even
viduals with continuous treatment28. generalizable national samples. In a Finn- in RCTs could lead to finding lower ef-
Poor adherence was also found to ex- ish national cohort, individuals treated fect sizes in studies of longer duration.
plain up to 36% of the effect of cannabis naturalistically with LAIs after their first A meta-analysis of 65 placebo-control-
on the number of relapses29. Individuals hospitalization for a schizophrenia epi- led maintenance RCTs found an overall
with suboptimal adherence were found to sode had one third the risk of re-hospi- NNT of 3 favoring antipsychotics over
have greater body mass index and were talization than individuals on oral coun- placebo in preventing relapse, but overall
less likely to live in independent housing terparts of the same antipsychotics36. treatment effects tended to decrease as a
than individuals with continuous adher- This was replicated in a Swedish cohort function of study duration9. The propor-
ence over 18 months. The magnitude of including all phases of illness, following tion of individuals unimproved/worse
these risk factors was small to moderate, patients for a median of 6.9 years. Six of was lower on antipsychotics, but this

150 World Psychiatry 17:2 - June 2018


difference decreased over time and was which followed 70 individuals with schizo- associated with these treatment strategies
non-significant in the longer-term studies. phrenia from early illness for 20 years, compared with long-term continuation of
Supporting the hypothesis that increas- 8% of the 15 unmedicated individuals antipsychotic treatment. DRDD studies
ing non-adherence on antipsychotics could had some degree of psychotic symptoms, often have the advantage of a longer time
decrease antipsychotic maintenance ef- versus 68% of the 25 individuals treated span than antipsychotic maintenance tri-
ficacy, the authors found a significantly continuously with antipsychotics14. In als, yet with greater degree of randomiza-
greater relapse preventive effect (p50.03) the Northern Finland 1966 Birth Cohort, tion and control than naturalistic cohort
in studies comparing LAIs vs. placebo which followed patients for almost 20 studies.
(HR50.31) than oral medications vs. pla- years, those who were off antipsychotics Wunderink et al13 conducted the study
cebo (HR50.46). In LAI studies, non-ad- were more often in remission, and no with the longest follow-up period to date,
herence could be identified and non- differences in remission rates between consisting of two phases. In the first
adherent patients were discontinued or treatment groups were found41,42. Simi- phase, 131 individuals with a first episode
excluded from the analyses9. larly, the OPUS cohort in Denmark found of psychosis were allocated to 2 years of
The number of patients with at least that, among the 90% of the individuals either symptom guided DRDD or treat-
one adverse effect did not differ between who did not have sustained remission 10 ment continuation48. The initial goal of
antipsychotics and placebo, and did not years after their first episode, more were stopping antipsychotic treatment in the
increase over time for individuals on on than off antipsychotics43,44. DRDD group was changed to dose reduc-
antipsychotics. No differences were ob- Nevertheless, in those non-randomiz- tion only, due to too many relapses after
served in sedation, although weight gain ed, uncontrolled studies, adherence lev- antipsychotic discontinuation. In the sec-
and at least one movement disorder els to antipsychotic treatment are un- ond phase, 103 individuals were evalu-
were significantly more frequent during known, and most importantly, there is a ated once after 5 years of uncontrolled
antipsychotic treatment9. high risk of confounding by indication community treatment13. In the initial
and reverse causation, in that greater ill- RCT, the DRDD group had twice as many
ness severity could be the cause of con- relapses as the maintenance group (43%
Long-term cohort studies tinued antipsychotic treatment, rather vs. 21%, p50.011), although about 20%
than being the effect. Interestingly, dif- were able to successfully stop the med-
Few placebo-controlled RCTs of anti- ication without relapses. There were no
ferent results were found in a retrospec-
psychotics last >3 years, with most last- differences in symptom severity, both
tive cohort study of individuals with
ing 1 year9. Most data beyond this groups having low Positive and Negative
schizophrenia whose access to antipsy-
initial period are derived from non-ran- Syndrome Scale (PANSS) scores through-
chotic treatment had been restricted. In
domized, non-controlled cohort and reg- out48. At 5 years, there were no differences
this cohort from rural China, those who
ister studies. These have the advantage of in relapse rates or symptom severity. How-
had access to antipsychotics did substan-
providing long-term data, not requiring ever, recovery rates were twice as likely
tially better after 14 years than those
consent and being highly representative in the initial dose-reduction group (40.4%
without access45.
of the overall population. However, given vs. 17.6%, p50.004), driven not by symp-
Thus, despite the pattern of patients
the lack of randomization and controlled tomatic remission (69.2% vs. 66.7%, p5
with worse outcomes being overrepre-
intervention, subgroups are subject to var- 0.79), but by functional remission (46.2%
sented in the treatment groups of several
ious types of selection biases, and conclu- vs. 19.6%, p50.01), and 8 of the 11 patients
cohort studies, the interpretation re-
sions are tentative. off antipsychotics for 2 years were in the
garding cause and effect is difficult, and
Non-randomized cohort studies often original dose-reduction condition. These
reverse causation cannot be excluded.
found that, at follow-up, individuals on results have been cited as important evi-
On the other hand, results from large,
antipsychotics had equal or greater ill- dence that antipsychotics could post-
national samples analyzed with statistical
ness severity compared with those off pone rather than prevent relapse, while
methods to adjust for baseline differences
antipsychotics. For example, in the Suf- impacting negatively on functional re-
support the notion that treatment failure
folk county cohort, 175 individuals with covery in the long-term12,14,15,17,19.
and hospitalization37, as well as mortality
schizophrenia showed a clinical decline These findings should be interpreted
risk from suicide46,47, are significantly
over the 20-year follow-up period40. This with caution. As the authors acknowledge,
greater in patients not receiving antipsy-
decline occurred despite high and con- the participants had very low symptom
chotics than in those who are.
stant rates of antipsychotic prescription severity. Their conclusions might not
(86.9% at baseline and 81.8% 20 years apply to more severely ill patients. Also,
later), and antipsychotic use was asso- Dose-reduction and dose- the difference in antipsychotic exposure
ciated with worse Global Assessment of discontinuation studies between the two groups was only ques-
Functioning (GAF) scores and negative tionably clinically meaningful (1.4 mg/
symptoms, yet lower disorganization Dose-reduction and dose-discontinua- day of haloperidol equivalents), without
and excitement40. In the Chicago cohort, tion studies (DRDD) evaluate outcomes significant differences in months per

World Psychiatry 17:2 - June 2018 151


patient without antipsychotic prescrip- ceive long-term antipsychotic treatment. life expectancy of individuals with schizo-
tion. Less than 50% of the sample ap- There is consistent evidence, though, sup- phrenia across different settings.
proached for the original RCT agreed to porting the efficacy of antipsychotics in A recent systematic review and meta-
participate, and only 43.7% of the pa- preventing relapse in the mid term (i.e., analysis including 11 studies from vari-
tients at baseline were diagnosed with 1-3 years) following stabilization. These ous countries found a weighted mean
schizophrenia48. Therefore, it remains pos- data come from studies of adherence, decrement in life expectancy of 14.5 years
sible that the results were related to fac- trials of LAIs, national registries, placebo- in patients with schizophrenia, with sig-
tors other than the 2-year intervention controlled maintenance trials and DRDD nificant variations depending on gender
(i.e., DRDD or antipsychotic maintenance trials. and country64. While overall life expec-
dose continuation), which was followed Most, but not all, of the studies with tancy has recently increased in developed
by 5 years of uncontrolled community follow-up >3 years reported worse out- countries, it is concerning that patients
care, especially given the small dose dif- comes associated with continued anti- with schizophrenia appear not to have
ferences between treatment arms at 7 psychotic use. However, these results are benefited from such improvements, so
years. The lack of blinded assessment and inconclusive, given small and selective that the mortality gap affecting these pa-
reverse causation could also have influ- patient samples and extensive risk of tients has increased65. The drivers of this
enced the results. bias13-15. Conversely, long-term register excess mortality seem to be poor physical
Antipsychotic dose reduction vs. stan- studies of much larger and representative health and decreased health care service
dard maintenance dose has also been national cohorts of patients diagnosed utilization in patients with schizophre-
examined in other studies with shorter with schizophrenia confirmed significant- nia66,67.
follow-up. In a meta-analysis of 13 trials ly less treatment failure and suicide-re- In the US, natural causes account for
with follow-up of 24 and 104 weeks (11 lated mortality in antipsychotic-treated a vast majority of deaths, with only 1/7
trials lasting 1 year), Uchida et al49 patients compared to those not treated related to unnatural causes (accidents,
found no differences between low anti- with antipsychotics37,46,47. suicide or homicide). Chronic medical
psychotic dose (50-100% of the defined In conclusion, there is a strong evi- illness associated with smoking, obesity
dence supporting mid-term efficacy, and and a sedentary lifestyle account for
daily doses50) and standard antipsychotic
a lack of convincing evidence against most of the variance in premature mor-
dose, with respect to overall treatment
long-term efficacy of antipsychotic treat- tality. These results seem to vary across
failure (p50.53) or hospitalization (p5
ment. countries, likely reflecting public health
0.40). Yet, very low dose (<50% of the
defined daily doses50) were associated characteristics. A 10-year longitudinal
with greater risk of hospitalization (p5 study in Ethiopia found that premature
0.002) and relapse (p50.0004). In a pilot PHYSICAL MORBIDITY AND mortality was double in patients with
MORTALITY schizophrenia, with infectious diseases
study, cognitive symptoms were signifi-
accounting for almost half of the causes
cantly improved when the antipsychotic
Schizophrenia is associated with a of premature death, and with a greater
dose was reduced to 50% of the defined
role of suicide in premature mortality68,69.
daily dose51. well-established excess of physical mor-
bidity and premature mortality, while A similar pattern has been found in other
A more recent uncontrolled discon-
antipsychotics are associated with car- developing countries70,71.
tinuation study with an intermediate
diovascular risk factors53-60. The metabolic and cardiovascular side
follow-up period found greater rates of
Individuals with schizophrenia have a effects of long-term antipsychotic treat-
symptom recurrence and lower func-
greater prevalence of sedentary lifestyle, ment have been a source of concern as
tional status in 46 individuals who had
obesity, cardiovascular illness, diabetes, possible contributors to the increase of
recovered from a single psychotic epi-
nicotine smoking and tobacco-related physical morbidity and premature mor-
sode and who had opted to being treated
disorders, sexually transmitted diseases, tality, especially in developed countries
with DRDD compared to 22 patients
obstetric complications, and altered where most of the mortality in schizo-
who had opted for continuation of anti-
pain sensitivity61,62, while also having low- phrenia is related to consequences of
psychotic treatment for 3 years52.
er rates of health care services utilization metabolic disturbance and cardiovascular
and medical treatment for such condi- disease55,56,72. While the metabolic conse-
Comments tions, which results in large unaddressed quences of long-term antipsychotic treat-
gaps in medical care63. While it is unclear ment are widely appreciated53,54,57,58,60,
There is a trade-off of strengths and the role that differences in health care sys- the understanding of their contribution
weaknesses between study designs, with tems play in physical morbidity in schizo- to morbidity and mortality in schizo-
generally greater chance of bias in longer- phrenia, given the limited availability of phrenia has evolved over the last several
term studies and, especially, uncontrolled comparable data from a variety of coun- years.
studies in which more symptomatic and tries61, it seems clear that this morbidity There has been a growing literature
impaired patients are more likely to re- plays an important role in reducing the identifying health care service utilization

152 World Psychiatry 17:2 - June 2018


patterns in schizophrenia associated with ate or low – doses had low mortality rates not receiving antipsychotics. This finding
worse outcomes. In a national Swedish due to suicide46. has been replicated with large effect sizes
cohort, individuals with schizophrenia Beyond these individual findings, a in various national registries, adjusting
were less likely to have received a diag- recent meta-analysis found a consistent for an extensive number of potential con-
nosis of cancer or ischemic heart disease association of antipsychotic use and dec- founders, and with some evidence sug-
at the moment of dying of these causes73. rement in all-cause mortality, with some gesting a time and dose effect.
These data suggest poor prevention and evidence of a dose effect75. The seeming Though these data are limited by their
early treatment of medical conditions. In disconnect between adverse antipsychot- observational nature, they are consistent
another sample, individuals with schizo- ic cardiovascular effects in short- and enough to provide support for a favor-
phrenia diagnosed with cardiovascular longer-term studies and reduced (or, at able risk-benefit balance for the long-
illness were less likely to use lipid-low- least, not elevated) all-cause and cardio- term use of antipsychotics in schizo-
ering and anti-hypertensive medication, vascular illness-related mortality in long- phrenia in reducing mortality.
which was altogether associated with term database studies may be explained
worse outcomes74. To what extent anti- by a beneficial link between improved
psychotic treatment moderates the asso- psychiatric symptom control and im-
ciation between schizophrenia and poor BRAIN STRUCTURE AND
proved healthy lifestyle behaviors as well
health care utilization is not yet well un- FUNCTIONING
as access to medical care78.
derstood. Despite being consistent, these register-
The role of antipsychotics in reducing Schizophrenia has been associated with
based findings should not be interpreted
premature mortality in schizophrenia various brain volumetric abnormalities
as clearly establishing a causal relation-
has been better characterized. Despite since the emergence of neuroimaging79.
ship between long-term antipsychotic
antipsychotic treatment elevating car- However, the nature and clinical relevance
treatment and reduced all-cause mortal-
diovascular risk factors, long-term treat- of these findings still remain unclear80,
ity, given the limitations of observational
ment is consistently associated with low- and even less so the role of antipsychot-
studies. However, national registries, de-
er mortality rates compared to no long- ics18. The cortical and subcortical regions
spite their exposure to potentially un-
term treatment46,47,75-77, but still higher found to have lower volume in schizophre-
measured confounders, currently consti-
rates than in individuals without schizo- nia have most frequently been the ante-
tute the most adequate method to assess
phrenia46. rior cingulate cortex, insula, hippocam-
the long-term effects of antipsychotics
National registries constitute the best pus, and thalamus81,82, although several
on morbidity and mortality. Future re-
approach to study the relationship be- other areas have been implicated, with
search should improve their design by
tween long-term antipsychotic treatment variability across studies probably due to
adjusting analyses for relevant potential
and all-cause mortality as well as mortal- methodological differences.
confounders that have not been mea-
ity related to cardiovascular illness, given Never treated patients with chronic
sured (e.g., body mass index, metabolic
the availability of cumulative dose data. schizophrenia show a significantly ac-
values, psychiatric illness symptom se-
In a seminal study, Tiihonen et al47 found celerated decline in prefrontal and tem-
verity, and functionality).
that, compared to individuals with schizo- poral cortical thickness83, suggesting a
phrenia not receiving antipsychotic treat- neurodegenerative illness course. Re-
ment, those with longer antipsychotic Comments duced hippocampal and thalamic vol-
treatment had greater decrements in pre- umes have been observed in individuals
mature mortality, including from cardio- Individuals with schizophrenia have at high risk of developing psychosis84.
vascular causes47. Given the possible sur- significantly greater physical morbidity High-risk individuals who transitioned
vivor bias, the same group studied the and premature mortality than the gen- to psychosis presented with further pro-
role of cumulative antipsychotic dose over eral population. While this finding is gression of the whole brain volume re-
a 5-year period in influencing mortality related to unhealthier lifestyle and lower duction, even before antipsychotic treat-
in schizophrenia adjusting for an exten- health care service utilization, the role of ment85, and reductions in brain regions,
sive number of variables. They found in antipsychotics is less clear. Long-term such as the anterior cingulate, have been
a separate sample that all – low, moder- antipsychotic treatment is associated identified as potential biomarkers indica-
ate and high – antipsychotic cumulative with significantly greater rates of meta- tive of greater risk of transition to psycho-
doses were associated with lower mortal- bolic and cardiovascular risk factors and sis86. Despite grey matter reduction being
ity rates than no antipsychotic use. Pa- disease, yet patients treated with anti- a consistent finding, what this means at
tients with schizophrenia with low and psychotics over the long-term seem to the neuropathological level is unclear87-91.
moderate – but not high – cumulative have significantly lower mortality rates, Brain tissue loss is a non-specific find-
doses of antipsychotics had lower rates including death due to cardiovascular ing, observed with antipsychotic expo-
of mortality due to cardiovascular disease, disease, at low and moderate doses, com- sure92, changes in body weight93, alco-
whereas those with high – but not moder- pared to individuals with schizophrenia hol use94,95, and steroid use96. Volumet-

World Psychiatry 17:2 - June 2018 153


ric changes in drug-na€ıve patients do psychotic withdrawal found that after one quence of long-term antipsychotic use
not seem to be correlated with clinical year there were no differences in volumetric that has been associated with dopami-
impairment or duration of illness, not parameters between the two groups102. nergic supersensitivity110, but also other
supporting a neurodegenerative hypoth- Brain volume reductions need to be possible mechanisms111, and with great-
esis83-86,97. A more recent perspective is interpreted within the context of the ef- er risk in genetically vulnerable popu-
that volumetric reductions reflect a re- fects of untreated psychosis and of clini- lations112.
duction of neuropil80, and that volumet- cal outcome findings. The reanalysis of a The estimated risk of tardive dyskine-
ric variations can be heterogeneous in study that had raised considerable con- sia with first-generation antipsychotics
schizophrenia, although decrements in cern about the potential dose-dependent is 3-5% per year of exposure (at least
specific regions, such as the anterior cin- adverse effect of antipsychotic treatment for the first 5 years)113, being lower
gulate cortex, might be more homoge- on brain tissue loss103 revealed that the with second-generation antipsychotics114.
neous and therefore more specific to duration of psychosis had a 3-fold greater Early parkinsonism and higher antipsy-
that disorder98. detrimental effect on total brain and fron- chotic doses have been associated with
A generalized decrement of grey mat- tal lobe grey matter loss compared to the this side effect115. A recent meta-analysis
ter volume associated with antipsychotic duration of antipsychotic treatment104. estimated a global mean prevalence of
treatment duration and cumulative doses Furthermore, brain volumetric changes 25% in patients with schizophrenia treat-
has been repeatedly reported92,99. How- do not seem to correlate with poor clin- ed with antipsychotics, with great vari-
ever, these studies are limited by the fact ical response or outcomes. In patients ability depending on geographical and
that the duration and cumulative dose of treated with clozapine, both a grey mat- treatment-related factors115.
antipsychotics can be a marker of illness ter decrement and a clinical improve- Some studies reported that patients
severity or illness duration, making it ment have been reported105, whereas in with tardive dyskinesia are at greater risk
difficult to distinguish a reduction due to other studies the opposite was found106. of rebound psychosis upon antipsychotic
illness severity, illness duration or anti- Moreover, measuring volumetric brain withdrawal116, development of treatment
psychotic exposure. In a meta-analysis of changes during antipsychotic treatment resistance117, and physical morbidity and
longitudinal studies, the grey matter dec- without assessing functional brain status mortality118, although these results have
rement was directly related to the cumu- confuses the discussion. A cross-section- not been consistently replicated119. The
lative dose of first-generation antipsy- al study in 23 antipsychotic-treated and degree to which chronic antipsychotic ex-
chotics during the window of observa- 21 untreated first-episode patients found posure plays a role in these potential out-
tion, whereas the opposite was true for significant cortical thinning within the comes associated with tardive dyskinesia
second-generation antipsychotics97. This former group in the dorsolateral pre- (i.e., whether, beyond causing that side
finding is difficult to interpret and, as ac- frontal and temporal cortex. However,
effect, chronic antipsychotic treatment has
knowledged by the authors, may in part the medicated patient group showed sig-
a causal role in these outcomes) is not well
be due to confounders, such as weight nificantly higher dorsolateral prefrontal
understood120.
gain associated with second-generation cortex activation and significantly better
Second-generation antipsychotics should
antipsychotics. cognitive performance than the unmedi-
be first-line maintenance treatment agents
Other findings contradict the notion cated group107.
to decrease the risk of tardive dyskinesia.
that antipsychotics cause a decrement Thus, the evidence does not seem to
Two agents, valbenazine and deutetrabe-
in grey matter in schizophrenia. The support a causal or detrimental relation-
nazine, have been recently approved in
ENIGMA neuroimaging consortium found ship between long-term antipsychotic
the US for the treatment of this side effect
that, among 2,028 patients, antipsychotic- use and clinically relevant brain volu-
of antipsychotic treatment, having shown
na€ıve individuals had greater volumetric metric changes, with some data even
moderate to high efficacy121,122.
deficits in the hippocampus compared suggesting that brain volume reductions
Following the hypothesized mecha-
with antipsychotic-treated ones100, where- could be associated with better brain
nism underlying tardive dyskinesia, do-
as thalamus and basal ganglia volume network integration.
deficits in untreated patients have been Contrary to the ambiguous literature pamine supersensitivity related psycho-
found to be corrected with antipsychotic on structural changes with chronic treat- sis either during antipsychotic treatment
treatment92,100. A longitudinal study com- ment, findings on functional changes or upon antipsychotic discontinuation
paring grey matter volumes before and have been more consistent. Long-term has been a theoretical concern117,123. The
after initiation of antipsychotic treatment antipsychotic treatment has been asso- hypothesis is that chronic dopaminergic
in first-episode patients found that anti- ciated with an increase in the number blockade resulting in dopamine D2 re-
psychotics minimized these decrements, and affinity of dopamine D2 receptors, ceptor upregulation and dopaminergic
particularly in the striatum101. Another which results in a state of dopaminergic hypersensitivity in the mesolimbic path-
study of patients who were stabilized on supersensitivity, and has been replicated way may increase the risk of relapse and
antipsychotic treatment and allocated to in animal16,108 and human models109. reduce antipsychotic efficacy in the long
either antipsychotic maintenance or anti- Tardive dyskinesia is a clinical conse- term.

154 World Psychiatry 17:2 - June 2018


Dopamine supersensitivity psychosis THE ROLE OF PSYCHOSOCIAL Interestingly, the evidence supporting
was first described in a series of ten case STRATEGIES IN MODIFYING THE the efficacy of CBT in reducing psychotic
reports of patients who had abrupt onset RISK-BENEFIT RATIO OF symptoms in individuals not taking anti-
of psychosis upon the discontinuation of ANTIPSYCHOTICS psychotic medication137, or individuals
antipsychotic treatment124. The existence whose symptoms fail to respond to anti-
of this phenomenon has been contro- While symptom reduction and re- psychotic treatment138,139, has been more
versial and only supported by small sponse, as well as relapse prevention, are consistent. This finding suggests that
studies125. Nevertheless, there has been relevant outcomes, functional recovery is the impact of CBT goes beyond improv-
a recent resurgent interest in dopamine a preeminent goal of treatment in schizo- ing adherence with antipsychotic medi-
supersensitivity as a potential cause of phrenia39. Unfortunately, when using cri- cations, having an antipsychotic effect
the emergence of treatment resistance teria based on both clinical and social on its own. However, to our knowledge,
123,124,126,127
. However, a meta-analysis domains, recovery rates in schizophrenia there have not been head-to-head com-
of RCTs found no differences in relapse have remained low, with a meta-analyti- parisons of CBT with long-term anti-
rates between abrupt and gradual anti- cally derived median of 13.5% across five psychotic dose reduction strategies that
psychotic withdrawal or between differ- decades, without improvement over time would provide data about CBT as a partial
ent antipsychotic doses prior to discon- (although only two studies contributed or total substitution for long-term anti-
data to the last decade)131. While, in an psychotic treatment139.
tinuation9. Moreover, if dopamine hy-
aforementioned meta-analysis9, antipsy- Family-based psychosocial treatments
persensitivity were a major reason for
chotic maintenance treatment was supe- were another of the interventions recom-
the lack of long-term efficacy, then the
rior to placebo in preventing relapse with mended by the Schizophrenia PORT, with
partial D2 agonist aripiprazole, which
an NNT 5 3, employment rates did not evidence for reducing relapses and rehos-
has not been associated with upregula-
differ, pointing toward the need for psy- pitalizations, and improving treatment
tion of dopamine D2 receptors, at least
chosocial interventions to achieve im- adherence134. These interventions are
in adult animal models128, should be
proved functional outcomes. based on psychoeducation, and are not
associated with significantly lower re-
A recent meta-analysis found a signif- generally conceived as partial or total al-
lapse rates than full dopamine D2 antag-
icant small to medium association be- ternatives to antipsychotics, but rather as
onists, but there are no data to support
tween clinical outcomes and personal augmentation. In a large Chinese study
this129,130.
recovery, but psychotic symptoms – that randomized first-episode patients to
which are the main target of antipsy- antipsychotic treatment alone or aug-
Comments chotic medications – showed a smaller mented with family interventions for one
correlation than affective symptoms with year, those in the augmentation arm were
Overall, tardive dyskinesia is the clear- personal recovery132. These data under- less likely to discontinue antipsychotics,
est adverse clinical consequence in brain score that antipsychotics alone are insuf- showed greater improvements in insight,
functioning of long-term antipsychotic ficient and that adjunctive multimodal social functioning and activities of daily
treatment, which may be related to dopa- psychosocial treatments are needed to living, as well as access to employment
mine supersensitivity in a subgroup of help stabilized patients achieve personal or education140. These results have been
vulnerable individuals. This risk should recovery goals133. substantially replicated141. In a trial that
be evaluated when considering long- The Schizophrenia Patient Outcomes compared family interventions augment-
term antipsychotic treatment, and pre- Research Team (PORT)134 reviewed the ing regular or reduced antipsychotic dose,
ventive strategies utilized. In addition, evidence supporting a wide variety of those treated with low-dose antipsychot-
patients should be examined before initi- psychosocial interventions for the long- ics and family therapy were more likely to
ating treatment to determine the pres- term treatment of schizophrenia. The relapse than those with family therapy
ence of preexisting abnormal involuntary committee recommended eight psycho- and regular antipsychotic dose142.
movements. social interventions with various indica- More recently, the Recovery After an
Other effects of long-term antipsy- tions and for different populations. Of Initial Schizophrenia Episode - Early Treat-
chotic treatment on brain structure and these, cognitive behavioral therapy (CBT) ment Program (RAISE-ETP) study tested
function, particularly neuropathological was specifically recommended, with evi- the feasibility and effectiveness of the
changes and the risk of dopamine super- dence supporting its efficacy in reducing integration of various psychosocial and
sensitivity psychosis, are insufficiently positive, negative and overall symptoms pharmacological interventions in the treat-
substantiated. The current literature does in individuals treated with antipsychotic ment of 404 first psychotic episode pa-
not provide consistent evidence to sup- drugs135. While one of the goals of CBT is tients in 34 community clinics across the
port irreversible functional and structural psychoeducation on antipsychotic drug US133. This study compared coordinated
brain changes as a consequence of long- adherence, the efficacy of CBT in improv- specialty care (which included CBT-based
term antipsychotic treatment other than ing this outcome has been inconclu- psychotherapy, family education and sup-
tardive dyskinesia. sive136. port, supported education and/or employ-

World Psychiatry 17:2 - June 2018 155


ment, and guided pharmacotherapy) with INDIVIDUAL DIFFERENCES IN THE ing genetic151 and neuroimaging152-154
treatment as usual, showing superiority RISK-BENEFIT RATIO OF LONG- perspectives. Also, individual risk scores
of the former in improving quality of life, TERM ANTIPSYCHOTIC based on clinical variables have been
increasing time in education or at work, TREATMENT developed to predict transition from clin-
and reducing symptom severity133. Be- ical high risk for psychosis to supra-
cause pharmacotherapy also differed be- While the diagnosis of schizophrenia threshold psychosis155, and future re-
tween the two compared conditions, it is has been associated with poor outcome search could develop similar models to
difficult to draw firm conclusions regard- and need for long-term antipsychotic predict treatment response. At present,
ing effects of specific modalities. How- treatment, the heterogeneity in response despite some promising findings, the field
ever, it seems unlikely that the psycho- and illness course has resulted in calls to is not ready to apply patient-level predic-
social interventions included in coordi- broaden the view towards a psychosis tors of antipsychotic response in real-
nated specialty care could serve as sub- syndrome with variable outcome pat- world care156. Future research should
stitute to medications, rather than as an terns147,148. Some studies suggest that a equally address the development of pre-
effective augmentation strategy, given the minority of patients could potentially dis- diction models for successful treatment
lack of differences in the antipsychotic continue antipsychotic treatment without discontinuation.
dose used between the two arms143. risk of relapse. The literature indicates
While psychosocial interventions seem that this would apply to between 4% and Comments
effective augmenting strategies, rather 30% of the patients that are stabilized
than partial or total alternatives to anti- after an acute episode43,48,52,149,150. To date there is no evidence-based
psychotics, they can help improve the This variable range likely reflects het- strategy that enables us to identify indivi-
long-term risk-benefit ratio of antipsy- erogeneity in the studied populations, duals who would benefit from antipsy-
chotics by improving symptomatic and criteria for diagnosis and relapse, dura- chotic dose reduction or discontinuation
psychosocial outcomes and by reducing tion of follow-up, and exposure to non- with minimal increase in relapse risk. Fu-
the risk of cardiometabolic side effects. pharmacologic interventions. Therefore, ture research should capitalize on the re-
A meta-analysis of various non-phar- we need better epidemiological data and cent advances in patient-level predictors
macological interventions, ranging from predictors of successful antipsychotic of treatment response in order to identify
healthy lifestyle and behavioral inter- discontinuation in patients presenting these low-risk individuals.
ventions to CBT-based psychotherapies, with a psychotic syndrome consistent
demonstrated their effectiveness in sig- with a diagnosis of schizophrenia. Some
nificantly reducing body weight, body studies have identified abrupt onset and
older age, female gender, higher GAF
CONCLUSIONS AND
mass index and serum lipids associated
RECOMMENDATIONS
with antipsychotic use144. Some of these scores, working, having a partner, living
advantages persisted over time. Unfortu- independently and the absence of sub-
Overall, antipsychotic maintenance
nately, challenges in engagement limit the stance abuse as significant predictors
treatment should be recommended for
effectiveness of these interventions145,146. of better outcomes43,149, whereas others
the mid term (i.e., 1-3 years), since there
have not been able to find any signifi-
is strong evidence supporting efficacy of
cant predictors52.
Comments antipsychotics in reducing relapses over
A more consistent observation, how-
this time frame. Data on long-term out-
ever, is that previous successful anti-
Psychosocial interventions are effec- comes are more equivocal and, although
psychotic withdrawal predicts successful
tive augmentation strategies for the the effect of antipsychotics seems to
withdrawal during follow-up13,43,48,149.
treatment of schizophrenia, particularly decrease over time, this could be an
This finding indicates that a minority of
CBT-based interventions, which seem to artifact of long-term study designs. In-
individuals with a psychotic syndrome
have antipsychotic effects independent creasing non-adherence and reverse
fulfilling criteria for schizophrenia can
of improving antipsychotic adherence. causation may play a significant role in
successfully discontinue antipsychotic
These interventions can be effectively treatment, and the risk of relapse proba- the observed time trends, while alter-
implemented beyond academic centers. bly decreases as they move past a critical native hypotheses, including dopamine
Evidence suggests that psychosocial high-risk period for relapse. However, to supersensitivity psychosis, are less well
interventions can improve the long-term date, there is no reliable evidence-based substantiated.
risk-benefit ratio of antipsychotics by method to identify such individuals. Additionally, mortality and neuropa-
improving functional, recovery-focused This question, however, may benefit thological findings do not support an
outcomes and by decreasing the burden from research that is being conducted accrual of damage from cumulative anti-
associated with antipsychotic treatment, aimed at patient-level prediction of treat- psychotic dose and duration (with the
rather than by necessarily allowing a ment response. A wide range of predic- exception of tardive dyskinesia). On the
decrease in antipsychotic doses. tors have been recently identified, involv- contrary, long-term antipsychotic main-

156 World Psychiatry 17:2 - June 2018


tenance treatment has consistently been sus the risks of antipsychotic treatment, 12. Murray RM, Quattrone D, Natesan S et al.
Should psychiatrists be more cautious about
associated with lower all-cause and and clearly present the probability of re-
the long-term prophylactic use of antipsy-
specific-cause mortality compared to lapse when stopping or continuing anti- chotics? Br J Psychiatry 2016;209:361-5.
antipsychotic discontinuation in large psychotic treatment. While the uncer- 13. Wunderink L, Nieboer RM, Wiersma D et al.
Recovery in remitted first-episode psychosis
national and representative samples of tainty is largest after the first episode of
at 7 years of follow-up of an early dose reduc-
patients with schizophrenia. psychosis, following a second episode tion/discontinuation or maintenance treat-
Despite lack of long-term random- the arguments for antipsychotic mainte- ment strategy: long-term follow-up of a
nance treatment are even greater. 2-year randomized clinical trial. JAMA Psy-
ized, placebo-controlled trials and resid- chiatry 2013;70:913-20.
ual uncertainty regarding a subgroup of Future research should include pre- 14. Harrow M, Jobe TH, Faull RN. Does treatment
patients who fulfill criteria for schizo- dictive models of successful treatment of schizophrenia with antipsychotic medica-
discontinuation in addition to predic- tions eliminate or reduce psychosis? A 20-
phrenia and who may only suffer one year multi-follow-up study. Psychol Med
single psychotic episode, it is reasonable tion of treatment response. 2014;44:3007-16.
to recommend antipsychotic treatment 15. Harrow M, Jobe TH, Faull RN et al. A 20-year
multi-followup longitudinal study assessing
in the long term (i.e., >3 years), although whether antipsychotic medications contrib-
with several additional suggestions. Con- ACKNOWLEDGEMENT ute to work functioning in schizophrenia.
tinued antipsychotic treatment with The first two authors contributed equally to this Psychiatry Res 2017;256:267-74.
paper. 16. Samaha A-N, Seeman P, Stewart J et al.
50% of the standard defined daily dose “Breakthrough” dopamine supersensitivity
should be implemented (going below during ongoing antipsychotic treatment leads
such doses increases the risk of relapse). to treatment failure over time. J Neurosci
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