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CHAPTER 17
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Role of Antipsychotics
in Mood Disorder
Treatment
Ilang M. Guiroy, M.D.
Tyler Wright, M.D., M.P.H.
Brian W. Wu, M.D., Ph.D.
Henry A. Nasrallah, M.D.
As with many other discoveries in the history of psychopharmacology, the
use of antipsychotic medications in mood disorders began with serendipity. The first
antipsychotic agent, chlorpromazine, was initially introduced as an anesthetic (Nasrallah and Tandon 2017), but it soon became apparent that it controlled not only the
delusions and hallucinations of schizophrenia but also those of mania. Other firstgeneration antipsychotics (FGAs), such as haloperidol, were later approved for use in
mania (which is a psychotic disorder), and many of the second-generation antipsychotics (SGAs; i.e., atypical antipsychotics) were also approved by the FDA for the
treatment of mania on the basis of efficacy findings in controlled clinical trials.
The use of antipsychotic drugs for the treatment of depression began with the use
of FGAs for depression with delusions or psychosis. The first tricyclic antidepressant
(TCA), imipramine, was another serendipitous discovery, found when the three-ring
phenothiazine structure of chlorpromazine was being modified to create a new antipsychotic that turned out to help depression but not schizophrenia. Subsequently, another drug developed as an antidepressant, amoxapine, turned out to have antipsychotic properties. A popular combination for psychotic depression in the 1970s was a
single pill containing a combination of the TCA amitriptyline (trade name Elavil) and
the FGA perphenazine (Trilafon). This combination drug was called Triavil.
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When the selective serotonin receptor inhibitors (SSRIs) were introduced in the late
1980s (fluoxetine) and 1990s (sertraline, paroxetine, citalopram), it soon became ap
parent that they increase prolactin levels, which implies that they reduce dopamine
activity by increasing serotonin activity and can technically be considered to have a
mild antipsychotic effect. Finally, several SGAs demonstrated antidepressant effects
(apart from their antimanic effects), either as monotherapy for bipolar depression or
as adjunctive therapy with antidepressants for patients with depression that had not
fully responded to antidepressants (this topic is discussed later in chapter).
Finally, there are the interesting cases of ketamine and pimavanserin, both of which
have been shown to have antidepressants effects. Ketamine is a psychogenic halluci
nogen found to have rapid antidepressant effects in treatment-resistant and refractory
depression. Pimavanserin, an inverse agonist of serotonin (5-hydroxytryptamine [5
HT]) type 2A (5-HT
soever), was approved in 2016 by the FDA for treatment of delusions and hallucinations associated with Parkinson’s disease. In a recent trial (Papakostas et al. 2020),
pimavanserin demonstrated significant antidepressant effects when added to a par
tially effective antidepressant. Ketamine highlights the role of hyperactive N-methyl-
D-aspartate (NMDA) glutamate receptors as a possible etiology of depression,
whereas pimavanserin points to inverse agonism of 5-HT
mechanism for treating depression. Both are new insights into therapeutic strategies
for depression and may shed additional light on the neurobiology of depression.
) receptors (with no dopamine receptor–blocking effects what-
2A
receptors as a therapeutic
2A
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First-Generation Antipsychotics for Treatment
of Mood Disorders
Mood disorders are highly prevalent and are a critical subgroup of psychiatric disorders. They include major depressive disorder (MDD), bipolar mania, and bipolar depression (Vieta and Sanchez-Moreno 2008). Lithium has long been a first-line therapy
for the treatment of bipolar disorder (since the early 1970s), together with anticonvul
sants such as carbamazepine (since the early 1980s) and valproate (since the early
1990s). The advent of antipsychotic agents in the early 1950s led to their use in all psy
chotic disorders, a group that included not only schizophrenia and schizoaffective
disorder but also bipolar mania and psychotic depression. Beginning with chlor
promazine, a strong dopamine type 2 (D
being widely used to treat MDD with or without psychotic features, The SGAs were
modeled after clozapine to have stronger 5-HT
receptor antagonism; they were introduced in the mid-1990s and became widely used
for the treatment of bipolar disorder and MDD both as monotherapy and in combination with mood stabilizers or antidepressants.
Haloperidol, a butyrophenone derivative representing the first nonphenothiazine
antipsychotic, was an FGA that became widely used in mood disorders. Its use in bi
polar disorder was studied as early as the 1970s, but it was not until decades later that
placebo-controlled trials took place (Vieta and Sanchez-Moreno 2008). Haloperidol
was shown to be significantly more efficacious than placebo (both as monotherapy
and in combination with lithium or valproate) for the treatment of mania (Cipriani et
) receptor antagonist, the FGAs were soon
2
antagonism in addition to dopamine
2A
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al. 2006). After the introduction of the SGAs, haloperidol was found to be as efficacious
as the SGA olanzapine for bipolar mania. Haloperidol was associated with less weight
gain but higher rates of extrapyramidal side effects (EPS). The olanzapine group had
significant improvement in quality of life in several measures when compared with
the haloperidol group (Tohen et al. 2003a).
The TCA amoxapine became a popular antidepressant in the United States in the
1980s because its response time was generally faster than that of other medications in
its class (Ban 1979). However, in both human and animal studies, this TCA was found
to have antipsychotic properties but also was associated with EPS and increased prolactin levels. It is believed that these effects are due to amoxapine’s strong antidopaminergic effects (Lydiard and Gelenberg 1981).
Reduction of dopamine tone may be a mechanism shared by SSRIs and antipsychotics. One hypothesis about the etiology of SSRI-associated sexual side effects suggests that they are the result of hyperprolactinemia. Increased serotonin inhibits
dopamine activity, which leads to the release of prolactin (Lyons et al. 2016), and in
creased serotonin in the brain can act upon neural dopamine receptors (Zhou et al.
2005). SSRI-associated sexual side effects can include decreased libido, arousal issues,
and delayed or absent orgasm or ejaculation (Rosen et al. 1999); problems such as
menstrual disturbances, impotence, and decreased fertility have also been reported
and can motivate a patient to discontinue SSRI therapy (Lyons et al. 2016). Antipsy
chotics are also well known to cause sexual side effects secondary to blockade of D
receptors (Park et al. 2012).
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The First Combination Therapy of an Antipsychotic
and an Antidepressant
The combination of perphenazine, an FGA, with amitriptyline, a TCA (i.e., Etrafon or
Triavil), was targeted toward patients with schizophrenia who also presented with
depression as well as toward patients who presented with depression in addition to
agitation or anxiety. It was believed that these two drugs had additive effects when
used together and that this combination represented a “broad-spectrum psychother
apeutic agent” that would be effective for these diagnoses. In the 1960s, a series of
small studies by Dorfman (1963), Kennedy and Miller (1963), and Smith (1963) had
found this drug combination to be effective. One study (Smith e Incas 1965) found
that recurrent depressions responded most rapidly. “Excellent” response was found
in 23 of 36 patients (64%), whose diagnoses included severe disorders such as bipolar
disorder, schizophrenia, and violent tantrums.
In a study that compared amitriptyline-perphenazine combination therapy with
monotherapy of either drug in the treatment of patients with psychotic depression,
78% (14 of 18) of the patients assigned to the combination therapy were responders,
in comparison with only 41% (7 of 17) of those assigned to amitriptyline alone and
only 19% (3 of 16) of those assigned to perphenazine alone (Spiker et al. 1985).
However, as with other medications, this combination therapy should be used
with caution in patients with bipolar depression because it can precipitate a switch
into a manic or hypomanic state. A thorough patient history, including family and
psychiatric history, should be taken, and caregivers for patients who are beginning
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this therapy should monitor them closely for behavioral changes or the onset of suicidality (Angst and Marneros 2001).
When Unipolar and Bipolar Disorder Were Treated
With the Same Drugs
As far back as Ancient Greece, mania and depression have been seen as separate but
related conditions (Angst and Marneros 2001). Kraepelin was the first psychiatrist to
describe two different types of psychosis, which he labeled dementia praecox and manic-
depressive illness (Trede et al. 2005). This classification was reflected in DSM-II (American Psychiatric Association 1968), which used classifications such as recurrent mania,
recurrent depression, and recurrent mania and depression. However, beginning with DSM
III (American Psychiatric Association 1980), bipolar disorder (the new name for
manic-depressive illness) and MDD were listed as two separate conditions, with bipo
lar disorder distinguished from MDD by the presence of mania. In their review of the
differences between bipolar and unipolar depression, Cuellar et al. (2005) noted that
the separation of the two disorders in DSM-III was guided by “increasing evidence
support[ing] the biological etiology and more severe lifetime course” of bipolar disorder compared with MDD).
Distinguishing between MDD and bipolar disorder for diagnostic purposes can be
difficult because depressive episodes can be a part of both disorders (Cuellar et al.
2005). The distinction made between bipolar and unipolar depression has been a
guiding principle of research for many decades (Cuellar et al. 2005), and this distinction is important because optimal treatment depends on the accuracy of the diagnosis. Specifically, the use of antidepressant monotherapy for patients presenting with
bipolar depression can lead to negative outcomes, including increased mood instabil
ity and easier triggering of a mood episode.
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Second-Generation (Atypical) Antipsychotics
for Treatment of Mood Disorders
Bipolar Depression
Olanzapine-Fluoxetine Combination
In the past, combination therapies (e.g., amitriptyline and perphenazine) were widely
prescribed in psychiatry. However, serious side effects, including suicidality and tardive dyskinesia, led to their use falling out of favor in the 1980s. More recently, the
FDA approved a combination of fluoxetine and olanzapine (trade name Symbyax) for
the treatment of bipolar I depression (Shelton 2006). The combination of these two
medications is believed to result in higher serotonin levels, which may help depressive symptoms (Shelton 2003). In patients with nonpsychotic, nonbipolar depression
who had not responded to SSRI monotherapy, the olanzapine-fluoxetine combination
(OFC) produced improvement in symptoms within 1 week of beginning treatment.
This improvement persisted throughout the length of the trial (Shelton et al. 2001).
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However, OFC has several side effects of concern (Shelton 2006). Olanzapine and
other SGAs have been linked to metabolic dysregulation, including weight gain, hy
perlipidemia, hyperglycemia, and diabetes mellitus (Newcomer 2005). To prevent
these adverse cardiometabolic effects, a standard weight management program in
volving diet and exercise should be implemented at the start of therapy, with or without the use of appetite suppressants such as topiramate. Biometric data, such as weight
and waist circumference, should also be carefully monitored (Shelton 2006).
Quetiapine
Quetiapine (trade name Seroquel) was developed in an attempt to create a drug similar to clozapine without the risk of agranulocytosis. It is a multireceptor antagonist
that has low affinity for the D
sistent with other SGAs; it is also a strong antagonist at histamine (H
property that explains its sedative effects. The effective dosage range used in placebocontrolled clinical trials was 150–750 mg/day. The maximum plasma concentration
was observed after 1–2 hours, and the half-life was 7 hours. Quetiapine was found to
be effective for monotherapy in the acute and maintenance treatment of bipolar dis
order and to be significantly better than placebo (Nemeroff et al. 2002). Lithium and
quetiapine produced similar rates of symptom improvement; however, quetiapine
also caused significant weight gain, somnolence, and dry mouth. No significant EPS
were noted in a 12-week study (Bowden et al. 2005). In the maintenance treatment of
bipolar disorder, quetiapine taken as an adjunct to lithium or valproate is particularly
effective in reducing both manic and depressive episodes (Lindström et al. 2017).
Quetiapine was the first SGA to be approved as monotherapy for bipolar depression, by virtue of the norepinephrine reuptake inhibition side effects of its active metabolite, norquetiapine. It was found to be equivalent to lithium in efficacy (Weisler
et al. 2011). Later clinical trials showed that quetiapine’s efficacy for unipolar depres
sion was similar to that of paroxetine, but because of its metabolic side effects, quetiapine was not approved for monotherapy of depression. However, FDA approved it for
use as adjunctive therapy with an antidepressant for treatment-resistant depression
(defined as inadequate response to one to three antidepressants).
receptor and high affinity for the 5-HT2A receptor, con-
2
) receptors, a
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Lurasidone
Lurasidone (trade name Latuda) received FDA approval for the treatment of acute
depression associated with bipolar I disorder in adults (Bawa and Scarff 2015), either
as monotherapy or as adjunctive treatment to either lithium or valproate (Loebel et al.
2014). The Program to Evaluate the Antidepressant Impact of Lurasidone (PREVAIL)
was planned in 2009 by Sunovion (the manufacturer of lurasidone) to determine the
effectiveness of the drug in the treatment of depression associated with bipolar I disorder. In this 6-week double-blind monotherapy study, patients were separated into
three groups: lurasidone 20–60 mg/day, lurasidone 80–120 mg/day, or placebo. The
primary efficacy parameter was a change from baseline in total Montgomery-Åsberg
Depression Rating Scale (MADRS) score at week 6.
Based on this parameter, patients in the lurasidone-treated groups showed significantly greater improvement when compared with the placebo group (i.e., –15.4 for
both lurasidone groups and –10.7 for placebo). Additionally, the response rates were
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higher in both lurasidone-treated groups versus the placebo group, with a number
needed to treat (NNT) of 5 for both lurasidone groups. Remission rates were signifi
cantly higher for both lurasidone groups as well, with NNTs of 6 and 7 for the lower
and higher dosages of lurasidone, respectively (McIntyre et al. 2013). The manufac
turer determined that lurasidone significantly improved depressive symptoms in patients with bipolar depression at dosage ranges of 20–120 mg/day (Loebel et al. 2014).
In addition, patients who received lurasidone showed significant improvements in
scores on the Sheehan Disability Scale and a quality-of-life scale compared with pa
tients who received placebo.
Treatment-Resistant Depression
Aripiprazole as Adjunctive Therapy
Aripiprazole (trade name Abilify; Otsuka American Pharmaceutical 2020) was the
first partial agonist antipsychotic thought to stabilize the dopamine system by reduc
ing dopamine activity when it is high and enhancing dopamine activity when it is
low. Aripiprazole is an agonist of presynaptic dopamine autoreceptors, a postsynap
tic partial agonist at the D
ris et al. 2002). Time to peak plasma concentration is 3–5 hours. Aripiprazole has a halflife of 75 hours, and the active metabolite’s half-life is 94 hours (Kinghorn and McEvoy
2005). Among the antipsychotics, aripiprazole does not lengthen the QTc interval, does
not cause hyperprolactinemia, is less frequently associated with EPS (although it has
been associated with akathisia), and is less frequently associated with severe metabolic
syndrome and weight gain.
Like quetiapine, aripiprazole is FDA approved as an adjunctive therapy for treatment-resistant MDD. However, in two FDA registration trials examining the efficacy
of aripiprazole for bipolar depression, aripiprazole failed to outperform placebo. For
bipolar I disorder maintenance therapy, aripiprazole used as an adjunct to lithium or
valproic acid increased the time to relapse to depressive or manic episodes (Marcus
et al. 2011). A small study showed that over 100 weeks, aripiprazole monotherapy
was better than placebo in delaying time to manic relapse but not in delaying time to
depressive relapse (Keck et al. 2007). Aripiprazole is particularly effective as an ad
junct to SSRI therapy in treatment-resistant depression (Papakostas et al. 2005). In a
randomized, placebo-controlled study of older adults (age >60 years) with treatmentresistant depression, 44% of patients who received aripiprazole augmentation of their
antidepressant treatment (i.e., venlafaxine extended release) achieved and sustained
remission (vs. 29% of those who received placebo) (Lenze et al. 2015). A secondary
analysis of MADRS scores on specific items found that the presence of sleep disturbance and the absence of anhedonia were predictive of symptom remission in response to aripiprazole augmentation (Gebara et al. 2018).
receptor, and a partial agonist at the 5-HT1A receptor (Bur-
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Brexpiprazole as Adjunctive Therapy
Brexpiprazole (trade name Rexulti) displays partial agonism at the 5-HT1A and D
receptors and antagonism at the 5-HT2A receptor and the norepinephrine α1B and α
receptors, and it shows moderate affinity for H1 receptors. In 2015, brexpiprazole received FDA approval for adjunctive use in treatment-resistant MDD. In a doubleblind randomized controlled trial, Thase et al. (2015) found that symptom reductions
2
2c
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with brexpiprazole were clinically and statistically significantly greater than those
with placebo.
Cariprazine as Monotherapy and Adjunctive Therapy
Durgam et al. (2016a) conducted a randomized, double-blind, placebo-controlled
study to examine the effectiveness of cariprazine as an adjunct to antidepressant
treatment in patients with treatment-resistant depression. In the study, patients con
tinued their antidepressant treatment and were randomly assigned (1:1:1) to receive
adjunctive cariprazine 1–2 mg/day, cariprazine 2.0–4.5 mg/day, or placebo and were
monitored for 8 weeks. The primary and secondary efficacy parameters were change
from baseline to week 8 in MADRS and Sheehan Disability Scale scores, respectively.
On the basis of the MADRS total score, cariprazine at 2.0–4.5 mg/day was found to
be superior to placebo.
Durgam et al. (2016b) also conducted an 8-week randomized, double-blind, placebo-controlled study in patients with bipolar I depression who were currently experiencing a major depressive episode. Patients were placed into either the placebo group
or one of three fixed-dosage cariprazine groups (0.75 mg/day, 1.5 mg/day, or 3 mg/
day). The primary and secondary outcomes in this study were scores from the MADRS
and the Clinical Global Impressions–Severity scale, respectively, at 6 weeks. Only the
cariprazine 1.5 mg/day group showed statistically significant improvement on every
efficacy measure. The cariprazine 3 mg/day group showed some efficacy, but it was
not statistically significant compared with the placebo group.
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Bipolar Mania
Ziprasidone
Ziprasidone (trade name Geodon) was the fifth SGA to be developed. It is an antagonist at the 5-HT
3–7 hours. The half-life is 4–7 hours if the drug taken with food; ziprasidone is best
absorbed when taken with a meal. In comparison with other SGAs, ziprasidone is less
likely to cause metabolic syndrome or hyperprolactinemia (Caley and Cooper 2002)
but is more likely to cause QTc prolongation (Mandrioli et al. 2015). Although ap
proval of ziprasidone was initially delayed due to concerns that QTc prolongation
would increase risk for arrhythmias and torsades de pointes, postmarketing studies
have not shown an increase in nonsuicidal mortality in real-world use of ziprasidone
compared with olanzapine (Camm et al. 2012). Ziprasidone was approved for bipolar
mania but was not superior to placebo as a monotherapy treatment for bipolar I depression or as an adjunctive therapy for treatment-resistant MDD (Patkar et al. 2015).
Ziprasidone’s nonsuperiority to placebo was replicated in multiple studies, including
those examining ziprasidone as an adjunct to lithium or divalproex in patients with
acute mania (Sachs et al. 2012).
Olanzapine
Olanzapine (trade name Zyprexa) was the first SGA to receive approval as monotherapy for bipolar mania. A randomized controlled trial found olanzapine monotherapy
(5–20 mg/day) to have a faster onset of symptom reduction than divalproex (14 days
vs. 62 days) for acute mania (Tohen et al. 2003b). However, over 47 weeks, no signifi-
and D2 receptors. The time to maximum plasma concentration is
2A
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