Efficacy of Psychopharmacological Interventions for Bipolar Disorders (Lithium – Carbamazepine – Valproic acids)

Running Head: EFFICACY OF PSYCHOPHARMACOLOGICAL INTERVENTIONS FOR BIPOLAR DISORDERS
Efficacy of Psychopharmacological Interventions for Bipolar Disorders
(Lithium – Carbamazepine – Valproic acids)
Prepared by: Saefullah A. Hassan
Supervisor: Johanna Zeibig

EFFICACY OF PSYCHOPHARMACOLOGICAL INTERVENTIONS FOR BIPOLAR DISORDERS
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Abstract
Bipolar disorders are mental disorder that causes dramatic changes in the mood, individuals with bipolar
have experiences high and low moods, that known as mania and depressive episodes. The fifth
American Psychiatric Association 2013 (DSM-5) describes three types of bipolar disorder: bipolar I
disorder, bipolar II disorder, and cyclothymic disorder. Bipolar disorders is common, the particular
prevalence of bipolar disorder depends on the concept of the classification between bipolar I and II
disorders, This scientific report includes various aspects of bipolar disorders in aspects of epidemiology,
diagnosis, differential diagnosis and treatment options. In this scientific report, you will see the effect of
the three medications on bipolar patients, which include lithium, carbamazepine and valproic acid, so
that each of them has a big effect in the treatment of bipolar disorders. In this scientific report we used
different meta-analysis and RCT studies for every medication, in all the studies the effect of
psychopharmacological interventions for bipolar disorders was apparent.

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Introduction
During the last century, the concept of bipolar disorders has evolved from the Kraepelin unitary model
of manic-depressive psychosis, that included unipolar and bipolar mood disorders with repeated central
feature(Muskin, 2015).The Bipolar disorders (previously known to as manic-depressive disorders) are
mood disorders characterized by an important diagnostic feature of mania or hypomania. Generally,
these disorders follow cyclic shapes of behavior, mood, and thought changes, alternating between
depression, and mania or hypomania. These episodic changes are only the basic features of a changing
and heterogeneous group of disorders(Preston, O’Neal, & Talaga, 2013). The fifth American Psychiatric
Association 2013 (DSM-5) describes three types of bipolar disorder: bipolar I disorder, bipolar II disorder,
and cyclothymic disorder. Manic symptoms are a defining characteristic of each of these disorders,
bipolar disorders are characterized by how acute and long-lasting manic symptoms are. These disorders
are referred to as "bipolar" because many people with mania will also experience depression during
their lifetime (mania and depression are considered opposite poles) (Kring & Beccaria, 2016). The DSM-5
section structure reflects a dichotomous model, with bipolar and related disorders having their own
section among schizophrenia and depressive disorders sections, this structure emphasizes not only the
differences between bipolar and depressive disorders, but also that the biological and clinical
characteristics connected with bipolar disorders can be considered intermediate between those seen in
schizophrenia and those seen in unipolar depressive disorders(Muskin, 2015). Bipolar disorders in
children and teenagers are serious psychological disorders that mostly interfere with the lives of
children and adolescents impacted and their families. Children and teens with bipolar disorder have very
higher risk of death and mortality rates than non-bipolar disorders, including psychosocial morbidity
with weak family-peer relationships(Kowatch, 2009). Bipolar disorder is a severe, popular and acute
condition with a wide of symptoms resulting in high morbidity and mortality rates, ranking second
between mental disorders as a cause of worldwide disability(Ceron-Litvoc, Soares, Geddes, Litvoc, &
Lima, 2009). Bipolar disorder is a chronic, impaired disorder that is characterized by significant mood
disruption, as well as grandiosity or unbalanced self-esteem, reduced need sleep, hypersexual behavior,
racing thoughts, poor decision making, and pressured speech. Bipolar disorder is connected with
economic problems, severe impairment, chronic and debilitating medical problems, and a 10 to 20-
times increase in risk for suicide. Bipolar disorder was rarely diagnosed in children and adolescents
before the mid-1990s, even in mental hospital units, which can provide treatment for more acutely
disruptive and affectively distorted young people, just 10% of child and adolescent discharges in the
United States had an initial diagnosis of bipolar disorder in 1996. In the latter part of the 1990s,
increased attention in published academic literature was directed towards bipolar disorder in children
and teenagers. From (1995) onwards, articles and reports started to appear in the academic literature
that suggested bipolar disorder manifests differently in children than in adults. In 1997, the American
Academy of Child and Adolescent Psychiatry (AACA) published practice criteria for the treatment of
bipolar disorder in children and adolescent, in 2004, the ratio of US inpatients diagnosed with bipolar
disorder increased to 34.11% for children and 25.86% for adolescents (Washburn JJ, West AE, & Heil JA,
2011)

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Bipolar I Disorder: One or more manic or hypomanic episodes with one or more major depressive
episodes are usually constitute the diagnosis of bipolar I disorder. Depression in bipolar disorder follows
the diagnostic criteria of major depression, except for shorter duration and increased frequency. A
mixed episode is defined as a period of at least one week. The criteria for both mania and depression
are met (with the exception of duration). Mixed episodes are characterized by severe loss in
occupational and social functioning, hospitalization and psychotic symptoms, between episodes, many
bipolar patients are relatively asymptomatic, although many of them continue to experience functional
impairment after symptom resolve, with the age increases, episodes become much more severe and
lengthy. With the publication of more recent results studies, the evidence suggests that for many
patients, the course of their disease will be very difficult, leading to significant psychosocial morbidity,
unfavorable results may be particularly common in secondary mania, rapid cycling and mixed
mania(Preston et al., 2013). The criteria of bipolar I disorder reflect a new and modern understanding of
the classic manic-depressive disorder or affective psychosis defined in the 19th century, which differs
from this classic interpretation only to the extent that both psychosis nor lifetime experience of a major
depressive episode is a requirement. Nevertheless, the vast majority of people whose symptoms meet
the criteria for a fully syndromal manic episode also experience major depressive episodes throughout
their lifetimes DSM-5, 2013). A person diagnosed with bipolar disorder may or may not have current
manic symptoms, in reality, even a person who only one week of manic symptoms years ago still has
bipolar disorder, even More so than episodes of major depressive disorder, bipolar episodes appear to
recur. More than half of people with bipolar I disorder experience four or more episodes in their
lifetimes (Kring & Beccaria, 2016). Mood in a manic phase is sometimes characterized as euphoric,
excessively happy, high or feeling at the top of the world. In several cases mood is so high that it can be
easily recognized as excessive and can be marked by uncontrolled and haphazard excitement for
occupational, sexual or interpersonal experiences, throughout the manic episode, the person may be
involved in various overlapping new projects. Projects are sometimes initiated with very little knowledge
of the subject, and that nothing seems to be out of the reach of the person, the enhanced and increased
levels of activity may occur at unusual times of the day. Some of the most common features are the
reduced need for sleep, which is different from the insomnia that a person wants to sleep or feels the
need to sleep but is unable to sleep. Speech can be fast, stressed, noisy, loud and hard to stop.
Sometimes the thoughts of the individual race at a rapid rate than can be expressed through speech.
The increased in goal-oriented activities sometimes consists of excessive planning and participation in
multiple activities, which include sexual, professional, religious or political activities. The expansive
mood, over-optimism, grandiosity, and poor judgment and poor decision making often result to
imprudent involvement in activities such as spending sprees, giving away possessions, imprudent
driving, foolish business investment, and sexual promiscuity that is rare for the person, although these
activities are probable to have terrible consequences (DSM-5, 2013).
The 12-month prevalence rate in United States was 0.6% for bipolar I disorder as described in
DSM-IV. Twelve-month prevalence of bipolar I disorder in 11 countries estimated from 0.0% to 0.6%.
The male-to-female lifetime prevalence rate is nearly 1.1:1. Also bipolar I disorder has some risk and
prognostic factors such as environmental, genetic and physiological factors, bipolar I disorder is much
more common especially-income countries than in low-income countries 1.4 vs. 0.7%. Separate,
divorced and widowed people have lower rates of bipolar I disorder than those who are married or have

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never been married, on the other hand the family history of bipolar disorder is one of most important,
strongest and most consistent genetic and risk factors for bipolar disorders. The people diagnosed with
bipolar I disorder appear to have comorbid mental disorders, with anxiety disorders, ADHD, substance
use disorder (DSM-5, 2013).
Bipolar II Disorder: Defined as one or more episodes of depressive and at least one episode of
hypomania, It has been suggested that bipolar II is hard to differentiate from major depression for a
number of reasons, first, most patients subjectively do not consider periods of elevated mood as
dysfunctional — or may even deny the existence of such periods because of the predominant depressive
element. Second, patients may exhibit irritability rather than the classic mood and behavioral symptoms
of hypomania. Finally, there is considerable variation between the ability of individual clinicians’ ability
to reliably assess for hypomania (Preston et al., 2013). Bipolar II Disorder requiring a lifetime experience
of at least one episode of major depression and at least one episode of hypomania, is no longer thought
to be a "milder" condition than bipolar I disorder, largely due to the amount of time that people with
this condition spend on depression and because the mood instability of people with bipolar II disorder is
usually accompanied by serious impairments in work and social performance (DSM-5, 2013). Current
evidence and data worldwide show that bipolar II disorder is truly more prevalent than bipolar I
disorder. This definitely appears to be true in an outpatient setting in which a total of 50% (and in one
French national study up to 65%) of people with major depressive disorder have been recorded to
conform to the bipolar II disorder pattern. The depressive stage of bipolar disorder, particularly
expressed in bipolar II and its soft expressions, has appeared as a major public health problem. Even
though some hypomanias last for weeks, the hypomania at the end of depressive episodes in the most
bipolar II disorder patients does not last long, it is usually measured in days, hypomanias with short
Period (less than 4 days) are familially similar to those with longer duration (more than 4 days) (Ruiz,
Sadock, & Sadock, 2017). In bipolar II disorder, all upswings are hypomania, not maniac. Therefore,
bipolar II disorder can develop into bipolar I disorder, but bipolar I disorder can never develop into
bipolar II disorder. Once a pattern of persistent hypomanic episodes is established, the person is likely to
stay in the category of bipolar II disorder, only 15% of people with three or more hypomanic episodes
will later develop into bipolar I disorder. Therefore, for most people, bipolar II disorder is a stable
diagnosis (Miklowitz & Gitlin, 2015). Bipolar II disorder is marked by a clinical pattern of repeated mood
changes and episodes comprising of one or more (major depressive) episodes. The common
characteristic of bipolar II disorder is impulsiveness, that may lead to suicide attempts and drug use
disorders, Impulsivity may also be due to continuous substance use disorder, personality disorder,
anxiety disorder, medical condition and other psychological disorders. The 12-month prevalence of
bipolar II disorder is 0.3% worldwide. The 12-month prevalence in the US is 0.8% the prevalence rate of
pediatric bipolar II disorder is hard to establish. The DSM-IV bipolar I, bipolar II, and bipolar disorder not
already defined yields a combined prevalence rate of 1.8% in the U.S. and non-U.S. Population samples
with higher rates 2.7% inclusive in youth 12 years of age or older. Also bipolar II disorder has some risk
and prognostic factors such as genetic and physiological factors, because the risk of bipolar II disorder is
usually higher between relatives of people with bipolar II disorder compared to people with bipolar I
disorder or major depressive disorder. On the other had the genetic factors affecting age at the onset of
bipolar disorders. Sometimes bipolar disorder is not associated with one or more psychological disorders

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that occur and the most common are anxiety disorders, anxiety disorders and substance abuse happen
at a higher rate in people with bipolar II disorder than in the general population (DSM-5, 2013).
Mixed state, or mixed mania, defines an episode with both manic and depressive and
hypomanic symptoms. The DSM-5 considers mixed characteristics as a (specifier) which means that it is
not a different type of episode but is given as an added descriptor to a manic or hypomanic episode.
Also, in DSM-5, a mixed state is diagnosed when the full criteria of a manic or hypomanic episode are
faced and three depressive symptoms from the major depression criteria (except for appetite or ability
to concentrate changes) coexist, these changes are consistent in how some clinicians use the term
mixed, describing a manic (or hypomanic) episode with the some depressive symptoms, because people
with mixed features usually do not show euphoria and grandiosity seen in classic mania, these episodes
may be misdiagnosed as agitated depressions. In mixed mania, the symptoms of mania are the main
features that determine mood, although the patient may complain more about the symptoms of
depression. Therefore, mixed mania / hypomania must be conceptualized and treated in the same
manner as manic / hypomanic episodes, not as depressive episodes (Miklowitz & Gitlin, 2015).
Cyclothymia: Also known as cyclothymia, it is a second chronic mood disorder (the other is
persistent depressive disorder), Just like the diagnosis of persistent depressive disorder, the criteria of
DSM-5 involve symptoms to be current in adults for at least 2 years. In cyclothymic disorder, the
individual has recurrent but mild symptoms of depression, which alternate with mild symptoms of
mania (Kring & Beccaria, 2016). The term cyclothymia disorder refers to recurrent mood instability in
which there are numerous periods of mild elation or mild depression that do not meet the severity
criteria for either major depression (MD) or hypomania, it is considered to be a milder variant of bipolar
disorder. Furthermore, it is not uncommon for episodes of more severe mood disorder to supervene in
the course of the disorder (Harrison, 2018). Scarcely diagnosed in clinical settings, but more commonly
seen in epidemiological samples, the DSM-5 concept of cyclothymia describes a chronic (at least 2 years)
low amplitude, frequent cycling bipolar variant. The mood changes of people with cyclothymia happen
most of the time and never show the number of symptoms or the length of time coherent with a
hypomanic / manic episode or depression(Miklowitz & Gitlin, 2015). The features of Cyclothymia include
periods of alternating depression and elation, of at least two years’ duration, that do not meet criteria
for either major depression (MD) or mania, throughout this two-year period, symptoms will never be
absent for more than two months. Occupational and social impairment may happen during the
depressive phase, however, commonly not during the hypomanic period, nevertheless, for several
people, the pervasive, irregular type of mood lability eventually affects personal and job relationships,
so that mood swings are a frequent complaint of people with certain personality disorders, it is
important to know the presence of related behavioral criteria for hypomania or depression before
establishing a diagnosis of cyclothymia. This is a chronic disorder, with which is around one-third of
people later developing major affective disorders (Preston et al., 2013).
The prevalence of cyclothymic disorder in the lifetime is nearly 0.4%-1 percent. The prevalence
in the clinics for mood disorders can be between 3% and 5%., Cyclothymia disorder in the general
population is apparently equally common among males and females, in clinical cases, females with
cyclothymic disorder can be more likely to exist for therapy than males. Also cyclothymic disorder has

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some risk and prognostic factors such as genetic and physiological factors, because bipolar I disorder,
bipolar II disorder and major depressive disorder are much more popular between first-degree biological
relatives of people with cyclothymic disorder than between the general population. The people
diagnosed with bipolar I disorder appear to have comorbid mental disorders, such as sleep disorders and
substance-related disorders can be present in people with cyclothymic disorders, on the other hand
many children with cyclothymic disorder treated in outpatient psychiatric settings have comorbid
mental illnesses, they are much more likely to have comorbid (ADHD) than other pediatric patients with
psychological disorders (DSM-5, 2013).
Epidemiology
The World Health Organization (WHO) and World Mental Health (WMH) surveys are the biggest
collection of international studies that provide prevalence rates of mood disorders, information on
bipolar disorders collected in a subset of 11 population-based surveys were collected in the Europe
(Bulgaria and Romania), Americas (Sao Paulo metropolitan area, Brazil, Colombia, Mexico, and United
States), Asia (Shenzhen, People’s Republic of China; Pondicherry region, India; and 9 metropolitan areas
in Japan), Lebanon, and New Zealand (Ruiz et al., 2017). Bipolar disorder is common, the particular
prevalence of bipolar disorder depends on the concept of the classification between bipolar I and II
disorders (Strakowski, 2014). The 12-month prevalence rate in United States was 0.6% for bipolar I
disorder as described in DSM-IV. 12 - month prevalence of bipolar I disorder in 11 countries estimated
from 0.0% to 0.6% (DSM-5, 2013), on the other hand, bipolar II disorder impacts about 0.5% of the
population, and while bipolar II disorder is obviously most common in women than men, further, bipolar
I disorder affects both men and women equally (American Psychiatric Association, 2010). Perlis and
colleagues (2004) measured age at onset of mood symptoms in 1,000 well already-characterized adult
bipolar patients participating in the National Institute of Mental Health Systematic Treatment
Enhancement Program for Bipolar Disorder (STEP-BD),clinical condition, dissociative disorder
(comorbidity), functional status and life quality were compared for groups with very early (younger than
13 years of age), early (13–18 years of age) and adult (over 18 years of age) onset of mood symptoms,
Perlis et al. recorded that 28 percent of these patients had very early onset, and 38 percent had early
onset. earlier onset was linked to higher rates of comorbid anxiety disorders and drug abuse, increased
relapse, increased likelihood of attempting suicide and violent acts, early or early onset of bipolar
disorder could herald a more serious course of chronic and comorbidity disease (Perlis et al., 2004).

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Figure 1. Bipolar disorder onset age (National Institute of Mental Health Systematic Treatment
Enhancement Program for Bipolar Disorder).
Burden of Disease: Bipolar disorders are usually a life-long illness for which there is no known cure. Even
though a number of treatments help reduce the risk and duration of episodes, there is no known
intervention to prevent all new episodes, Thus, people with bipolar disorder will experience emotional
and cognitive symptoms throughout their lives, a lot of studies examined the long-term result of the
disease in people with bipolar disorders, ranging from 1 to 40 years of age. When a first manic episode
happens, more than 90% of people may progress to a life-long bipolar disorder; specifically, persistent
manic, hypomanic, or depressive episodes. On the other hand, people with bipolar disorders have a
greater rate of premature death than the general population at almost every age. While suicide is a
major part of this increased risk, people with bipolar disorders exhibit higher rates of a different medical
conditions leading to this increased risk. In addition, people with bipolar disorder are at danger of early
death from heart disease, which is two to three times higher than the general population. Suicide is a
popular result of bipolar disorders, up to 15% of people with bipolar disorder attempt suicide, with the
greatest risk in the first 5–10 years of disease (Strakowski, 2014).
Risk factors: In determining the risk factors for bipolar disorder, it is important to differentiate risk
factors from those that are lifetime risk factors (e.g. hereditary factors or genetic factors) and those that
are risk factors for the development of a mania episode or depression (e.g. life events). Therefore, in
identifying risk factors for lifelong susceptibility, genetic factors are the biggest single risk factor.
Nevertheless, when one considering who is vulnerable to mania over the next 6 months, genetic factors
may play a relatively minor role, and predictions will better be based on other variables such as past
history, being treated for depression with antidepressant drug, childbirth, and the approach of spring or
summer, Even though, organic factors such as some kind of central nervous system damage or harms
are common risk factors in young adults, late - onset bipolar disorder (over 50 years of age) organic
central nervous system disease is an increasing factor for the development of mania. For younger adults,

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head injuries and AIDS are two significant aetiological factors in a small number of cases of bipolar
disorders (Gelder, 2012).
Diagnostic criteria of bipolar disorders according to DSM-5:
Bipolar I Disorder:
Manic Episode:
A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood and
abnormally and persistently increased goal-directed activity or energy, lasting at least 1 week
and present most of the day, nearly every day (or any duration if hospitalization is necessary).
B. During the period of mood disturbance and increased energy or activity, three (or more) of the
following symptoms (four if the mood is only irritable) are present to a significant degree and
represent a noticeable change from usual behavior:
1- Inflated self-esteem or grandiosity.
2- Decreased need for sleep (e.g., feels rested after only 3 hours of sleep).
3- More talkative than usual or pressure to keep talking.
4- Flight of ideas or subjective experience that thoughts are racing.
5- Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli),
as reported or observed.
6- Increase in goal-directed activity (either socially, at work or school, or sexually) or
psychomotor agitation (i.e., puφoseless non-goal-directed activity).
7- Excessive involvement in activities that have a high potential for painful consequences (e.g.,
engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments).
C. The mood disturbance is sufficiently severe to cause marked impairment in social or
occupational functioning or to necessitate hospitalization to prevent harm to self or others, or
there are psychotic features.
D. The episode is not attributable to the physiological effects of a substance (e.g., a drug of
abuse, a medication, other treatment) or to another medical condition.
Note: A full manic episode that emerges during antidepressant treatment (e.g., medication,
electroconvulsive therapy) but persists at a fully syndromal level beyond the physiological effect
of that treatment is sufficient evidence for a manic episode and, therefore, a bipolar I diagnosis.
Note: Criteria A-D constitute a manic episode. At least one lifetime manic episode is required for
the diagnosis of bipolar I disorder.
Hypomanic Episode:
abnormally and persistently increased activity or energy, lasting at least 4 consecutive days and
present most of the day, nearly every day.
B. During the period of mood disturbance and increased energy and activity, three (or more) of
the following symptoms (four if the mood is only irritable) have persisted, represent a
noticeable change from usual behavior, and have been present to a significant degree:

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3- More talkative than usual or pressure to keep talking.
as reported or observed.
psychomotor agitation.
C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of
the individual when not symptomatic.
D. The disturbance in mood and the change in functioning are observable by others.
E. The episode is not severe enough to cause marked impairment in social or occupational
functioning or to necessitate hospitalization. If there are psychotic features, the episode is, by
definition, manic.
F. The episode is not attributable to the physiological effects of a substance (e.g., a drug of
abuse, a medication, other treatment).
Note: A full hypomanic episode that emerges during antidepressant treatment (e.g., medication,
of that treatment is sufficient evidence for a hypomanic episode diagnosis. However, caution is
indicated so that one or two symptoms (particularly increased irritability, edginess, or agitation
following antidepressant use) are not taken as sufficient for diagnosis of a hypomanic episode,
nor necessarily indicative of a bipolar diathesis.
Note: Criteria A-F constitute a hypomanic episode. Hypomanic episodes are common in bipolar I
disorder but are not required for the diagnosis of bipolar I disorder.
Major Depressive Episode:
A. Five (or more) of the following symptoms have been present during the same 2-week period
and represent a change from previous functioning; at least one of the symptoms is either (1)
depressed mood or (2) loss of interest or pleasure.
Note: Do not include symptoms that are clearly attributable to another medical condition.
1- Depressed mood most of the day, nearly every day, as indicated by either subjective report
(e.g., feels sad, empty, or hopeless) or observation made by others (e.g., appears tearful). (Note:
In children and adolescents, can be irritable mood.)
2- Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly
every day (as indicated by either subjective account or observation).
3- Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of
body weight in a month), or decrease or increase in appetite nearly every day. (Note: In
children, consider failure to make expected weight gain.)
4- Insomnia or hypersomnia nearly every day.

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5- Psychomotor agitation or retardation nearly every day (observable by others; not merely
subjective feelings of restlessness or being slowed down).
6- Fatigue or loss of energy nearly every day.
7- Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly
every day (not merely self-reproach or guilt about being sick).
8- Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by
subjective account or as observed by others).
9- Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a
specific plan, or a suicide attempt or a specific plan for committing suicide.
B. The symptoms cause clinically significant distress or impairment in social, occupational, or
other important areas of functioning.
C. The episode is not attributable to the physiological effects of a substance or another medical
condition.
Note: Criteria A-C constitute a major depressive episode. Major depressive episodes are
common in bipolar I disorder but are not required for the diagnosis of bipolar I disorder.
Note: Responses to a significant loss (e.g., bereavement, financial ruin, losses from a natural
disaster, a serious medical illness or disability) may include the feelings of intense sadness,
rumination about the loss, insomnia, poor appetite, and weight loss noted in Criterion A, which
may resemble a depressive episode. Although such symptoms may be understandable or
considered appropriate to the loss, the presence of a major depressive episode in addition to
the normal response to a significant loss should also be carefully considered. This decision
inevitably requires the exercise of clinical judgment based on the individual’s history and the
cultural norms for the expression of distress in the context of loss.
Bipolar I Disorder
A. Criteria have been met for at least one manic episode (Criteria A-D under “Manic Episode”
above).
B. The occurrence of the manic and major depressive episode(s) is not better explained by
schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other
specified or unspecified schizophrenia spectrum and other psychotic disorder.
Bipolar II Disorder:
Diagnostic Criteria:
Hypomanic Episode:
abnormally and persistently increased activity or energy, lasting at least 4 consecutive days and
present most of the day, nearly every day.
B. During the period of mood disturbance and increased energy and activity, three (or more) of
the following symptoms have persisted (four if the mood is only irritable), represent a
noticeable change from usual behavior, and have been present to a significant degree:

12
3- More talkative than usual or pressure to keep talking
as reported or obsen/ed.
psychomotor agitation.
C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of
the individual when not symptomatic.
D. The disturbance in mood and the change in functioning are observable by others.
E. The episode is not severe enough to cause marked impairment in social or occupational
functioning or to necessitate hospitalization. If there are psychotic features, the episode is, by
definition, manic.
F. The episode is not attributable to the physiological effects of a substance (e.g., a drug of
abuse, a medication or other treatment).
Note: A full hypomanic episode that emerges during antidepressant treatment (e.g., medication,
of that treatment is sufficient evidence for a hypomanic episode diagnosis. However, caution is
indicated so that one or two symptoms (particularly increased irritability, edginess, or agitation
following antidepressant use) are not taken as sufficient for diagnosis of a hypomanic episode,
nor necessarily indicative of a bipolar diathesis.
Major Depressive Episode:
A. Five (or more) of the following symptoms have been present during the same 2-week period
and represent a change from previous functioning; at least one of the symptoms is either (1 )
depressed mood or (2) loss of interest or pleasure.
Note: Do not include symptoms that are clearly attributable to a medical condition.
1- Depressed mood most of the day, nearly every day, as indicated by either subjective report
(e.g., feels sad, empty, or hopeless) or observation made by others (e.g., appears tearful). (Note:
In children and adolescents, can be irritable mood.)
2- Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly
every day (as indicated by either subjective account or observation).
3- Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of
body weight in a month), or decrease or increase in appetite nearly every day. (Note: In
children, consider failure to make expected weight gain.)
4- Insomnia or hypersomnia nearly every day.
5- Psychomotor agitation or retardation nearly every day (observable by others; not merely
subjective feelings of restlessness or being slowed down).
6- Fatigue or loss of energy nearly every day.

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7- Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly
every day (not merely self-reproach or guilt about being sick).
8- Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by
subjective account or as observed by others).
9- Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a
specific plan, a suicide attempt, or a specific plan for committing suicide.
B. The symptoms cause clinically significant distress or impairment in social, occupational, or
other important areas of functioning.
C. The episode is not attributable to the physiological effects of a substance or another medical
condition.
Note: Criteria A-C above constitute a major depressive episode.
Note: Responses to a significant loss (e.g., bereavement, financial ruin, losses from a natural
disaster, a serious medical illness or disability) may include the feelings of intense sadness,
rumination about the loss, insomnia, poor appetite, and weight loss noted in Criterion A, which
may resemble a depressive episode. Although such symptoms may be understandable or
considered appropriate to the loss, the presence of a major depressive episode in addition to
the normal response to a significant loss should be carefully considered. This decision inevitably
requires the exercise of clinical judgment based on the individual’s history and the cultural
norms for the expression of distress in the context of loss.
Bipolar II Disorder
A. Criteria have been met for at least one hypomanic episode (Criteria A-F under “Hypomanic
Episode” above) and at least one major depressive episode (Criteria A-C under “Major
Depressive Episode” above).
B. There has never been a manic episode.
C. The occurrence of the hypomanic episode(s) and major depressive episode(s) is not better
explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional
disorder, or other specified or unspecified schizophrenia spectrum and other psychotic disorder.
D. The symptoms of depression or the unpredictability caused by frequent alternation between
periods of depression and hypomania causes clinically significant distress or impairment in
social, occupational, or other important areas of functioning.
Differential diagnoses:
Differential diagnoses for bipolar disorder I
Major depressive disorder: MDD can be accompanied by manic and hypomanic symptoms, when the
person presents in a major depression episode, one should rely on a corroborating history of past
episodes of mania or hypomania, symptoms of irritability can be correlated with either MDD or bipolar
disorder, which adds to diagnostic complexity.
panic disorder, Generalized anxiety disorder, posttraumatic stress disorder, or other anxiety
disorders: All those other differential diagnostic disorders should be considered either a primary

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disorder or, in several cases, a comorbid disorder, A careful background of symptoms is necessary to
differentiate generalized anxiety disorder from bipolar disorder, as anxious ruminations can be confused
for anxious and racing thoughts, and efforts to minimize anxious feelings may be considered impulsive
behavior. Likewise, the symptoms of PTSD should be distinguished from bipolar disorder. It is useful to
assess the episodic nature of the symptoms described, as well as recognizing symptom triggers in
creating this differential diagnosis.
Other bipolar disorders: Diagnosis of bipolar I disorder is distinguished from bipolar II disorder
through identifying whether there have been any previous episodes of mania, Other identified or non-
specific bipolar and associated disorders must be differentiated from bipolar I and II disorders through
determining whether either episodes involving manic or hypomanic symptoms or episodes of depressive
symptoms fail to meet all of the criteria for these conditions.
Substance - medication-induced bipolar disorder: Drug use disorders may appear with addictive
mania symptoms that should be distinguished from bipolar I disorder; responding to mood stabilizers
during substance / drug mania may not necessarily be a diagnosis of bipolar disorder, there may be
significant overlap in light of the tendency of people with bipolar disorder to overuse substances during
an episode. A main diagnosis of bipolar disorder should be founded on the basis of symptoms that stay
once substances are no longer used (DSM-5, 2013).
Borderline personality disorder: People with borderline personality disorder show persistent mood
instability turbulent interpersonal relationships, self-destructive and often recurrent suicidal behavior,
and impulsivity. The development is usually gradual resulting from a chronic disturbance in
interpersonal relations, bipolar disorder is characterized from borderline personality disorder by the
occurrence of different, affective episodes (especially mania), periods of euthymia, and sometimes a
relatively different age at onset, furthermore, these two conditions can also be very hard to
differentiate at times, especially in adolescents. However, these conditions are not mutually exclusive,
so they may co-occur. While bipolar disorder is equally popular between the genders, borderline
personality disorder is much more common among women(Strakowski, 2014).
Attention-deficit / hyperactivity disorder (ADHD): This condition can be misdiagnosed as a bipolar
disorder, particularly in teenagers and children, several symptoms intersect with symptoms of mania,
such as fast speech, distractibility, racing thoughts, and much less sleep, the (double counting) of
symptoms related to both bipolar disorder and ADHD can always be avoided if the clinician specifies
whether the symptoms reflect a different episode (DSM-5, 2013).
Differential diagnoses for bipolar disorder II
Major depressive disorder: Maybe the most difficult differential diagnosis to consider is major
depressive disorder, that may be followed by hypomanic or manic symptoms which do not meet the full
criteria. This is particularly true in the assessment of people with symptoms of irritability that may be
correlated with either major depressive disorder or bipolar disorder II(DSM-5, 2013).

15
Schizophrenia: Schizophrenia is a complicated disorder distinguished by chronic psychotic symptoms,
deteriorating personality, and usually profound functional impairment. Many people with schizophrenia
often suffer from depression. Psychosis usually occurs during manic episodes, and may also happen with
depression throughout bipolar disorder, which leads to confusion among these conditions. Nonetheless,
bipolar disorder with psychotic characteristics can also be distinguished from schizophrenia by
identifying affective symptoms which are more common and prominent than the co-occurring
psychosis. In addition, psychosis in bipolar disorder is mainly limited to affective episodes, while
schizophrenia, psychosis is persistent separately of affective symptoms (Strakowski, 2014).
Cyclothymic disorder: For cyclothymic disorder, there are frequent times of hypomanic symptoms and
several periods of depressive symptoms that do not meet the symptom or period criteria for a major
depressive episode, bipolar II disorder is differs from cyclothymic disorder by the presence of one and
more major depressive episodes. When a major depressive episode happens after the first 2 years of
cyclothymic disorder, the extra diagnosis of bipolar II disorder is given.
Panic disorder or other anxiety disorders: Anxiety disorders should be considered in just the
differential diagnosis and may often be present as co-occurring conditions.
Other bipolar disorders: Diagnosis of bipolar II disorder must be distinguished from bipolar I disorder
by carefully considering whether previous episodes of mania and other specified or unspecified bipolar
and associated conditions by confirming the presence of completely syndromal hypomania and
depression.
Substance use disorders: Drug and substance use disorder is included in the differential diagnosis
(DSM-5, 2013).
Treatment
Though the best treatment for bipolar disorder includes both medical and non-medical modules,
effective psychopharmacology is necessary. Pharmacological intervention is organized according to the
affective stage of the disorder, though this organization must not be interpreted to suggest
disconnection of treatment across stages. The evidence base for medications that are commonly used to
treat bipolar disorders is shown in (Table 1).
Table 1
Commonly used pharmacologic treatments in Bipolar Disorders:
Medication Range (daily dose, mg)

16
Lithium
Chlorpromazine
Valproic acid
Haloperidol
Risperidone
Olanzapine
Ziprasidone
Quetiapine
Aripiprazole
Lurisadone
Paliperidone
Asenapine
600-2400
300-900
750
5-15
2-6
5-30
40-160
200-800
5-20
20-160
3-12
10-20
Clozapine
Divalproex
Carbamazepine
Lamotrigine
Oxcarbazepine
300-900
500-2500
200-1600
100-300
600-2400
Medical treatment of bipolar disorders is a rapidly evolving complex field. The development of
new therapies has helped to improve the definitions of disease subtypes and generated significant new
management options. Though the mood stabilizers Lithium, Carbamazepine, Valproate, and the
standard pharmacotherapy of bipolar disorders may be argued, antipsychotics have extremely been
used. These various drugs have different pharmacodynamics, pharmacokinetics, drug-drug interactions
and side effects, It offers not only new therapeutic possibilities, but also a number of new potential
risks, so, clinicians face the challenge of combining complex data on efficacy spectra with the approved
pharmacological properties for antidepressants, anxiolytics and for mood stabilizers and antipsychotics
and other medications, in efforts to ensure safe, effective and modern pharmacological treatments for
patients with bipolar disorders (Ketter, 2010).
1- Lithium: it has been described early in the 19th century as a psychotropic medicine, when (Carl
Lange) investigated that lithium salts have played a preventive therapeutic role in the treatment
of resistant depression, (Aubry, Ferrero, & Schaad, 2007), however, at that time, statistics and
controlled trials were not known and the observations stayed clinical observations (Akiskal &
Tohen, 2011), these observations were largely forgotten in the following years until the middle
of the 20th century, until Australian physician (John Cade 1949) became interested in metabolic
mechanisms which could be involved in manic conditions, after examining that lithium injections
induced a noticeable placidity in animals, Cade deduced that lithium should possess
(tranquilizing) properties. After experimenting by taking lithium himself in order to exclude the
possibility of serious side effects, Cade carried out for the first research study with 10 manic
patients who responded positively to therapy. The first double-blind, European controlled study
dates back to 1954, lithium was also studied in the United States in the 1960s. Many decades of

17
experience can now be taken into account when describing lithium (Aubry et al., 2007). Lithium
prophylaxis has become widely used in the years that followed, but sometimes there were still
doubts about its effectiveness (Akiskal & Tohen, 2011). Various pharmacological actions have
been attributed to lithium, but the process in which this ion exercises its antimanic impact has
not been clearly identified. Animal studies has shown that chronic lithium therapy reduces the
expression of some genes at the Central Nervous System (CNS) level. Lithium impacts the
generation of intracellular messengers which are formed when membrane receptors are
stimulated by neurotransmitters. The most comprehensive efficacy of lithium in the treatment
of manic conditions has been proved. In reality, both open and controlled studies that assessing
the effects of lithium have been organized in more than a 1,000 patients in the manic phase.
Cited the most important studies in the (table 2) (Aubry et al., 2007).
Table 2
Open and controlled studies of lithium in the treatment of mania
Authors Number of patients Results in % of response
(Cade, 1949)
(Noack and Trautner, 1951)
(Glesinger, 1954)
(Schou et al., 1954)
(Schou et al., 1955)
(Rice, 1956)
(Andriani et al., 1958)
(Belling, 1959)
(Schou, 1959)
(Wharton and Fieve, 1966)
(Schlagenhauf et al., 1966)
(Blinder, 1968)
(Van der Velde, 1970)
(Kingstone, 1960)
(Swann et al., 1987)
(Bowden et al., 1994)
(Kafantaris et al., 2003)
(Bowden et al., 2005)
(Kushner et al., 2006)
10
30
21
38
48
37
14
32
119
25
68
22
75
17
19
179
100
302
786
100
83
71
84
81
92
93
75
76
68
90
95
73
94
68
49
63
53
46
Lithium has been recommended and assessed for depression since the 1960s, controlled studies
in bipolar patients showed improvement in much more than half of patients with depression, Moreover,
one of the issues with the use of lithium for depression is the high lithium levels (about 1 mmo1/ l) used
in many positive studies, these high levels are sometimes associated with side effects and are not

18
suggested for use in clinical practice. Studies conducted from an experimental point of view on the long-
term effect of lithium on depression show that lithium provides better protection against manic relapse
than depressive relapse, this was reported by a recent review and meta-analysis of randomized
controlled trials involving approximately 800 patients comparing lithium to placebo in the long-term
treatment of BP disorder. There's at best just a moderate positive effect of lithium against depressive
relapse (Aubry et al., 2007). Lithium can play a role in the prevention of depression in bipolar disorder,
however, the evidence for its effectiveness in severe bipolar depression is limited and is based on older
trials with unsatisfactory designs. A much more recent placebo-controlled study in bipolar depression
discovered that lithium was less effective than quetiapine and had few positive differences from placebo
(Harrison, 2018).
Although Lithium has been the most widely studied pharmacological agent used in the
treatment of childhood bipolar patients disorder, Just two randomized, double-blind trials comparing
lithium with placebo were performed, The first study identified 25 bipolar patient disorders adolescents
with comorbid substance abuse, Of (21) patients who completed the study, 6 out of 10 (60 percent)
reacted to lithium compared to one out of 11 (9.1 percent) with placebo. The second trial was a double-
blind discontinuation trial in bipolar patients teenager lithium responders in which lithium or placebo
was assigned over a period of 2 weeks. Patients who persisted lithium monotherapy did not differ from
the placebo group in the mania exacerbation levels that were large in both groups, moreover, the short
period of two weeks of follow-up may have impacted the results. In their study, Weller et al. (2002)
indicated that lithium would be especially efficacious when the onset of bipolar patient disorders occurs
at the beginning of adolescence, however, the reaction to treatment is thought to be less marked than
in adults, maybe due to the presence of ' mixed ' or dysphoric manic phases or the preponderance of
psychotic symptoms, features that often accompany weak response to treatment in adults, in a 6-week
randomized research, which include 42 (bipolar patients disorder I and II) patients aged 6–18 years,
comparing the effectiveness of lithium, valproate and carbamazepine in children and teens with mixed
or manic episode (Aubry et al., 2007)
Most lithium side effects are associated with dose and plasma level (Taylor, Barnes, & Young,
2019). Various side effects, which affect several organs, have been described for lithium. they can be
moderate or severe, and have a major impact on patient compliance, Apart from the possible effect of
lithium on renal function, the side effects of lithium are reversible when treatment is cancelled (Aubry et
al., 2007), maybe the limiting factor for the using lithium is the danger of toxicity and adverse effects,
symptoms of toxicity include slurred speech, loss of balance, ataxia , tremor, muscle twitches, cardiac
arrhythmias, and nystagmus that may progress to coma and even to death (Strakowski, 2014). Negative
lithium reactions that happen in > 10% of patients include polydipsia, tremor, abnormal taste, diarrhea,
and nausea, but, very little common side effects are include polydipsia, cognitive dullness, polyuria,
gastrointestinal distress, weight gain, tremor, acne, and hypothyroidism, with the risk of most adverse
events linked to dose or plasma concentrations. For some patients, mild cognitive impairment is also the
most worrying side effect and is considered to be a major source of drug non-compliance (Kasper &
Hirschfeld, 2005). Lithium is sometimes responsible for increasing urinary concentration capacity –
nephrogenic diabetes insipidus – as a result of thirst and polyuria (Taylor et al., 2019). Lithium remains a

19
gold standard mood stabilizer and a model for other agents investigating their possible mood stabilizers,
although its limited therapeutic index lithium remains a popular therapy for bipolar disorders (Kasper &
Hirschfeld, 2005).
Monitoring and Prescribing of lithium guidelines are summarized in table 3 (Taylor et al., 2019).
Table 3.
Prescription and monitoring of lithium
Indications Mania and hypomania episodes, bipolar disorder prophylaxis, and persistent
depression. Decreases aggression and suicidality;
Pre‐lithium
work‐up
E‐GRF and TFT. ECG advised for patients who risk factors for or existing heart disease.
Baseline assessment of weight and calcium desirable
Prescribing Begin at 400 mg in the night (200 mg in the older people). Plasma level after 7 days,
then 7 days after each dose change until the target level is achieved.
Monitoring Plasma lithium every 6 months (more regular monitoring is needed in those
prescribed interacting medications, the older people and those with established
renal impairment or other relevant physical illness). eGFR and TFTs every 6 months.
Weight (or BMI) and calcium should also be monitored.
Stopping Decrease slowly over at least 1 month
Avoid incremental reductions in plasma levels of >0.2 mmol/L
Lithium can be the most effective medicine for bipolar disorder in practice, many meta-analysis
randomized controlled trials (RCTs) have shown that lithium is effective in the treatment of bipolar
disorders, such as the (Severus E et al., 2014) study, aim of this study is determine the effectiveness of
lithium treatment in preventing episodes of mood disorders in people with bipolar disorders and to
assess whether it is effective in preventing both depressive and manic episodes. It consists of 806
studies, they identified 806 studies. As a result, 731 records were removed while the remaining 75 were
records for qualification. For a variety of reasons, as detailed in (figure 1)

20
The 11 studies could be included for qualitative and quantitative research. Seven studies have
been included in this part of the updated review and six studies included just bipolar patients (Prien et
al. 1973; Bowden et al. 2000; Calabrese et al. 2003; Bowden et al. 2003; Amsterdam and Shults 2010;
Weisler et al. 2011). One study recorded on groups of bipolar disorders and unipolar disorders that were
randomized separately (Kane et al. 1982), and two studies were similar in design, but one of the
recruited patients who had recently recovered from a depressive episode (Calabrese et al. 2003, and
other recruited patients who have recently recovered from a manic or hypomanic episode (Bowden et
al. 2003). Severus and his colleagues analyzed the data comparing lithium with placebo and other drop-
out therapies for causes other than mood episode and completion of the study, those trials included
those comparing lithium with placebo and those comparing lithium with an alternative therapy
(anticonvulsant or atypical antipsychotic) to stop mood episodes where the follow-up lasted at least 3
months. Seven studies (1,580 participants) were included in the comparison of lithium with placebo.
Lithium was much more effective than placebo in the prevention of overall mood episodes (see figure 2)
(Severus E et al., 2014).

21
Figure 2 Prevention of any episode in bipolar disorders patients in RCTs comparing lithium with placebo
On the other hand, the lithium is very effective for bipolar disorder patients, this have shown in
the (Findling et al., 2015), it was consist of 153 participants and 81 (53%) of them were randomized to
receive lithium, this study is randomized, double-blind, placebo-controlled consisted of pediatric
participants (ages 7–17 years) with BP-I/manic or mixed episodes compared lithium (n = 53) versus
placebo (n = 28) for up to 8 weeks, in this study the lithium was better to placebo in the decreasing of
manic symptoms in pediatric patients treated with BP-I, also, lithium was largely well tolerated in this
number of patients and was not linked with weight gain, separating it from other agents prescribed to
treat youth with bipolar disorder, but few side effects appear on the participants (see table 3).
2- Carbamazepine: is a chemical molecule with a tricyclic structure found by Morel in Basel,
Switzerland, in 1953, the spectrum of antiepileptic action of Carbamazepine was identified in 1963 by
(Theobald and Kunz), that same year that it was marketed in Switzerland and then in France under the
name Tegretol, the Japanese doctor Takezaki was the first one to identify the efficacy of carbamazepine
for bipolar patients disorders, furthermore, the significance of carbamazepine as a mood stabilizer
became obvious after the first studies published in the USA by Ballenger and Post in 1980. The mode of
action of CBZ is only partially known. It is currently thought that this action includes, in particular the

22
stabilization of the sodium and potassium channels, the decrease of the calcium flow and the up-
regulation of GABAB receptors (Aubry et al., 2007).
Carbamazepine is useful and effective an acute treatment in 30–60 percent of patients with
mania (see table 4), we will see this effectiveness in the one meta-analysis (Hirschfeld & Kasper, 2004),
this trial consists of (17) controlled studies for the years (1966-2002), the aim of this study is determine
the available information on the effectiveness of carbamazepine in the therapy of bipolar disorder and,
present data on the associated compound, oxcarbazepine, a new generation anticonvulsant in the
treatment of bipolar disorder. On the other hand, the prophylactic effects of carbamazepine were
suggested by an overall response level of 63% in 14 controlled or partially controlled trials (from 9
months to 3 years) which is similar to that recorded for lithium. The impact of carbamazepine was
approximately equal in manic and depressive episodes. 8 of the 14 prophylaxis trials were controlled
including placebo-controlled parallel group, randomization to carbamazepine or lithium, and
randomization to carbamazepine or lithium. Three controlled studies (Denicoff et al., 1997; Lusznat et
al., 1988; Watkins et al., 1987) required adjunctive therapy as needed, and patients were refractory to
lithium in all studies except Coxhead et al. (1992). Additional descriptions of these studies (see table 5)
Table 4
Controlled studies of carbamazepine in acute mania

23
Table 4
Controlled trials of carbamazepine in the prophylaxis of bipolar disorders
The (Okuma et al., 1981), double-blind controlled study have shown the carbamazepine very
useful for treatment of manic and depressive episodes (see table 6), this study on the prophylactic
impact of carbamazepine on recurrent manic -depressive psychotics was conducted in 22 patients using
inert placebo in ten subjects as a control drug. Carbamazepine was given in a dose of 200-600 mg for 1
year. Patients between 13 and 64 years of age with bipolar disorders and they had experienced an
episode at least once a year in the 2 years preceding the study, of which at least one episode was manic;
and patients and their families agreed to participate in the study, and the severity of manic or
depressive disorder was measured in accordance with the Mania and Depression Rating Scale by the
Clinical Psychopharmacology Research Group in Japan. Twenty-two participants (10 males and 12
females) were examined, 12 in the carbamazepine group and 10 in the placebo group. Their ages ranged
from 21 to 64 years (average 42.8 years). Seven of the 22 cases were dropped out and three of these
patients in the CBZ group and one in the placebo group have been included in the statistical analysis for

24
global judgement. Among the 22 carbamazepine subjects, carbamazepine was found to be effective in
60 % of cases and inert placebo in 22.2 % of cases.
Table 6
Prophylactic effect of carbamazepine (CBZ) on manic-depressive disorder
Few data can be found on carbamazepine in children and adolescents (Wagner, 2004), several
researchers suggest the use of carbamazepine as an alternative or association therapy in patients who
do not react to lithium in a satisfactory manner, furthermore, many serious side effects have been
reported, such as aplastic anemia and agranulocytosis which may appear with symptoms such as sore
throat and fever, therefore, the treatment of carbamazepine in young patients needs regular clinical and
biological follow-up (Aubry et al., 2007).
The side effects of carbamazepine are different from those of lithium (Basco & Rush, 2005), but,
the common side effects of carbamazepine are included fatigue, dizziness and sedation. Carbamazepine
can also produce a dose-dependent bradyarrhythmia, up to 10% of people with carbamazepine develop
rash, a small percent of which a small percent progresses to Stevens-Johnson syndrome, that can be life
threatening (Strakowski, 2014). Most of the side effects that happen during carbamazepine treatment
are mild and disappear when the posology is reduced, they just justify discontinuation of therapy in
about 6% of treated patients (Aubry et al., 2007). More 50% of patients who receiving carbamazepine
experience adverse effects, and the medication is associated with potentially severe side effects. As we
mentioned the most common dose-related adverse effects of carbamazepine include neurological
symptoms like nausea, ataxia, diplopia, blurred vision and fatigue, some effects are typically transient
and sometimes reversible with dose is reduction. Older patients, nevertheless, can be more sensitive to
side effects. In fact, carbamazepine can reduce total and free levels of thyroxine and increase free levels
of cortisol, however these effects are rarely clinically significant. Weight gain is also dangerous and
common side-effect of carbamazepine. Many rare side effects include systemic hypersensitivity
reactions, cardiac conduction diseases, psychiatric symptoms (such as sporadic cases of psychosis) and,
very rarely, renal effects (such as hematuria, proteinuria, renal failure and oliguria (American Psychiatric
Association, 2010).

25
Monitoring and Prescribing of carbamazepine guidelines are summarized in table 7 (Taylor et al.,
2019).
Table 7
Monitoring and Prescribing of carbamazepine
Indications Mania (not first stage), bipolar depression (weak evidence), unipolar depression (weak
evidence) and prophylaxis of bipolar disorder (third line after antipsychotics and
Valproate). Alcohol withdrawal (may be poorly accepted).
Carbamazepine is approved for treatment of bipolar disorders in people who do not
respond to lithium
Pre‐
carbamazepine
work‐up
U&Es, the FBC and the LFTs. Baseline assessment of the weight desirable
Prescribing Dose titrate upwards against response and side effects; start with 100–200 mg and
target for 400 mg (many patients may require higher doses)
Notice that the modified-release formulation (Tegretol Retard) may be given once or
twice daily, is connected with less extreme fluctuations in serum levels and is usually
better tolerated.
Plasma levels may be used to ensure adequate dosing and treatment compliance
Blood must be taken immediately before to the next dose. Carbamazepine causes its
own metabolism; serum levels (when used) must be re-checked a month after dose
increase.
Monitoring U&Es, FBC and LFTs if clinically indicated
Weight (or BMI)
Stopping Reduce slowly over at least one month.
3- Valproic acid: Valproic acid (valproate) was produced by Burton in the 19th century (1881), however
its antiepileptic activity was known in 1963. Just several years later, (Lambert et al. 1966) confirmed its
effectiveness as a mood stabilizer. Currently, United States FDA approves valproic acid in the treatment
of mania. It is often commonly used as a mood stabilizer in maintenance therapy for relapse prevention,
even though has not yet been officially approved for this indication. Valproic acid has just been widely
studied for the treatment of manic episodes. Randomized controlled trials have also shown that
valproate is successful and effective in the treatment of mania (see table 3), one of the benefits of
valproic acid for the treatment of manic phases is that it can be administered with loading doses of
20mg daily, this posology which is followed by difficult unwanted effects in normothymic patients, is
usually quite well tolerated by agitated patients in the manic episode, this loading dosage makes it easy

26
to achieve a therapeutic level very quickly, helping the antimanic impact to appear within the first days
of treatment (Aubry et al., 2007).
There are many meta-analysis randomized controlled trials (RCTs) have shown that valproic acid
is effective in the treatment of bipolar disorders, such as (Smith et al., 2010) study, the aim of this study
was to analyze existing data on the effectiveness and tolerability of valproate in the treatment of severe
bipolar depression, methods of this trial were randomized controlled trials in which valproate and
placebo were compared using an electronic database search in October 2008. The searches identified
1466 potentially relevant studies, they selected four randomized, controlled, double blind trials of 142
participants were included, quality was high, although the sample sizes of each analysis were small. The
duration of the study was six weeks (2 studies) and eight weeks (2 studies) (see table 8). Meta-analysis
showed a huge difference in favour of valproate in the reduction of depressive symptoms, both in the
depression symptom scale (standardized mean difference (SMD) −0.35 (95% confidence interval, −0.69,
−0.02)) and in participants with at least 50% improvement in symptoms — relative risk (RR) 2.00 (1.13,
3.53). There was no evidence of difference in mania symptoms, withdrawal for any cause, lack of
effectiveness or side effects, side effects that occurred valproate (sleepiness, fatigue, muscle weakness,
headache diarrhea and dry mouth (see table 9). In the end it has shown the valproate was effective in
reducing the depressive symptoms of acute bipolar depression and has been well tolerated.
Table 8
Characteristics of included trials

27
Table 9
Random effects Meta-analysis of side effects in valproate RCT versus placebo for the treatment of
bipolar depression
The other RCT study (Kowatch R.A et al., 2015), the aim of this study was to determine the
efficacy and safety of Valproic acid versus Risperidone in children between the ages 3–7 years with
bipolar I disorder during a mixed or manic episode. Methods of this study were forty-six children with
the Diagnostic and Statistical Manual of Mental Disorders. 4th edition, Text Revision (DSM-IV) diagnosis
of bipolar disorder, manic and hypomanic, or mixed episodes, was recruited over a 6-year period from
two clinical outpatient programs for a double blind, placebo controlled trial in which participants were
randomized in a 2:2:1 ratio to risperidone solution, valproic acid, or placebo. After 6 weeks of therapy,
the least-mean Young Mania Rating Scale (YMRS) total score changed (see figure 3), adjusted for
baseline YMRS scores, from baseline to treatment group: valproic acid 10.0+2.46 (p=0.50); risperidone
18.82 + 1.55 (p=0.008); and placebo 4.29+3.56 (F=3.93, p=0.02). Treatment with valproic acid has
resulted in an increase in weight /BMI and a reduce in total red blood cells (RBC), hemoglobin and
hematocrit. There was also a big difference between participants treated with risperidone and subjects
treated with valproic acid (p=0.004). Risperidone was separated from placebo at week 4 (p=0.01) on the
MMRM test. In 50% of valproic acid treated participants (p=0,001); 88% of risperidone-treated
participants (p=0,001); and 0% of placebo-treated participants, also there was few side effects on the
subjects (see table 10).

28
Figure.3. Weekly Young Mania Rating Scale (YMRS) scores by treatment group.
Table 10
Side effects of the subjects in the study of Kowatch, et al. (2015)
In generally, common side effects of Valproic acid include weight gain, hair loss, tremor,
unspecific pain complaints, and sedation (Strakowski, 2014). Valproic acid can lead to nausea, inactivity
and confusion may sometimes occur with the start of doses greater than 750 mg / day. Weight gain may
be significant, especially when Valproic acid is used in mix with clozapine, most side effects of Valproic
acid are dose related (Taylor et al., 2019). In addition, valproic acid has a large therapeutic window.
Unintended overdose is rare, and purposeful overdose is less probable to be fatal than lithium.

29
Furthermore, in rare cases, valproate may lead to life-threatening side effects, and patients should be
advised to report the sometimes subtle symptoms of these reactions immediately. Therefore, patients
receiving valproate should be advised to contact their psychiatrist or primary care physician quickly if
they show symptoms of these conditions (American Psychiatric Association, 2010).
Monitoring and Prescribing of carbamazepine guidelines are summarized in table 11 (Taylor et
al., 2019).
Table 11
Monitoring and Prescribing of Valproic acid
Indications Mania hypomania, bipolar depression and prophylaxis of bipolar affective disorder.
Can decrease aggression in a range of psychiatric disorders
Notice that sodium valproate is only recommended for epilepsy and semi-sodium
valproate for acute mania.
Pre‐
carbamazepine
work‐up
The FBC and LFTs. Baseline assessment of weight desirable
Prescribing Titrate dose upwards against response and side effects. Loading doses may be used
and are usually well tolerated.
Notice that CR sodium valproate (Epilim Chrono) may be prescribed once daily. All
other formulations should be given at least twice daily.
Plasma levels may be used to assure adequate dosing and treatment compliance.
Blood must be taken immediately before to the next dose.
Monitoring FBC and LFTs if clinically indicated
Weight (or BMI)
Stopping Decrease slowly over at least one month.

30
Discussion:
Bipolar disorder is a common condition with a very high burden of disease, including high social and
economic costs, drug abuse, disability large suicide risk and increased all-cause mortality, incomplete
control of long-term morbidity and, in particular, poor balance of depressive parts of the disorder. In
spite of that its high prevalence of therapy-resistance, trials of pharmacological treatment options in
bipolar disorders stay extremely limited, highly variable in the reliability of their designs and generally
inconclusive. Most of the trials reviewed involved relatively small numbers of participants, as we see this
thing in the study Smith et al., (2010), Hirschfeld & Kasper, (2004) and Okuma et al., (1981), on the other
hand, many studies have not determined the effect of the medications on children or elder people.
Although all medications have side effects such as fatigue, dizziness, sedation, weight gain, hair loss,
tremor, unspecific pain complaints, sedation, nausea, inactivity and confusion, but we saw they have a
lot of positive effect to improve people with bipolar disorders like in Severus, et al., (2014) meta-analysis
study, lithium was superior to placebo for the treatment of mood episodes, and lithium is superior in the
prevention of manic episodes, furthermore, there is no major difference in overall mood episodes,
depressive episodes, drop-out due to factors other than mood episodes, or completion of studies. We
also saw that the Findling, et al.(2015) RCT study that lithium has been shown to be effective in acute
treatment of pediatric BP-I, with the dosing regimen used, lithium has been shown to have a generally
acceptable side effects profile. On the other hand, the Hirschfeld & Kasper, (2004) meta-analysis study

31
have shown the use of carbamazepine in acute bipolar disorders has been supported by good evidence,
and it has shown the efficacy of carbamazepine in acute mania is widely similar to that of lithium,
valproate and antipsychotics. We also saw that the Okuma et al., (1981) RCT study that carbamazepine
appears to prevent the recurrence of manic and depressive episodes. In the Smith et al., (2010) meta-
analyses study showed that the valproic acid is effective for the treatment of acute bipolar depression,
there was a significant reductions in depression based on symptom results and significantly more
subjects with at least 50 percent improvement in symptoms of depression. Lithium stays the most useful
treatment choice for people with bipolar disorders, but this drug is not used in Kurdistan because we do
not have the necessary devices to determine the proportion of lithium in the body.

32
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