Meet the Expert

EFFECT OF CORTISOL IN MANIA DISORDER

Oleh:
Sashitharan (P.669)
Teguh Karyadi (P.674)

Pembimbing :
Dr.Yaslinda Yaunin, Sp.KJ

BAGIAN PSIKIATRI
FAKULTAS KEDOKTERAN UNIVERSITAS ANDALAS
RSUP DR. M DJAMIL PADANG
PADANG
2011
Definition of Bipolar Disorder

Bipolar Disorder ( also known as Maniac Depression ) is characterized by

alternating periods of extreme moods. A person with Bipolar disorder experiences

cycling of moods that usually swing from being overly elated or irritable (mania) to sad

and hopeless (depression) and then back again, with periods of normal mood in between.

Bipolar disorder is a common, recurrent, severe psychiatric illness that affects an

individual's mood, behavior and ability to think clearly. A person's family history and

genetics often play an important role in the greater likelihood of someone having this

disorder in their lifetime.

Increased stress and inadequate coping mechanisms to deal with that stress may

also contribute to the disorder's manifestation. For those affected by bipolar disorder, life

is an emotional roller coaster of intense highs and crippling lows.

Bipolar disorder is most often experienced as a swing between a manic and a

depressed mood, which may often be related to increased stress or other event in a

person's normal life. Many treatment options are available to help control these extreme

changes in mood.

Anything , any circumstance, can trigger a person to shift in mood, and sometimes there

is no obvious trigger at all. Often, the first manic episode is triggered because of some

external stressor the person has experienced. However, an important point of Bipolar

disorder is that the person's extreme moods often seem to come on of their own accord.
Bipolar I disorder is characterized by episodes of mania that alternate with periods of

depression or periods in which individuals have simultaneously occurring manic and

depressive symptoms called mixed states.

In contrast, bipolar II disorder is characterized by recurrent episodes of depression and

milder symptoms of mania, called hypomania. Hypomanic episodes typically do not

impair an individual's ability to function to the extent that full-blown manic episodes do

Additionally, hypomanic episodes are not complicated by psychotic symptoms.

Endocrine system in bipolar disorder

The role of dysfunctional endocrine systems in the pathogenesis of mood

disorders has been the focus of research for many decades. The complexity of endocrine

systems and their interaction with neural networks frustrated early attempts to establish

links between endocrinology and neuropsychiatry. According to a 2005 summary of

bipolar disorder research by Brian Koehler, Ph.D., cortisol secretion increases just before

the manic or hypomanic phase of bipolar disorder begins. He reports that the higher the

cortisol level, the more severe the manic phase.

Hypothalamic-pituitary-adrenal axis

The HPA axis, as it name indicates, is a feedback loop including the

hypothalamus, pituitary, and adrenal glands, regulatory neural inputs, and a variety of

releasing factors and hormones

During physical or psychological stress, the HPA axis is activated. The

hypothalamus secretes two hormones, corticotropin-releasing hormone(CRH) and

arginine vasopressin. CRH acts on the pituitary to stimulate adrenocorticotropic hormone

(ACTH) release. ACTH reaches the adrenal cortex through the systemic circulation and

interacts with receptors on adrenocortical cells stimulating the production and release of

cortisol. Cortisol is a glucocorticoid stress hormone that has a panoply of centraland

peripheral effects mediated by two intracellular specialized glucocorticoid receptor

subtypes: the high-affinity type I receptor or mineralocorticoid receptor (MR), and the

low-affinity type II receptor or glucocorticoid receptor (GR). The relative contribution of

the two receptors (GR and MR) in the regulation of HPA activity is not yet clear. MRs

have a high affinity

for endogenous glucocorticoids, such as cortisol, and for the salt-regulating

hormone aldosterone. The GRs have a relatively low affinity for cortisol but bind avidly

to synthetic steroids such as dexamethasone (DEX). These differences in affinity suggest

that MRs play an important role in regulating basal cortisol levels when hormone levels

are low. The HPA axis has an autoregulatory mechanism mediated by cortisol. When

cortisol levels rise, as in response to stress or circadian fluctuations, the MRs are

saturated. The GRs become the main transducer of

glucocorticoid activity and, therefore, the primary mediator of the HPA feedback. The

autoregulatory mechanisms are crucial in the maintenance of the homeostatic function of

the HPA axis. Changes in GR number, function, or binding affinity may be important in

altering the homeostatic function of the HPA axis observed in healthy individuals. The

loop is completed with the negative feedback of cortisol on the pituitary, hypothalamus,

and higher brain centers.

HPA axis function is frequently investigated by measuring changes in cortisol, ACTH, or

CRH release. The DEX suppression test (DST) is a sensitive measure of the functional

integrity of the GR-mediated negative feedback mechanism: the cortisol-suppressing

activity of the synthetic

glucocorticoid, DEX, is an indicator of GR status . A dose of DEX is given in the

evening, and cortisol samples are obtained the next day. A normal response would be an

inhibition of cortisol release resulting from negative feedback by DEX through the GRs.

A newer test is the combined DEX/CRH challenge test, in which the HPA axis is both

stimulated by the administration of CRH and inhibited with DEX . This test is said to be

more sensitive for detecting HPA abnormalities in patients with depression .

Cortisol and glucocorticoid receptor abnormalities in depression

In 1975, Stokes and colleagues made the first observations of increased escape

from cortisol suppression in patients with depression. Patients with HPA dysfunction, as

in depressive disorder, respond with a paradoxically increased release of corticotropin

and cortisol, whereas controls do not show such response. Many clinical studies have

confirmed HPA hyperactivity

in patients with severe mood disorders

HPA hyperactivity is characterized by

_ Hypersecretion of CRH

_ Increased plasma cortisol levels

_ Blunted corticotropin response to CRH

_ Increased cortisol levels in the plasma, urine, and cerebrospinal fluid

_ Exaggerated cortisol responses to corticotrophin

_ Enlarged pituitary and adrenal glands

Cortisol and bipolar disorder

Dysregulation of ACTH and cortisol response after CRH stimulation have been

reported in bipolar patients, but altered states of the HPA axis have mostly been

demonstrated in patients with depressive or mixed episodes. This difference may arise

from fewer studies of glucocorticoid regulation in patients with mania. Nevertheless,

some interesting findings can be extracted from these studies. Reports of cortisol non

suppression in response to DEX in both unipolar and bipolar disorders do suggest a

primary GR abnormality in these disorders . An enhanced response to corticotropin

releasing hormone was found in manic patients when compared with controls . The

differences disappeared when the patients who relapsed after 12 months were excluded.

The changes in CRH secretion seem to appear before the manic or hypomanic symptoms

are clinically evident. Therefore, this test seems to be trait-dependent. This enhanced

response might result primarily from enhanced pituitary responsiveness to CRH. Within

the subtypes of affective illness, abnormal DST results are more common during

depression in the course of bipolar disorder than in unipolar mood disorder . HPA

dysregulation does not seem to be linked to any particular type of episode, because these

alterations were found in patients during acute depression and during mania . Others

postulate that HPA alterations are not state markers of bipolar disorder because circadian

hypersecretion of cortisol occurred in depressed,

hypomanic, and euthymic phases .

Pituitary gland volume, a marker of its functional status, has been used to

examine HPA axis dysfunction . A decreased volume of the pituitary was found persons

with in bipolar disorder, when compared with healthy controls, but not in persons with

unipolar disorder. This finding is consistent with pituitary hypoactivity in response to

HPA stimulation in patients with

bipolar disorder.

The severity of the manic episode seems to be highly correlated to the degree of

neuroendocrine alteration. Anxiety, insomnia, and the intensity of depression were highly

correlated with cortisol response. Severity of depression was correlated with baseline

cortisol concentration only in the bipolar group, not in the unipolar group. This finding

may suggest a relationship between HPA pathology and severity of mood episode in

bipolar disorder. A more heterogeneous status of the HPA system in unipolar patients

might be related to greater diagnostic heterogeneity (and thus a lower validity of the

phenotype).

Reports of cortisol function in mania are inconsistent. Some studies find normal cortisol

suppression on the DST, but others find rates of nonsuppression comparable to those

found in depression . Moreover, it has been suggested that patients with mixed mania

may be more likely than those with pure mania to exhibit DST nonsuppression. In Evans’

study , patients with pure episodes of mania exhibited normal cortisol suppression, and

the mixed-episode patients exhibited cortisol nonsuppression. Other studies have

confirmed abnormal cortisol suppression in bipolar disorder, especially in mixed-episode

patients.
Symptom resolution does not necessarily result in a normal response to the DEX/CRH

test, indicating that HPA axis dysfunction may not simply be an epiphenomenon of

illness. Bipolar patients exhibited significantly higher cortisol concentrations than

unipolar patients in acute episodes as well as in remission, and the authors conclude that a

higher degree of HPA system dysfunction is present in bipolar disorder than in unipolar

depression . In a pilot study, stable, lithium-responsive patients with bipolar disorder

were found to have a significantly enhanced salivary cortisol response on waking, when

compared with healthy controls. This response is said to reflect an enduring tendency to

abnormal cortisol regulation, even in stable patients.

Higher cortisol concentrations were found in both nonremitted and remitted

patients with bipolar disorder .The HPA axis dysfunction could be a potential trait marker

in bipolar disorder and thus possibly indicative of the core pathophysiologic process in

this illness.

The effect of treatments

An in vitro study has shown that some treatments used in mood disorders affect

GR function . Tricyclic antidepressants increase the GR mRNA in primary neuronal

cultures, whereas in vivo studies show an increase in GR protein and binding capacity.

These changes have also been reported, in rats, with the mood stabilizer lithium and

following electroconvulsive therapy. According to some studies, lithium augmentation in

treatment resistant unipolar depression increases the cortisol response to the DEX/ CRH

test , but studies in bipolar disorder have found that lithium does not change cortisol
response or CRH concentration. Some studies have shown that the resolution of

depressive symptoms with use of amitriptyline, paroxetine, or tianeptine normalizes the

HPA axis . According to Heuser et al, during antidepressant treatment,‘‘a gradual

reinstatement of appropriate glucocorticoid receptor function occurs,’’ inducing normal

responses to DEX/CRH. In another study, however, the absence of a treatment response

to antidepressants did not alter cortisol output on the DEX/CRH test . Furthermore, a

significant correlation was found between carbamazepine dosage and cortisol response in

the DEX/CRH test (cortisol response increases with increasing doses of carbamazepine).

A more recent study has shown that patients taking carbamazepine had lower

dexamethasone levels and were more likely to respond than those not taking

carbamazepine . When DEX windows were applied, however, there was no difference in

DEX levels between patients and controls, suggesting that an effect of psychotropic

medication on cortisol output through DEX metabolism is unlikely.

Summary

There is robust evidence demonstrating abnormalities of the HPA axis in bipolar

disorder. Hypercortisolism may be central to the pathogenesis of depressive symptoms

and cognitive deficits, which may in turn result from neurocytotoxic effects of raised

cortisol levels. Manic episodes may be preceded by increased ACTH and cortisol levels,

leading to cognitive problems and functional impairments. Identification and effective

treatment of mood and cognitive symptoms of mood disorders are clinical goals, but

currently available treatments may fall short of this ideal. Manipulation of the HPA axis

has been shown to have therapeutic effects in preclinical and clinical studies, and recent
data suggest that direct antagonism of GRs may be a future therapeutic strategy in the

treatment of mood disorders.

In bipolar disorder (formerly called manic-depressive illness), episodes of
depression alternate with episodes of mania or a less severe form of mania called
hypomania. Mania is characterized by excessive physical activity and feelings of
elation that are greatly out of proportion to the situation.

• Heredity probably plays a part in bipolar disorder.

• Episodes of depression and mania may occur separately or together.
• Periods of excessive sadness and loss of interest in life alternate with
periods of elation, extreme energy, and often irritability, with periods of
relatively normal mood in between.
• Doctors based the diagnosis on the pattern of symptoms.
• Drugs that stabilize mood, such as lithium Some Trade Names
LITHOBID
and certain antiseizure drugs, and sometimes psychotherapy can help.

Bipolar disorder is so named because it includes the two extremes, or poles, of

mood disorders—depression and mania. It affects slightly less than 4% of the
U.S. population to some degree. Bipolar disorder affects men and women
equally. However, women are more likely to have symptoms of depression, and
men are more likely to have symptoms of mania. Bipolar disorder usually begins
in a person's teens, 20s, or 30s.

Bipolar disorders are classified as

 • Bipolar I disorder: People have had at least one manic episode and
usually depressive episodes
• Bipolar II disorder: People have had major depressive episodes, at least
minor manic (hypomanic) episode, but no full manic episodes

Did You Know...

• Certain physical disorders and
drugs can cause symptoms of
bipolar disorder.

• People experiencing mania often

think they are in their best form.

Causes

Hereditary is thought to be involved in the development of bipolar disorder.

Abnormal levels of certain substances the body produces, such as the
neurotransmitters norepinephrine Some Trade Names
LEVOPHED
or serotonin, may be involved. (Neurotransmitters are substances that nerve cells
use to communicate.)

Bipolar disorder sometimes begins after a stressful event, or such an event

triggers another episode. However, no cause-and-effect relationship has been
proved.

The symptoms of bipolar disorder—depression and mania—can occur in certain

disorders, such as high levels of thyroid hormone (hyperthyroidism). Also,
episodes may be triggered by drugs, such as cocaine and amphetamines.

Some Causes of Mania

Condition Examples
Brain and nervous system • Brain tumors
disorders • Head injury
• Huntington's disease
• Multiple sclerosis
• Seizures that affect the temporal lobe (complex
partial seizures)
 • Stroke

• Sydenham's disease
Connective tissueSystemic lupus erythematosus (lupus)
disorders
Infections • AIDS
• Encephalitis
• Influenza

• Syphilis (late stage)

Hormonal disorders High levels of thyroid hormones (hyperthyroidism)
Drugs • Amphetamines
• Antidepressants (most)
• Antidepressant withdrawal
• Bromocriptine Some Trade Names
PARLODEL

• Cocaine
• Corticosteroids
• Levodopa

• Methylphenidate Some Trade Names

CONCERTAMETHYLINRITALIN

Symptoms

In bipolar disorder, episodes of symptoms alternate with virtually symptom-free

periods (remissions). Episodes last anywhere from a few weeks to 3 to 6 mo.
Cycles—time from onset of one episode to that of the next—vary in length.
Some people have infrequent episodes, perhaps only a few over a lifetime,
whereas others have four or more episodes each year (called rapid cycling).
Despite this large variation, the cycle time for each person is relatively
consistent.

Episodes consist of depression, mania, or less severe mania (hypomania). Only a

minority of people alternate back and forth between mania and depression with
each cycle. In most, one or the other predominates to some extent.

Depression: Depression in bipolar disorder resembles depression that occurs

alone (see Mood Disorders: Symptoms). People feel excessively sad and lose
interest in their activities. They think and move slowly and may sleep more than
usual. They may be overwhelmed with feelings of hopelessness and guilt.

Mania: Episodes of mania end more abruptly than those of depression and are
typically shorter, lasting a week or longer. People feel exuberant, energetic, and
elated or irritable. They may also feel overly confident, act or dress
extravagantly, sleep little, and talk more than usual. Their thoughts race. They
are easily distracted and constantly shift from one theme or endeavor to another.
They pursue one activity (such as business endeavors, gambling, or dangerous
sexual behavior) after another, without thinking about the consequences (such as
loss of money or injury). However, people tend to think that they are in their best
mental state.

People lack insight into their condition. This lack plus their huge capacity for
activity can make them impatient, intrusive, meddlesome, and aggressively
irritable when crossed. As a result, they may have problems with social
relationships and may feel that they are being treated unjustly or are being
persecuted. Some people have hallucinations, hearing and seeing things that are
not there.

Manic psychosis is an extreme form of mania. People have psychotic symptoms

that resemble schizophrenia (see Schizophrenia and Delusional Disorder:
Schizophrenia). They may have extremely grandiose delusions, such as of being
Jesus. Others may feel persecuted, such as being pursued by the FBI. Activity
level increases markedly; patients may race about and scream, swear, or sing.
Mental and physical activity may be so frenzied that there is a complete loss of
coherent thinking and behavior (delirious mania), causing extreme exhaustion.
People so affected require immediate treatment.

Hypomania: Hypomania is not as severe as mania. People feel cheerful, need

little sleep, and are mentally and physically active. For some people, hypomania
is a productive time. They have a lot of energy, feel creative and confident, and
often function well in social situations. However, people in this mental state
often make commitments that they cannot keep or start projects that they do not
finish. They are easily distracted and easily irritated, sometimes resulting in
angry outbursts. They rapidly change moods. People with hypomania may
recognize such effects and be bothered by them, as are the people around them.

Mixed Episodes: When depression and mania or hypomania occur in one

episode, people may momentarily become tearful in the middle of elation, or
their thoughts may start racing in the middle of depression. Often, people go to
bed depressed and wake early in the morning and feel elated and energetic. At
least one of three people with bipolar disorder have mixed episodes.

Diagnosis

The diagnosis is based on the distinctive pattern of symptoms. However, people

with mania may not accurately report their symptoms because they do not think
anything is wrong with them. So doctors often have to obtain information from
family members. Doctors also ask people whether they have any thoughts about
suicide.

Doctors review the drugs being taken to check whether any could contribute to
the symptoms. Doctors may also check for signs of other disorders that may be
contributing to symptoms. For example, they may do blood tests to check for
hyperthyroidism.

Doctors determine whether people are experiencing an episode of mania or

depression so that the correct treatment can be given.

Treatment

For severe mania or depression, hospitalization is often required. For less severe
mania, hospitalization may be needed during periods of overactivity to protect
people and their family members from disastrous financial activities or sexual
behavior. Most people with hypomania can be treated as outpatients. People with
rapid recycling are more difficult to treat. Without treatment, bipolar disorder
recurs in almost all people.

Treatment may include drugs to stabilize mood (mood stabilizers, such as lithium
Some Trade Names
LITHOBID
and some anticonvulsants), antipsychotic drugs, and certain antidepressants, as
well as psychotherapy. Electroconvulsive therapy is sometimes used when mood
stabilizers do not relieve depression. Phototherapy may be used when moods are
related to the seasons.

Lithium: Lithium Some Trade Names

LITHOBID
can lessen the symptoms of mania and depression. Lithium Some Trade Names
LITHOBID
helps prevent mood swings in many people. Because lithium Some Trade Names
LITHOBID
takes 4 to 10 days to work, a drug that works more rapidly, such as an
anticonvulsant or a newer (second-generation) antipsychotic drug, is often given
to control excited thought and activity.

Lithium Some Trade Names

LITHOBID
can have side effects. It can cause tremors, muscle twitching, nausea, vomiting,
diarrhea, thirst, excessive urination, and weight gain. It often worsens a person's
acne or psoriasis. However, these side effects are usually temporary and are often
lessened or relieved when doctors adjust the dose. Sometimes lithium Some
Trade Names
LITHOBID
must be stopped because of side effects, which then resolve. Doctors monitor the
level of lithium Some Trade Names
LITHOBID
in the blood with regular blood tests because if levels are too high, side effects
are more likely. Long-term use of lithium Some Trade Names
LITHOBID
can cause hypothyroidism and rarely can impair kidney function. Therefore,
thyroid and kidney function must be monitored with regular blood tests.

A very high level of lithium Some Trade Names

LITHOBID
in the blood can cause persistent headaches, mental confusion, drowsiness,
seizures, and abnormal heart rhythms. Side effects are more likely to occur in
older people and people with impaired kidney function. Women who are trying
to become pregnant must stop taking lithium Some Trade Names
LITHOBID
because rarely, lithium Some Trade Names
LITHOBID
can cause heart defects in a developing fetus.

Anticonvulsants: The anticonvulsants carbamazepine Some Trade Names

TEGRETOL
, oxcarbazepine Some Trade Names
TRILEPTAL
, and valproate Some Trade Names
DEPACON
may be used to treat mania when it first occurs or to treat mania and depression
when they occur together (mixed state). Unlike lithium Some Trade Names
LITHOBID
, these drugs do not damage the kidneys. However, carbamazepine Some Trade
Names
TEGRETOL
can greatly reduce the number of red and white blood cells. Rarely, valproate
Some Trade Names
DEPACON
damages the liver (primarily in children) or severely damages the pancreas. With
close monitoring by a doctor, these problems can be caught in time.
Carbamazepine Some Trade Names
TEGRETOL
and valproate Some Trade Names
DEPACON
can be useful, especially when people have not responded to other treatments.
Oxcarbazepine Some Trade Names
TRILEPTAL
has fewer side effects.

Lamotrigine Some Trade Names

LAMICTAL
is sometimes used, especially during episodes of depression. Lamotrigine Some
Trade Names
LAMICTAL
can cause a serious rash. Rarely, the rash becomes the life-threatening Stevens-
Johnson syndrome (see Itching and Noninfectious Rashes: Stevens-Johnson
Syndrome (SJS) and Toxic Epidermal Necrolysis). People who are taking
lamotrigine Some Trade Names
LAMICTAL
should watch for any new rash or flu-like symptoms and report these symptoms
to the doctor.

Antipsychotics: Sudden manic episodes are increasingly treated with second-

generation antipsychotics because they act quickly and the risk of serious side
effects is less than that with other drugs used to treat bipolar disorder. These
drugs include aripiprazole Some Trade Names
ABILIFY
, olanzapine Some Trade Names
ZYPREXA
, quetiapine Some Trade Names
SEROQUEL
, risperidone Some Trade Names
RISPERDAL
, and ziprasidone Some Trade Names
GEODON
.

Long-term side effects may include weight gain and the metabolic syndrome.
Metabolic syndrome (see Obesity and the Metabolic Syndrome: Metabolic
Syndrome) is excess fat in the abdomen with reduced sensitivity to insulin's
effects (insulin resistance), a high blood sugar level, abnormal cholesterol levels,
and high blood pressure. The risk of this syndrome may be lower with
aripiprazole Some Trade Names
ABILIFY
and ziprasidone Some Trade Names
GEODON
.

Antidepressants: All antidepressants can cause swings from depression to

hypomania or mania, sometimes rapidly. Therefore, these drugs are used only for
short periods and usually are given along with a mood-stabilizing drug. Their
effect on mood is closely monitored. At the first sign of a swing to hypomania or
mania, the antidepressant is stopped.

Psychotherapy: Psychotherapy is often recommended for people taking mood-

stabilizing drugs, mostly to help them take their treatment as directed. Group
therapy often helps people and their partners or relatives understand bipolar
disorder and its effects. Individual psychotherapy may help people learn how to
better cope with problems of daily living.

Education: Learning about the effects of the drugs used to treat the disorder can
help people take them as directed. People may resist taking the drugs because
they believe that these drugs make them less alert and creative. However,
decreased creativity is relatively uncommon because mood stabilizers usually
enable people to function better at work and school and in relationships and
artistic pursuits.

People should learn how to recognize symptoms as soon as they start, as well as
learn ways to help prevent symptoms. For example, avoiding stimulants (such as
caffeine and nicotine Some Trade Names
NICORETTENICOTROL
) and alcohol can help, as can getting enough sleep.

Doctors or therapists may talk to people about the consequences of their actions.
For example, if people are inclined to sexual excesses, they are given
information about how their actions can affect their marriage and about health
risks of promiscuity, particularly AIDS. If people tend to be financially
extravagant, they may be advised to turn their finances over to a trusted family
member.