Maina Mood stabilizers lithium Valproic Acid carbamazepine

1. VANDANA SHARMA
M.PHARM
INDIPENDENT PHARMA TUTOR
(8 YEARS)
OM SAM SANESHCHARYA NAMAH SHREE KRISHAN SHARNAM MAMAH
STUDY MATERIAL FOR PHARMACY STUDENTS

2. MOOD STABILIZERS
 A mood stabilizer is a psychiatric pharmaceutical drug used to
treat mood disorders characterized by intense and sustained mood
shifts, typically bipolar disorder type I or type II or schizophrenia.
Mood stabilizers are licensed as part of the long-term treatment
for:
bipolar disorder (manic depression)
mania and hypomania
sometimes recurrent severe depression
schizophrenia.
Some of the individual drugs called mood stabilizers are actually
very different chemical substances from each other. But health
care professionals often group them together, because they can all
help to stabilize mood if patient experience problems with
extreme highs, extreme lows, or mood swings between extreme
highs and lows.

3. Bipolar disorder
 Bipolar disorder, formerly called manic depression, causes
extreme mood swings that include emotional highs (mania or
hypomania) and lows (depression). When patient become
depressed, patient may feel sad or hopeless and lose interest or
pleasure in most activities. When patient mood shifts in the other
direction, patient may feel euphoric and full of energy. Mood
shifts may occur only a few times a year or as often as several times
a week.
 Although bipolar disorder is a disruptive, long-term condition, In
most cases, bipolar disorder can be controlled with medications
and psychological counseling (psychotherapy).

4. Bipolar Disorder (Manic-Depressive Illness)
 Mania: 1 wk of (Hypomania
4 days)
 Elevated, Expansive, Irritable
Mood :
 inflated self-esteem or
Grandiosity
  need for sleep (rested with
<3hrs)
  talkative
 Flight of ideas, racing
thoughts
 Distractibility
  goal-directed activity /
psychomotor agitation.
  pleasurable activity. w
painful consequence
(spending, sex, investments)
 Depressive episode: 2 wks (5 Total
Sx)
 Depressed (Irritable in kids)
 Anhedonia
  /  appetite
  /  sleep
 psychomotor agitation
/retardation
 Fatigue /  energy
 worthless / guilt
  concentration / indecisive
 suicidal ideation

5. Bipolar Disorder continue…
 BP-I: Mania (with/without Depression)
 Mania or
 Mania-Depression ( First Mania than Depression)
 BP-II: Depression and hypomania
 Depression-mania (First Depression than Mania)
 Cyclothymia: Mania-Depression (First mania than Depression)
 Mixed episode: Mania + Depression (At same time)
 Rapid cycling: 4 or more episodes / yr.

6. Schizophrenia
 Schizophrenia is a mental disorder characterized
by abnormal social behavior and failure to
understand what is real. Common symptoms
include false beliefs, unclear or confused
thinking, hearing voices, reduced social engagement and
emotional expression, and a lack of motivation.
 People with schizophrenia often have additional mental
health problems such as anxiety disorders, major
depressive illness, or substance use disorder. Symptoms
typically come on gradually, begin in young adulthood,
and last a long time.

7. Symptoms of schizophrenia
 Experience hallucinations (most reported are hearing voices),
 delusions (often bizarre or persecutory in nature), and
 disorganized thinking and speech.
 The last may range from loss of train of thought, to sentences only loosely
connected in meaning, to speech that is not understandable known as word
salad.
 Social withdrawal,
 sloppiness of dress and hygiene, and
 loss of motivation and judgment
 There is often an observable pattern of emotional difficulty, for example lack of
responsiveness.
 Impairment in social cognition is associated with schizophrenia, as are
symptoms of paranoia. Social isolation commonly occurs.
 Difficulties in working and long-term memory, attention, executive
functioning, and speed of processing also commonly occur.
 In one uncommon subtype, the person may be largely mute, remain
motionless in bizarre postures, or exhibit purposeless agitation, all signs
of catatonia.
 About 30 to 50 percent of people with schizophrenia fail to accept that they
have an illness or comply with their recommended treatment. Treatment may
have some effect on insight.

8. Positive and negative (Schizophrenia)
 Schizophrenia is often described in terms of positive and negative (or
deficit) symptoms.
 Positive symptoms are those that most individuals do not normally
experience, but are present in people with schizophrenia. They can
include delusions, disordered thoughts and speech,
and tactile, auditory, visual, olfactory and gustatory hallucinations,
typically regarded as manifestations of psychosis. Hallucinations are also
typically related to the content of the delusional theme. Positive
symptoms generally respond well to medication.
 Negative symptoms are deficits of normal emotional responses or of
other thought processes, and are less responsive to medication. They
commonly include flat expressions or little emotion, poverty of
speech, inability to experience pleasure, lack of desire to form
relationships, and lack of motivation. Negative symptoms appear to
contribute more to poor quality of life, functional ability, and the burden
on others than do positive symptoms. People with greater negative
symptoms often have a history of poor adjustment before the onset of
illness, and response to medication is often limited.

9. Mania
 The word derives from the Greek (mania), "madness, frenzy" and the verb
(mainomai), "to be mad, to rage, to be furious".
 Means severely elevated mood called as mania
 In this disorder noradrinaline (NA) and Dopamine level is increase
 Mania is more than just feeling good or even euphoric.
 With true mania, people can be described by words like "frantic", "hyperactive"
or over-excited.
 Often a person's thoughts and speech is so "fast" that it tumbles over itself and
becomes fragmented by following tangents of thoughts and ideas.
 Cycling between mania and depression is the hallmark of bipolar disorder
(previously called manic-depression).
 Mania: Inappropriate euphoric mood/ an irrational but irresistible motive for a
belief or action.
Detail about Depression I have discussed in Previous Slides.
Topic Named as “ Antidepressants” on slide share

10. Symptoms of Mania
 Dramatic increase in energy; decreased need for sleep and food
 Racing thoughts; pressured/tangential speech; rapid-fire conversation
 Feelings of euphoria; invincibility
 Distractibility; irritability
 Impulsivity; poor judgment (questionable business transactions, wasteful
expenditures of money)
 Intrusive, provocative, aggressive or even violent behavior
 Hypersexuality; reckless sexual behaviors
 Hyper-religiosity
 Increased alcohol or drug abuse
 Delusions
 Elevated self-esteem
 Grandiose plans, ideas, beliefs (feeling like one has super powers or talents)

11. Mood Stabilizers
 Used to treat bipolar disorder, Mood stabilizers suppress swings
between mania and depression.
 Mood-stabilizing drugs are also used in borderline personality disorder and
schizoaffective disorder.

12. Drugs used as Mood Stabilizers
 Lithium
The 5 individual drugs that can be used as mood stabilizers are:
 Carbamazepine
 Lamotrigine
 Valproate
 Asenapine
 Olenzapine
 Haloperidol

13. Lithium
 Lithium comes under the category of Mineral
 Lithium is the "classic" mood stabilizer, the first to be approved by the US FDA,
and still popular in treatment.
 Therapeutic drug monitoring is required to ensure lithium levels remain in the
therapeutic range: 0.6 or 0.8-1.2 mEq/L (or millimolar).
 The precise mechanism of action of lithium is still unknown, and it is
suspected that it acts at various points of the neuron between the
nucleus and the synapse. Lithium is known to inhibit the enzyme GSK-
3B. This has the effect relieving pressure on the circadian clock -
which is thought to be often malfunctioning in people with bipolar
disorder - and positively modulates gene transcription of brain-derived
neurotrophic factor (BDNF). The resulting increase in neural plasticity
may be central to lithium's therapeutic effects.
 Lithium may also increase the synthesis of serotonin.
Detailed MOA

14. MOA’s Summary
 Decreased NA and Dopamine release and
 Decreased Sodium content load of human body by increase
loss of sodium through urine ( Because sodium is responsible
for excitability)
Side effects
1. Lithium inhibits ADH (Anti diuretic hormone named as vasopressin)
Increase urine formation (Poly urea and poly thrust)
Note-
 Vasopressin synthesized in hypothalamus
 Vasopressin Store and secrete from posterior pituitary gland
 Vasopressin work at Nephrone (Site -IV /collecting duct

15. 2.Inhibits Iodination of tyrosine
Hypothyroidism (Decreased T3 and T4 synthesis)
Note- In short
 Tyrosine + I2 MIT and DIT T3 and T4
3. Lithium have insulin like action on blood glucose
Hypoglycemia

16. S/E
 Signs and symptoms of toxicity include nausea, vomiting,
diarrhea, and ataxia.
 The most common side effects are lethargy and weight gain.
 The less common side-effects of using lithium are blurred
vision, slight tremble in the hands, and a feeling of being
mildly ill.
 In general, these side-effects occur in the first few weeks after
commencing lithium treatment. These symptoms can often
be improved by lowering the dose.

17. Drug interactions
Drugs Interaction Result
Thiazides (Loss of sodium and water) +
Lithium (Loss of sodium and water)
Additive loss of sodium and water (Sever
dehydration)
NSAIDs (Antidiuretic action) + Lithium Decrease excretion of lithium in urine
Lithium toxicity
Tetracycline + Lithium Lithium toxicity
Contraindication-
Lithium is small ion so it secret in milk, saliva, cross placenta so
avoid in lactating mother and in pregnancy

18. Note-
 Plasma protein binding of lithium =0%
 Narrow therapeutic plasma concentration range mean
slight decrease in conc.= no effect/therapeutic failure or
slight increase in conc.= toxic effect
 That’s why MONITORING OF PLASMA
CONCONCONTRATION MUST
 monitoring of plasma conc. Of Lithium is done = by
measuring Salivary lithium conc.

19. Valproate/ Valproic acid
Valporic acid IUPAC Name-
2-propylpentanoic acid
VPA MOA
Its anti manic effect has been attributed to the
blockade of voltage-dependent sodium channels
and increased brain levels of gamma-
aminobutyric acid (GABA). The GABAergic effect
is mainly contribute towards the anti-manic
properties of valproate.
In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory
synaptic neurotransmitter, GABA, possibly by inhibiting GABA degradative
enzymes, such as GABA transaminase, succinate-semi aldehyde
dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells.

20. VPA Uses
 It can be given intravenously or by mouth. Long acting
formulations exist.
 Valproate (VPA), is a medication primarily used to treat
 epilepsy and
 bipolar disorder and
 to prevent migraine headaches.
 It is useful for the prevention of seizures in those
with absence seizures, partial seizures, and generalized
seizures.

21. VPA: Common S/E
 GI distress
 Sedation
 Liver transaminase elevation
 Tremor
 Hair loss
 Weight gain-increased appetite
 Thrombocytopenia (elders)
 Teratogenic: neural tube, cranio-facial
VPA: Less Common S/E
 Neutropenia
 Coagulopathies, platelet
Function
 endocrine abnormalities
 Amenorrhea, polycystic
ovary?
 Hypothyroidism
 Hypo cortisolemia
VPA: Rare Dangerous SE
 Idiosyncratic Hepatic Failure
 lethargy, anorexia, jaundice,
bleed, edema
 Acute Hemorrhagic
Pancreatitis
 Bone Marrow Suppression

22. Drug interaction
Name of Drugs Result of Interaction
VPA + e.g. of Protine-bound drugs
(Asprin, phenobarbitone,
Carbamazepine, warfarin, digoxin)
free-VPA
VPA +[ TCAs( Tricyclic
antidepressants), Carbamazepine,
phenobarbrbiton, phenatoin,
lamotrigine]
VPA levels of liver-metabolism of
drugs these are metabolized by P450
(name drugs are mentioned in
bracket)
VPA + p450 inhibitors (fluoxetine) VPA levels
 Valproate inhibits CYP2C9, glucuronyl transferase, and epoxide hydrolase and is
highly protein bound and hence may interact with drugs that are substrates for any
of these enzymes or are highly protein bound themselves. It may also potentiate the
CNS depressant effects of alcohol. It should not be given in conjunction with other
antiepileptics due to the potential for reduced clearance of other antiepileptics
(including carbamazepine, lamotrigine, phenytoin and phenobarbitone) and itself.

23. Carbamazepine (CBZ)
Carbamazepine IUPAC Name-
5H-dibenzo[b,f]azepine-5-carboxamide
 Carbamazepine is also a GABA receptor
agonist, as it has also been shown to
potentiate GABA receptors made up of
alpha1, beta2, and gamma2 subunits.
This mechanism may contribute to its
efficacy in neuropathic pain and bipolar
disorder. Carbamazepine is a serotonin
releasing agent and possibly even
a serotonin reuptake inhibitor.
MOA

24.  Carbamazepine is used
 off-label as a second-line treatment for bipolar disorder and
 in combination with an antipsychotic in some cases of schizophrenia when
treatment with a conventional antipsychotic alone has failed.
 In the United States, the FDA-approved medical uses are
 epilepsy (including partial seizures, generalized tonic-clonic seizures andmixed
seizures),
 trigeminal neuralgia, and
 manic and mixed episodes of bipolar I disorder.
Uses
Adverse effects
 In the US, the label for carbamazepine contains warnings concerning:
 Effects on the body's production of red blood cells, white blood cells, and
platelets: aplastic anemia and agranulocytosis, decreased white blood cell or
platelet counts
 increased risks of suicide

25. Adverse effects
 Common adverse effects may include drowsiness, dizziness, headaches and
migraines, motor coordination impairment, nausea, vomiting, and/or
constipation. Alcohol use while taking carbamazepine may lead to enhanced
depression of the central nervous system.
 Less common side effects may abnormal heart rhythms, blurry or double vision.
Drug interactions
 Carbamazepine has a potential for drug interactions; caution should be used in
combining other medicines with it, including other antiepileptics and mood
stabilizers.
 Carbamazepine, as a CYP450 inducer, may increase clearance of many drugs,
decreasing their concentration in the blood to subtherapeutic levels and
reducing their desired effects.

26. Drug interactions
Valproic acid and valnoctamide
(inhibit microsomal epoxide
hydrolase (MEH), the enzyme
responsible for the breakdown of
carbamazepine-10,11 epoxide into
inactive metabolites) + carbamazepine
prolonging the effects of carbamazepine
and delaying its excretion.
Grapefruit juice (inhibiting CYP3A4
enzymes in the gut wall and in the liver)
+ carbamazepine
raises the bioavailability of
carbamazepine
Methadone + Carbamazepine (increases
the processing of methadone)
resulting in lower blood levels of
methadone.

27. Continue…………..