1. Types of Bipolar Disorder (Bipolar I & II) 2. DSM-5 diagnostic Criteria of Mania & Hypomania 3. Pathophysiology of Bipolar Disorder 4. Mood Stabilizers (Class A & B) 5. Mood De-stabilizers 5. Lithium (History, Pharmacokinetics, Mechanism, Uses, Side effects, Drug Interactions Toxicity)

1. Drug Therapy of Bipolar
M/D Disorder
Prof. Sawsan Aboul-Fotouh
Department of pharmacology, faculty of Medicine, Ain shams University
‫اضطراب‬
‫وجدانى‬
‫ثنائى‬
‫القطب‬

2. Bipolar manic depressive disorder (~ 2%)
Episodes of Depression alternating with episodes of
Mania (Bipolar I) or Hypomania (Bipolar II).

3. DSM-5 diagnostic criteria for Manic Episode: ‫نوبة‬
‫الهوس‬
A. Persistent elevated, or irritable mood and ↑ energy, lasting ≥ 1 week and present most of
the day, every day
B. During this period, ≥ 3 of the following symptoms
1. Grandiosity.
2. ↓ Need for sleep (e.g., feels rested after only 3 hours of sleep).
3. Hyper-talkative.
4. Flight of ideas .
5. Distractibility
6. psychomotor agitation
7. ↑ activities →high potential for painful consequences
C. Significantly impaired functioning (Social or occupational) or need hospitalization.
D. Ruling out substance-related cause or other medical condition or psychiatric disorder.
Hypomania as Mania symptoms EXCEPT
(A) Lasting at least 4 days, (B) No impaired function, No hospitalization

4. Onset usually < 30 yrs, Bipolar II > Bipolar I, Also Mixed & Rapid Cycling (>4/yr)
(Depression : Mania > 3 : 1)
(Female also > Rapid cycling, > Suicide, > EPS with AP)
(Depression : Mania = 3 : 1)

5. Neurobiology of Bipolar Disorder
DA, 5-HT, NE,
GABA/Glutamate
Psychoanalytic
Learned
helplessness Inflammatory ..
Cognitive HPA axis& TSH
Dysfunction
Mitochondrial
Dysfunction
BDNF
Brain
Images
Kaplan, 2019
Kindling
Epigenetic
Circadian R
Stress

6. Management of Bipolar disorder

7. Goals of treatment (No Cure)
For Life
TTT Goal: to control Symptoms, stabilize mood &Restore functioning.
-12

8. Treatment of Bipolar disorder
1. Pharmacological treatment:
a.Lithium (Anti-manic, Mood stabilizers, Antidepressant)
b.Antipsychotics (Anti-manic, Mood stabilizers, Antidepressant)
c.Anticonvulsants (Mood stabilizers ….)
d.Antidepressants (2nd or 3rd line in Bipolar depression with mood stabilizers)
e.Benzodiazepines (sedatives in acute manic or hypomanic episode)
2. ECT in refractory or emergent cases (6-8 sessions)
3. Psychotherapy:
Psychotherapy + anti-manic drugs (e.g Lithium) is more effective than either alone.
(Kaplan Handbook, 6th ed. 2019)

9. Antidepressants monotherapy NOT recommended → Switch to mania.
They are only used simultaneously with mood stabilizer (lithium or....)
Lithium = Li
&/or Antipsychotics
& Antipsychotics
/or Valproate
+
(1)
(2)
(3)
Euthymic

10. Antidepressants monotherapy NOT recommended → Switch to mania.
They are only used simultaneously with mood stabilizer (lithium or....)
Lithium = Li
&/or Antipsychotics
& Antipsychotics
/or Valproate
+
(1)
(2)
(3)
Euthymic

11. Mood stabilizers
“Drug that can decrease vulnerability to episodes of mania or depression
and not exacerbate the current episode or maintenance phase of treatment”
Prevent mood shifts to mania (or hypomania) and depression
Class B
Class A
Li , Anticonvulsants & Antipsychotics T&At

12. Monotherapy or adjunctive to Li or divalproex
Lurasidone (2013)
Antipsychotic in Bipolar

13. (The Maudsley Prescribing Guidelines in Psychiatry, 13th ed., 2018)
Treatment of
Acute mania or
Hypomania
First:
Combine 2 or 3 drugs (Li. or
Valproate + APDs + BZD), if
inadequate
Second:
Consider the 3 drugs (Lithium
+ Valproate + APDs) ,
if inadequate
Third:
Add ECT for mania with
psychosis or catatonia, or add
clozapine for TTT-resistance
APDs > effective than Li &
anticonvulsants in Acute M.
esp. Risperidone, Olanzapine
& Haloperidol
(bec. Of delayed onset)
NICE guidelines
Onset: Li (5-20 days), Valproate (3-10 days)

14. When Antiepileptics are More Effective
than Lithium as Mood Stabilizer ?
1.Mixed Mania (Dysphoric)
2.Rapid Cycling (>4/yr)
3.Psychotic Mania
4.Multiple Manic episodes
5.History of Drug Abuse
Anti-kindling effect

15. Antibiotics
Mood De-stabilizers
“Drug that can precipitate or exacerbate episodes of mania or depression”

16. Lithium
The ”Gold standard” for
treating bipolar disorder
400 mg
“Anti-manic, Mood stabilizers, Antidepressant”

17. • Li is FDA-approved in 1970 for Mania TTT > 7 yrs.
• History ….. Alexander Ure (1840) , John Cade
• Lithium efficacy: 49-79%
• Onset of action: 5-21 days (Delayed)
• Dosage Form:
Tablets or cap. (400mg CR, 300-600 mg)
Syrup (=204 mg/5ml Li carbonate
Lithium
Monovalent cation similar to Na (before Na in periodic table)
Australian psychiatrist John Cade
1949

18. (Synaptic plasticity &Neuroprotective)
(Anti-manic)
(Mahli et al, 2013 and modified)
A. Old
In Bipolar: ↑ Na & ↑ Ca level IC.
Li ↓ these by replace Na+ ions IC.
B. Recent : (neurotransmitters)
1. ↓ DA & ↑ 5HT
2. Modulates GABA/Glutamate balance
(↓glutamate &↑GABA)
3. Intracellular signaling: Li
a- ↓ IMPase, IPPase → ↓ Myinositol →
↓ neuronal phosphoinositides recycling
b- ↓ PKC and MARCKS which are
over-activated in mania → anti-manic.
c - ↓ GSK-3 → ↑ BDNF & Bcl-2 → ↑
neurogenesis in hippocampus DG.
so ↓ Apoptosis & ↑ Neuroplasticity
d- Balance cAMP signaling
Mechanism of action of Lithium
↑ 5HT
Uk

19. 1. Absorption: Complete; Peak level ≈2 hr for IR & ≈12 hr for CR. T1/2 ≈ 24 hrs
3. Distribution: Vd = 0.5 -0.9 L/kg; ( ̴ total body fluid), No PPB. “Plasma :CSF ≈ 3.6 :1” after 24hr
3. Metabolism: No “Li is Best Choice in Hepatic impairment”
4. Excretion: Renal GF Li clearance ~ 20% of cr. clearance (& 30% in manic attack).
60-80% reabsorbed in PCT (as Na). Li reabsorption ↑ when Na reabsorption ↑ (-ve Na
balance as Diarrhea, Vomiting, ↑Sweating , Diuretics… or dehydration…. may→ Li toxicity).
- Circadian rhythm of glomerular filtration GF→ Li clearance ~30% higher during daytime (so
higher dose in the morning).
- If single CR dose give at night (as Li induce polyurea after 12 hr→ Morning… & need lower dose)
Pharmacokinetics of Lithium
Plasma :CSF ≈ 3.6 :1
(Katzung, 2018)

20. Lithium blood level and dose
Target plasma level (TPL) is:
- 0.8–1.2 mEq/L for Acute Mania and
- 0.6–0.8 mEq/L for Maintenance.
(kaplan Handbook 6th ed., 2019).
When & How Check?
- 5 -7 days from TTT start “=Css”
- 12 hr after last dose. “Peak CR”
Weekly till reach TPL then /2-6 months
400 mg
Lithiumeter
A daily dose
1200–1800 mg → TPL 0.8–1.2 mEq/L.
Titrate: Start 400mg then ↑ /W till TPL
within 2 – 4 weeks “Trial 4 Weeks”
Once daily Dose at night is preferred
> 1.5 mEq/L

21. 1. Mood stabilizer:  Mood swings ….
2. Anti-manic effects
3. Anti-depressant effects
4. Anti-suicide effects
5. Anti-impulsivity (others: SSRIs, Antiepileptics, APD esp. Clozapine)
6. Anti-thyroid (↓ thyroid Hormones)
Pharmacological Actions of lithium
American Academy of Psychiatry, 2015

22. A. Well Established (FDA Approved)
1. Acute Manic episode (TPL 0.8–1.2 mEq/L)
2. Maintenance therapy of Bipolar disorder (TPL 0.6–0.8 mEq/L)
B. (Reasonably Well Established)
1. Depressive episode Bipolar disorder
2. Rapid-cycling bipolar I disorder
3. Cyclothymic disorder
4. Major depressive disorder (as an augmenting agent) and maintenance.
5. Schizoaffective disorder
6. Clozapine-induced Agranulocytosis (+BM)
C. Evidence of Benefit in Particular Groups
1. Schizophrenia
2. Aggression (episodic), explosive behavior, and self-mutilation
3. Conduct disorder in children and adolescents
4. Cluster headache prevention
5. Graves disease (Hyperthyroidism)
Therapeutic Indications of lithium
And unilateral

23. Adverse Effects Precautions
1. CNS: fine tremors (≈50%), ↓Cognition •Coarse tremors & GIT symptoms
are early warning signs of toxicity.
2. GIT: nausea - vomiting - diarrhea.
3. Renal:
- Antagonizes ADH: polyuria → thirst.
(Nephrogenic diabetes insipidus ≈30%).
- Renal tubular damage.
• Monitor kidney function.
4. Thyroid : Benign enlargement
with or without
hypothyroidism (≈ 10%).
• Monitor thyroid function.
5. Toxic drug :
a) Narrow TI (0.6-1.2 mEq/l → > 1.5 mEq/l Toxic).
b) Long t½ .
c) Cumulative.
• Monitor Li+ serum level.
• Adjust dose in ↓Li+ excretion, as in:
1. Na+ depletion by diuretics.
2. Renal dysfunction
3. Old age (↓ renal function).

24. CI: Hypercalcaemic or hyperparathyroidism should not receive lithium
Other side effects & precautions

25. Other side effects & precautions
On-treatment Monitoring:
Plasma lithium, eGFR and TFTs should be checked every 6 months.
1. CNS : ↓ cognition & Memory, slow, Dull mood, Drowsiness
(but Not hypnotic)
2. CVS: Benign T-wave changes, Sinus node dysfunction
3. Hyperparathyroidism →↑osteoporosis & ↑ Ca, R stones with Chronic Li
4. Leukocytosis in acute use (ttt Clozapine-Leukopenia) while carbamazepine → neutropenia
4. Skin: Acne, psoriasis, hair loss (esp. with Valproate)
5. Weight gain (esp. with Valproate)
6. Uncommon neurologic:
Mild Parkinsonism & ataxia. peripheral neuropathy,
pseudotumor cerebri, as myasthenia gravis, and ↑ risk of seizures

26. lithium is renally eliminated,
➢ Best choice in hepatic impairment
➢ Need Dose adjustment in renal dysfunction .
Lithium
Pre-lithium: CBC, ECG, thyroid function tests (TFTs), eGFR, Ca & a pregnancy test (pregnancy ↑ Li clearance).
Lithium Calculator (russellcottrell.com)

27. Lithium during Pregnancy
• Risk “D” category Li ……….
• Li → cardiac Ebstein’s anomaly (0.05–0.1%) X10.
• Recently, Li carries low risk of teratogenicity
• Li in breast milk, Conc. ≈30-50% of serum (NIH &
BAP recommend not to breastfeed whilst taking Lithium)
• Li toxicity in newborns: “floppy baby”.
Lethargy, cyanosis, poor suck & ↑ reflexes, and hepatomegaly
Guidelines
- The Best to shift her on Atypical Antipsychotic &/or Lamotrigine (BUT less effective)
- Most antipsychotics are category C (except clozapine B but has risk of Agranulocytosis)
- If Li -controlled→ Stop Li in 1st trimester & then give Li (stop 24-48 hr before labor)
- During pregnancy → ↑ Li dose due to ↑ T body fluid, ↑ Plasma volume & ↑ GFR ↑ 50%)
- After Labor →↓ Dose of Li as Bl. volume ↓ by 1/3 → ↑ Li conc. may → Toxicity
Lithium is effective & safe mood stabilizer during pregnancy (> 3 months)

28. A. Pharmacodynamic interactions: With
1. APDs: → ↑ lithium-induced neurologic side effects and NMS.
2. Carbamazepine, Lamotrigine, Valproate, and clonazepam → ↑ lithium-induced
neurologic side effects
3. SSRIs, Li ↑ 5HT side effects & 5-HT hyperarousal & serotonin syndrome.
4. Iodides ↑ hypothyroid effect of lithium (as ↓ thyroid hormone production).
5. ECT: → ↑ ECT duration & post ECT delirium risk (Stop Li 24 hrs before ECT)
Lithium Drug Interactions
(Clinical Psychopharmacology An update, 2019)

29. B. Pharmacokinetic interactions
1. Drugs ↓ Li Level
a. Xanthines : (theophylline, caffeine,) ↓ Na reabsorption at PCT → ↓ Li reabsorption → ↑ Li
CL → ↓ Li level. due to diuresis & natriuresis at PCT & ↑COP, PGE2 & cAMP by Xanthines
2. Drugs ↑ Li Level → Li Toxicity
a. Carbamazepine → ↓ Li clearance → ↑ Li Level. (uk mech ??)
b. Diuretics (Thiazides, K-sparing, Loop diuretics), when diuretics lead to Na and water
depletion → ↑ compensatory Na reabsorption (& hence Li) in PCT → ↓ Li clearance with thiazides
by 50% and to lesser extent or no with Amiloride and Loop diuretic → ↑ Li Level
c. NSAIDs &ACE inhibitors & ARBs: ↓ Li clearance & ↑ Li level 25%-400% → Li
toxicity. However, some NSAIDs “sulindac & Aspirin” have no or little interaction with Li.
-NSAIDs reduce renal blood flow via inhibition of prostaglandins
-ACEIs &ARBs unknown mechanism but may be due to decrease GFR
Lithium Drug Interactions

30. Drugs ↓ Li Level
Xanthines
(theophylline, caffeine,)
Lithium Drug Interactions
Drugs ↑ Li Level
→ Li Toxicity
1. Carbamazepine
2. Diuretics
3. NSAIDs
4. ACE inhibitors

31. mEq/L mEq/L mEq/L
mEq/L
Vomiting - diarrhea -
coarse tremor
lethal levels (> 2.0 mEq/L),
Causes or Risk Factors
1. ↑ Intake (Suicide “BP 15%” or accidental)
2. ↓ Excretion (Drugs.., Renal impairment, Sodium and volume depletion as ……, Fever)

32. Management of Lithium Toxicity
Sodium overloading is not recommended in Li toxicity
1. Stop Li, & G. lavage & A charcoal if acute ingestion
2. ↑Fluid intake (maintain electrolytes)
3. Diuresis Osmotic or Forced (NEVER thiazide or loop D)
4. Dialysis : Hemodialysis (& Peritoneal D less effective)
Repeat/6-8hr till Nontoxic Li range.
Hemodialysis Is the most effective esp. if:
Severe Toxicity S&S or Fluid intake contraindicated (CHF, Cirrhosis)
or Li level > 3 mEq/L or renal failure (RF).
“No Antidote”