2. Mood vs. Reason
The idea that mood is different from reason comes from Plato.
He described logos (reason) and thumos (spiritedness or mood).
From logos we derive the word logic.
From thumos we derive words such as dysthymic, euthymic etc.
In the Phaedrus, Plato depicts logos as a charioteer driving the two
horses eros and thumos (i.e. love and mood ).
Meaning: love and mood are to be guided by rationality.
3. Distinction between mood disorders and thought
disorders comes from Emil Kraepelin
In Kraepelinian model schizophrenia and bipolar disorder are separate
entities.
Schizophrenia is a chronic unremitting illness with poor outcome and a
decline in function(non restitutio ad integrum) whereas bipolar
disorder is a cyclical illness with a better outcome and good restoration
of function between episodes (restitutio ad integrum).
4. The physiology of the prefrontal cortex support
Kraepelin’s theory
dorsolateral prefrontal cortex(DLPFC)
- regulates cognitive functioning
ventromedial prefrontal cortex(VMPFC)
– involved in emotional processing
anterior cingulate cortex(ACC)
– involved in selective attention(dorsal ACC)
emotional regulation(ventral ACC)
orbital frontal cortex (OFC)
–regulates impulses and compulsions
5. Circuits
The areas of the prefrontal cortex are connected with
the subcortical areas by loops or circuits (limbic
circuits, striatal circuits, etc.).
Emotion is regulated by cortico- striato-thalamic-
cortical (CSTC) circuits.
7. Emotional symptoms such as sadness or hapiness are
regulated by VMPFC and the amygdala (the activity is
high in the resting state of depressed patients).
8. Manic patient’s neuronal response to no-go task:
impulsive symptoms of mania, such as risk taking and
pressured speech are related to activity in the OFC.
9. Elevated/irritable mood circuits reflect inefficient information
processing in VMPFC, Amygdala, OFC
They are modulated by serotonergic, noradrenergic
and dopaminergic projections
from brainstem nuclei.
Symptoms such as risk taking and
pressured speech
are manifestations of poor impulse control,
thus regulated by the orbital frontal cortex(OFC).
10. Grandiosity, flight of ideas, and racing thoughts
circuits
Are linked to inefficient
information processing in
the same brain regions associated
with psychosis(nucleus accumbens)
and DLPFC.
These areas receive
serotonergic, dopaminergic and
noradrenergic projections
11. Sleep circuits
Reflect inefficient information
processing in the
hypothalamus,
thalamus,
basal forebrain
Entire prefrontal cortex.
All of these brain regions are
modulated by serotonin,
dopamine and norepinephrine.
12. Distractibility circuits
Reflect inefficient information
processing in the
striatum and
DLPFC
which causes increased goal
directed activity or agitation.
The striatum receives only
serotonergic and
dopaminergic innervation,
while DLPFC receives also serotonergic
input.
13. FDA: “There is no such thing as a mood
stabilizer.”
Psychiatrists: “Long live mood stabilizers!”
14. What is a Mood Stabilizer
Originally, a mood stabilizer was a drug that treated mania and prevented its
recurrence, thus “stabilizing” the manic pole of bipolar disorder.
More recently, the concept of “mood stabilizer” has been defined in a wide-ranging
manner, from “something that acts like lithium” to “an anticonvulsant used to
treat bipolar disorder” to “an atypical antipsychotic used to treat bipolar
disorder.”
An ideal mood stabilizer would need to be efficacious for both the acute phase of
bipolar mania/depression as well as for the maintenance phase of bipolar
illness.
At the present time no single drug meets these criteria.
In reality different agents are efficacious for different phases of the bipolar illness.
Some agents are more “mania minded” and thus able to “treat from above”, other
agents are more “depression minded” and thus able to treat “from below”.
16. FDA approved Drugs for Mania and
Maintenance Therapy in Bipolar Disorder
The following drugs are FDA approved for the treatment of acute mania in
bipolar disorder:
Aripeprazole, Carbamazepine ER, Chlorpromazine, Divalporex
ER, Lithium, Olanzapine, Quetiapine, Risperidone and Ziprazidone.
The following drugs are FDA approved for maintenance therapy in bipolar
disorder: Aripeprazole, Lithium, Divalporex, Lamotrigine and Symbiax
(Olanzapine /Fluoxetine combination).
Quetiapine has FDA approval for the treatment of the acute phase of
both bipolar mania and bipolar depression, but not for the maintenance
phase.
18. Clinically the following medication groups
are used for affective stabilization
Lithium
Anticonvulsants
Atypical Antipsychotics
Other Agents:
Memantine
Amantadine
Ketamine
Cacium Channel Blockers (L type)
Riluzole
19. Lithium in Acute Mania
Lithium efficacy: 49-79%
Onset of action: 5-21 days
Predictors of response: classic mania, few
episodes, initial manic episode
Tolerability: cognitive dulling, tremor, renal
failure, polyuria, GI upset, thyroid suppression, weight
gain, sick sinus syndrome.
Keck PE Jr., McElroy St. Nathan PE, Gorman JM. A guide to treatments that work 1997;
Dinesen H et al. Acta Neurol Scand. 1984
20. Lithium – drug interactions
Antipsychotics : may increase lithium toxicity
Bupropion: may increase seizure risk
Carbamazepine : rare neurotoxicity
Diuretics: increase lithium level.
Iodine salts: increase in hypothyroidism
Neuromuscular blockers: respiratory depression
NSAIDs: increase in lithium levels
SSRIs: rare serotonin syndrome
Theophylline: decrease in lithium levels
Urinary alkalinizers: decrease in lithium levels
Verapamil: can both increase or decrease lithium
levels
21. Lithium-Mechanism of Action
Works on at least three systems in the brain (possibly four).
1. Second messengers: modulates the balance between GABA
and Glutamate (inhibitory vs. excitatory neurotransmitters).
2. Prevents apoptosis by inhibiting GSK 3 enzyme and
facilitating BDNF.
3. Enhances serotonergic transmission.
4. Possible antipsychotic effect by blocking the postsynaptic
dopamine receptors hypersensitivity .
22. Both Lithium and Valproate
have neuro-protective effects
PRO -APOPTOTIC
Novel GSK3 inhibitors
FACTORS: GSK3
(currently being
enzyme, BAD(bcl-
developed) might
associated-death-
prove to be effective
promoter) and stress
antimanic agents.
PRUNE the dendritic
tree and the number of
synapses.
ANTI-APOPTOTIC
FACTORS: BDNF, Bcl-2
gene. Increase dendritic
arborization and the
number of synapses.
23. Apoptosis vs. Neurogenesis in the Adult
Hippocampus
Stress, depression or drugs activate apoptosis in the
hippocampus by promoting GSK3(resulting in
decreased size of the hippocampus)
Lithium, Valproate and Lamotrigine stimulate BDNF
which promotes adult neurogenesis in the dentate
nucleus of hippocampus.
27. Calcium channels -
VSCCs can have
multiple regulatory proteins.
Beta units are intracellular.
Gama units span the
membrane.
The alpha2 delta unit
consists of two parts:
a delta part that
spans the membrane and an
alpha2 part that is
extracellular.
VSCCs ha have a snare that punctuates
the presynaptic vesicle, releasing the
neurotransmitter (excitation-secretion
coupling).
28. FDA Indications of Anticonvulsants
Different anticonvulsants have different indications as
mood stabilizers.
Divalporex ER: acute mania, maintanance treatment of
bipolar d/o(Divalporex), migraine prophylaxis.
Lamotrigine: maintenance treatment of bipolar 1 d/o,
Carbamazepine ER: acute mania (as controlled release
formulation Equetro).
29. Divalporex in Acute Mania
Efficacy: 49-70%
Onset of action: 3-10 days
Predictors of response: comparable efficacy in
classic, mixed, and rapid cycling.
Keck PE Jr., McElroy St. Nathan PE, Gorman JM. A guide to treatments that work 1997; Dinesen H et
al. Acta Neurol Scand. 1984
30. Valproate: Side Effects and
Toxicology
Good News first:
Several studies indicated that Valproate reduces total
cholesterol, LDLs and HDLs and protects against the
adverse effects of some antipsychotic drugs on lipid
function.
Casey et al. 2003 showed that as an adjunct of Olanzapine
or Risperidone, Valproate lowered cholesterol levels in
patients with schizophrenia and schizoaffective d/o.
Improves cognition - Aldenkamp et al. 2000 completed a
double blind 20 week randomized clinical trial in which
Valproate caused improvement in short term verbal
memory.
31. Pancreatitis
Valproate is associated with infrequent idiosyncratic acute pancreatitis.
In three migraine trials, the rates of elevation of amylase were similar
between the Valproate and placebo groups (Pellock et al. 2002). These
studies showed that precautionary amylase levels provide little benefit
in predicting pancreatitis. For this reason psychiatrists should be
guided by clinical symptoms.
Hepatotoxicity – usually limited to patients younger than 2.
Bowden et al. in 2000 completed a 1 year study of 187 patients on
Valproate. This study showed improvement in laboratory indices for
hepatic function and no hepatotoxicity.
Tohen et al. in 2003 – in a 47 week study had similar results.
Risk for hepatotoxicity – combination with Carbamazepine.
32. And the bad news about Valproate
GI effects (nausea, vomiting, diarrhea, dyspepsia and anorexia)
are dose dependent and occur early in the treatment.
Tremor – resembles benign essential tremor and is seen more in
patients with seizure d/o.
Sedation – mild to moderate sedation is common.
Hair loss – is due to chelation of trace metals in the intestines.
Hematological effects – leukopenia and thrombocytopenia are
directly related to serum levels above 100 microgrames/ml.
Weight gain – 3-4 lb weight gain is seen in 3-29% of patients
treated with Valproate over 3-12 months
Polycystic ovarian syndrome – occurs in 4-12% of women, but
appears to be more frequent in women with epilepsy.
33. Lamotrigine as Monotherapy in
Bipolar Mania
Lamotrigine has FDA approval for
maintenance treatment for Bipolar 1 disorder.
Both Lamotrigine and Lithium were superior to
placebo in preventing recurrence of mood episodes.
Lamotrigine has also been studied as maintenance
monotherapy in Bipolar 2 disorder.
41% of Lamotrigine patients vs. 26% of placebo
patients were stable without relapse for the 6 months
duration of two studies (2000, 2003).
Special consideration:
When given with Valproate – the dose needs to be
lowered by 50 %. Also with valproate the risk for rash is higher.
Bowden et al. Arch. Gen. Psychiatry 2003; Calabrese et al. J. Clin. Psychiatry 2000
35. Carbamazepine indications, side effects
and drug-drug interractions
Carbamazepine and Oxcarbazepine have no FDA indications for Bipolar
disorder.
However in 2004 FDA approved Equetro (carbamazepine ER) for the treatment
of acute manic and mixed episodes.
Adverse effects:
-Black box warning regarding the risk for aplastic anemia (16/1,000.000
pt./year) and agranulocytosis (48/1,000.000 pt./year).
-Hyponatremia
-Increase in cholesterol and triglycerides (unlike Valproate).
Drug-Drug interactions: CBZ is a potent CYP enzyme inducer 3A3 and 3A4, for
this reason it decreases its own serum concentration(autoinduction) and that
of many other medications including antipsychotics and antidepressants.
36. Anticonvulsants and folate
deficiency
Older anticonvulsants decrease folate levels, leading to
anemias, increased homocysteine levels and psychiatric
problems.
Data are beginning to emerge that even the newer
anticonvulsants and also Valproate may deplete folate.
Measuring homocysteine levels is a more accurate way of
determining if someone has folate deficiency(because
folate has to be methylated into L-methyltetrahydrofolate
in order to be used by the brain).
37. Atypical antipsychotics
Established efficacy for both psychotic and nonpsychotic mania.
Antagonism at D2 receptor explains antipsychotic properties.
Antagonism at 5HT2A receptors (which indirectly reduce glutamate) may
account for the reduction of manic symptoms.
38. Chlorpromazine
FDA approved for:
Manic type of manic depressive illness
Combativeness
Explosive/hyperexcitable behavior in children
Psychosis
40. Evidence Based Prescribing of Drug
Combinations for Bipolar Disorder
Atypical-Lithium Combo
Lithium with any atypical antipsychotic(especially
Olanzapine, Risperidone and Quetiapine).
Atypical-Depakote Combo
Divalporex(Depakote) with any atypical
antipsychotic(especially Olanzapine, Risperidone and
Quetiapine).
Olanzapine-Fluoxetine Combo
Symbyax
41. Reasonable Adjunctive Uses for
Anticonvulsants without Mood Stabilizing
Properties
Any combination containing
Gabapentin, Pregabalin, Topiramate, Levetiracetam, Zonis
amide, Tiagabine .
Can be used for treating anxiety: adjunctive
gabapentin, pregabalin.
Can be used for weight loss: adjunctive Topiramate or
Zonisamide.
Can be used for improving sleep: adjunctive
Gabapentin, Pregabalin or Tiagabine.
43. Are antidepressants mood de-stabilizers?
Bipolar patients usually spend much more time in the depressed phase than in the manic
phase.
Antidepressants may be effective for bipolar depression.
But not everyone agrees about if/how/when antidepressants should be used.
Sachs et al. 2007 completed a study (part of the STEP-BD – Systematic Treatment
Enhancement Program for Bipolar Disorder) an NIMH sponsored study in which 23% of
patients with bipolar depression treated with an antidepressant in combination with a
mood stabilizer achieved euthymia for at least 8 consecutive weeks.
27% of patients who had placebo added to a mood stabilizer achieved euthymia.
Other large studies confirmed these findings.
Risk of rapid cycling and switch to mania limit the use of antidepressants in bipolar
depression (slippery slope).
Gijsman et al. Am J Psychiatry 2004.
