Explores psychological, medical and primary care treatment and self-care for bipolar disorder from the biological bases of brain function and medication management to the psychological integrated care and treatment plan for health complexity and bipolar treatment needs.

1. NEUROPHARMACHOLOGY
LECTURE 1 – NEUROBIOBEHAVIORAL
OVERVIEW OF BIPOLAR DISORDER AND
TREATMENT

2. • Understanding the biology helps both psychotherapy and medication management of
bipolar disorders.
• There are three main theories of bipolar disorder:A. Dopamine over-expression, B.
Kindling and diathesis stress model, and C. Sub-cortical seizures.
• Taking a whole person approach including social rhythms, psychological skills, healthy self
view, and medication management has the best prognosis for patients with a diagnosis of
bipolar disorder.
THREE CONCEPTS FROM TODAY

3. MOOD DISORDERS
• Unipolar Depression: Disrupts life through increased
irritability, isolation and robs people of joy.
• Bipolar Disorder a Disorderly Disorder. It leads to
extremes in behaviors and moods.
• An Unique Mind is a memoir by Dr Kay Redfield Jamison
who lives with bipolar disease.
• She is a well respected psychiatrist with a prestigious career.
• Had personal struggles with wanting to take medications.

4. Crooked Beauty is a poetic documentary that chronicles artist-activist Jacks McNamara's
transformative journey from childhood abuse to psych ward patient to pioneering mental health
advocacy.
It is an intimate portrait of her intense personal quest to live with courage and dignity, and a
powerful critique of standard psychiatric treatments.
Poignant testimonials connect the fissures and fault lines of human nature to the unstable
topography and mercurial weather patterns of the San Francisco Bay Area.
Crooked Beauty reshapes mental health stigmas through a new healing culture and political
model for living with madness as a tool of creativity, inspiration and hope.
www.crookedbeauty.com
https://www.youtube.
com/watch?v=qgAaIBl
q-cs

5. HISTORY OF
BIPOLAR DISORDER
• 400 BC - Hippocrates links
the black bile of melancholia with
the yellow bile of mania.
• 1899 - Emil Kraepelin introduces
the term "manic-depressive” into
psychiatric textbooks.
• 1949 - Australian doctor John
Cade discovers the efficacy of
lithium as a treatment.
• 1968 - The DSM changes to the
term manic-depressive illness and
biological perspectives come to
dominate.
• 2010 - New draft of DSM
proposed.

6. RATES AND
EPIDEMIOLOGY
• For most the onset for Bipolar
occurs in
late teens and early 20’s.
• Rates in general population for
adults is between 1% and
4% depending on criteria.
• In elders in community rates are
between 1% and .5%
• Rates in nursing homes are as high
10%.
• Psychosocial factors increase
severity of symptoms and
predicts health, behavioral
problems, and rate of relapse.
• Family relationships, Poverty, Racism,
Lack of Social Relationships, Life
Stress are Key Factors in Prognosis.

7. MOOD DISORDER
DIAGNOSIS
1. Identify episode of mania,
hypomania, depression or
mixed episode.
2. From the episode the
diagnosis is given.
3. In bipolar the rate of change
and severity of symptoms are
key diagnostic questions.

8. DIAGNOSIS BIPOLAR SPECTRUM
• Bipolar I disorder: One or more manic episodes. Subcategories specify whether
there has been more than one episode, and the type of the most recent episode.
• Bipolar II disorder: No manic episodes, but one or more hypomanic episodes and
one or more major depressive episode.Hypomanic episodes do not go to the full
extremes of mania.
• Cyclothymia: A history of hypomanic episodes with periods of depression that do
not meet criteria for major depressive episodes.
• Bipolar Disorder NOS (Not Otherwise Specified): This is a catchall category,
diagnosed when the disorder does not fall within a specific subtype.
• Rapid cycling: Most people who meet criteria for bipolar disorder experience a
number of episodes, on average 0.4 to 0.7 per year, lasting three to six months.Rapid
cycling is defined as having four or more episodes per year.

9. Bipolar Disorder: Sami Khalife,Vivek Singh, David J. Muzina
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/psychiatry-psychology/bipolar-disorder/#f0015

10. NEUROBIOLOGICAL CHANGES
• MRI studies in bipolar disorder: Increase in the volume of the
lateral ventricles, globus pallidus, abnormalities in hypothalamic-
pituitary-adrenal axis (HPA axis).
• The "kindling" theory:A genetic predisposition is catalyzed by
stressors that lowers threshold for mood episodes and disrupts
emotional regulation.After this occurs often enough mood
symptoms self-perpetuate.
• Disruptions in mitochondria and neuron pump also have been
identified.
• Individuals with bipolar disorder have alterations in:
Circadian rhythms, sleep, diurnal cortisol and melatonin.

11. PSYCHOSOCIAL
FACTORS AND
SYMPTOMS
• Individuals with bipolar disorder can lead very
productive lives if there is the right social and
emotional support.
• More then individuals with psychosis individuals
with bipolar tend to be in higher paying work.
• However there is often a lower reported quality
of life for individuals with bipolar disorder
despite successes.
• If there are significant life stressors, poor social
support, chaos, etc. there is another life course
for the illness.

12. BIOLOGY OF BIPOLAR
DISORDER
• Disruptions in itterative loops (feed back loops):
• Striatal–Thalamic–Prefrontal – Modulates
behavioral regulation and motor planning. Sub-
cortical regions are different from controls.
• Amygdala, Midline Cerebellum – Limbic
modulating regions are disrupted in bipolar
disorder and effected by bipolar medication.
• Anterior Cingulate Cortex, Dorsolateral
Prefrontal
Cortex – Abnormal activation may disrupt
frontal lobe functioning leading to biplar
symptoms.
https://www.youtube.com/watch?v=W1TMZASC
R-I

13. BIOLOGY OF BIPOLAR
DISORDER
• Disrupted Iterative Loops (feed back
loops):
• SGPFC (a region of anterior
cingulate) and amygdala project to
hypothalamus and may lead to
neurovegetative symptoms.
• Damage to the Caudate head (part
of basal ganglia) can lead to frontal
lobe dysfunctions that change the
feed back loops (iterative loops)
between these symptoms and may
cause bipolar disorder.

14. BIOLOGY OF
BIPOLAR DISORDER
• Disrupted metabolism, neurochemicals:
• Change in D2 (dopamine 2) binding sites in
individuals with psychotic features and
bipolar.
• Differences in choline production in the
striatum (not mood dependent), cingulate
(dependent on mood), and frontal lobes.
(may be reflective of depression states)
• Changes are found in metabolism as
measured by changes in functioning in
metabolites. May indicate a
hypermetabolism leads to changes in how
the brain fires. Some studies indicate lithium
reverses this but not Depakote. (decreased
marker in DLPC = emotional regulation)

15. BIOLOGY OF BIPOLAR
DISORDER
“…patients not treated with antipsychotics
or mood stabilizers exhibited significantly
higher activation throughout the motor
cortex, basal ganglia and thalamus
compared with patients who were receiving
these medications, suggesting that mood
stabilizers and antipsychotics may normalize
cortical and subcortical hyperactivity
associated with bipolar disorder.”

17. IMPLICATIONS
• These findings may imply
that the brain of individuals
with bipolar might have two
challenges:
Hyperactive subcortical
regions.
Hypoactive frontal lobe
regulation of emotional
processes.

18. BIO-PSYCHOSOCIAL
TREATMENTS
• Medications: Lithium,Anticonvulsants (Depakote
& Tegretol),Atypical Antipsychotics.
• CNS Depressants (e.g. Benzodiazepines)
• Anti-depressants have limited data and most data
show that they are not effective.
• Psychotherapy regard to relapse prevention:
• Cognitive behavioral therapy.
• Family-focused therapy.
• Psychoeducation
• Psychotherapy regard to residual depr. symptoms:
• Social rhythm therapy.
• Cognitive-behavioral therapy.

19. DISCUSSION:
• ManagingTreatment Adherence…

20. NEUROPHARMACHOLOGY
LECTURE 2 – PHARMACOTHERAPY AND
INTEGRATED CARE OF BIPOLAR
DISORDER IN PRIMARY CARE

21. RECAP LECTURE ON BIOBASIS
THREE CONCEPTS
• Understanding the biology helps both psychotherapy and
medication management of bipolar disorders.
• There are three main theories of bipolar disorder:A. Dopamine
over-expression, B. Kindling and diathesis stress model, and C. Sub-
cortical seizures.
• Taking a whole person approach including social rhythms,
psychological skills, healthy self view, and medication management
has the best prognosis for patients with a diagnosis of bipolar
disorder.

22. IMPLICATIONS OF
NEUROSCIENCE
• Findings may imply that the
brain of individuals with
bipolar might have two
challenges:
• Hyperactive subcortical
regions.
• Hypoactive frontal lobe
regulation of emotional
processes.

23. BIO-PSYCHOSOCIAL TREATMENTS
• Medications: Lithium,Anticonvulsants (depakote &
tegretol),Atypical Antipsychotics.
• CNS Depressents (e.g. Benzodiazipines)
• Anti-depressants have limited data and most data show
that they are not effective.
• Psychotherapy regard to relapse prevention:
• Cognitive behavioral therapy.
• Family-focused therapy.
• Psychoeducation
• Psychotherapy regard to residual depr. symptoms:
• Social rhythm therapy.
• Cognitive-behavioral therapy.

26. http://psychopharmacologyinstitute.com/antips
ychotics-videos/first-second-generation-
antipsychotics-treatment-bipolar-disorder/
VIDEO OF BIPOLAR MEDICATION
PSYCHOPHARM INSTITUTE

27. SIDE EFFECT PROFILES: LITHIUM
• Nausea, vomiting, and diarrhea.
• Trembling.
• Increased thirst and increased
need to urinate.
• Weight gain in the first few
months of use.
• Drowsiness.
• A metallic taste in the mouth.
• Abnormalities in kidney
function.
• Abnormalities in thyroid
function
Side effects include: Black outs, slurred speech,Arhythmia
or a heart block, and an increased white blood cell count.

28. https://psychopharmacologyinstitute.com/moo
d-stabilizers/mechanism-action-lithium-
illustrated-review/
VIDEO LITHIUM MECHANISM OF
ACTION PSYCHOPHARM INSTITUTE

29. SIDE EFFECT PROFILES
ANTI-PSYCHOTICS
• Blurred vision
• Dry mouth
• Drowsiness
• Muscle spasms or tremor
• Involuntary facial tics
• Weight gain
• Constipation
Health problems…
• Rapid Weight Gain
• Risk of Diabetes
• Increased risk of heart
disease (rare) and stroke.
• Increases in levels of the
hormone prolactin that may
result in development of
breasts and milk production.
• Orthostatic hypotension.
NOTE:Antipsychotics, particularly atypicals, appear to cause changes in
insulin levels by blocking the muscarinic M3 receptor

30. WITHDRAWL ANTIPSYCHOTICS
• Common Withdrawl Symptoms:
Nausea, emesis, anorexia,
diarrhea, rhinorrhea, diaphoresis,
myalgia, paresthesia, anxiety,
agitation, restlessness, and
insomnia.
• “Super Sensitive Psychosis”
Some cases a withdrawl
psychosis caused by medication
not a resergence of symptoms.
• Tardivedysconisia as a withdrawl
symptom.
• Withdrawl can occur even
switching between medications.
Not all providers use this
information.
Cholinergic Rebound Rare:
Symptoms and Signs Diarrhea (and Diaphoresis) and
abdominal cramping Urination, Miosis (pinpoint pupils),
Bradycardia (muscarinic) orTachycardia (nicotinic),
Emesis (Nausea andVomiting), Lethargy,
Salivation Anxiety or Agitation, Seizures, Coma

31. WITHDRAWAL
ANTIPSYCHOTICS
• Common Withdrawal Symptoms: Nausea, emesis, anorexia,
diarrhea, rhinorrhea, diaphoresis, myalgia, paresthesia, anxiety,
agitation, restlessness, and insomnia.
• “Super Sensitive Psychosis” Some cases a withdrawal psychosis
caused by medication not a resurgence of symptoms.
• Tardivedysconisia as a withdrawal symptom.
• Withdrawal can occur even switching between medications. Not
all providers use this information.
Cholinergic Rebound Rare:
Symptoms and Signs Diarrhea (and Diaphoresis) and
abdominal cramping Urination, Miosis (pinpoint pupils),
Bradycardia (muscarinic) orTachycardia (nicotinic),
Emesis (Nausea andVomiting), Lethargy,
Salivation Anxiety or Agitation, Seizures, Coma

32. SIDE EFFECT PROFILES
ANTI-CONVULSANT
• All anticonvulsants can cause side
effects. Between 44 and 95
percent of the people taking them
experience at least one.
• The most common are dizziness,
sleepiness, and nausea.
• Some of the newer
anticonvulsants cause swelling of
hands and feet, weight gain, blurry
vision, trouble concentrating, and
memory lapses.
• Topamax – Weight loss, kidney
stones, skin crawling paresthesia's.

33. SIDE EFFECT PROFILES
ANTI-CONVULSANT
• Depakote andTegretol – Monitor drug levels, hepatic functioning and for
Depakote impact on pancreas. (Periodic liver testing for Depakote)
• Life-threatening rashes, including Stevens-Johnson Syndrome (Tegretol,
Oxcarbazepine & Lamotrigine).
• Oxcarbazepine & Pregabalin (Lyrica): Rare first dose anaphylactic shock.
• Carbamazepine, divalproex/ valproic acid, lamotrigine, oxcarbazepine:Although
rare, serious and life-threatening multi-organ hypersensitivity might occur
during the first two weeks of treatment. Symptoms are diverse but include
multiple organ systems.
• All anticonvulsants can increase suicidality.

34. SIDE EFFECTS FOR IMMEDIATE CONSULT
WITH DOCTOR
• Overheating or dehydration: If you feel hot, dizzy, or faint, head to a cooler area or take a
cool shower or bath and drink plenty of fluids. Call your doctor to report your symptoms.
• Chest pain, shortness of breath, or persistent elevated or irregular heart beats:
These symptoms could be related to a number or possible side effects or blood level
problems and are medical emergencies.
• Skin reactions: Allergies and skin reactions can happen with any medication and should be
reported immediately. Some medications can cause severe and dangerous skin conditions.
• Seizures or loss of consciousness: Seizures and loss of consciousness may be related to
various medication side effects and should be considered a medical emergency.
• Involuntary muscle movements: Some medications can cause muscle reactions that need
to be addressed before they become long-term problems.
• Suicidal thoughts, severe agitation or worsening of your symptoms: Although these
are not necessarily side effects of any medication, some medications may aggravate your
bipolar symptoms or simply fail to treat them, leading to thoughts of suicide or other negative
emotional and behavioral symptoms.
http://blogs.psychcentral.com/bipolar/2008/12/managing-bipolar-medication-side-effects/

35. PSYCHOLOGICAL
TREATMENTS
• Cognitive BehavioralTherapy:
Targets the relationship between
thoughts, feelings and behaviors.
• Family FocusedTherapy: Helps
recognize signs of impending
episodes or relapses, increase
communication and conflict
resolution, teaches problem-
solving skills, and helps individual
create concrete steps to get
support in a crisis.
• Psychoeducation: Teaches
individuals about the disorder and
helps develop tools to manage
symptoms.

36. INTERPERSONAL
AND SOCIAL
RHYTHM
THERAPY
• Is a treatment combining
psychological and medical
interventions.
• Finds “dysregulation in
circadian rhythms” as a cause
for episodes.
• PET found effects of sleep
deprivation in the medial
prefrontal cortex (mood and
emotion regulation centers).
• Sleep deprivation leads to
increase in positive mood for
people who are depressed.

37. THREE PATHWAYS TO
BIPOLAR EPISODE
1) Stressful life events.
2) Disruptions in social
rhythms.
3) Medication
non-adherence.

38. INTERPERSONAL
AND SOCIAL
RHYTHM
THERAPY
1) The link between mood and life events.
2) The importance of maintaining regular daily
rhythms.
3) The identification and management of potential
precipitants of rhythm dysregulation with special
attention to interpersonal triggers.
4) The facilitation of mourning the lost healthy self.
5) The identification and management of affective
symptoms.

39. CASE CONSULTATION

40. CLOSING QUESTIONS
?
?
?

41. NEUROPHARMACHOLOGY
LECTURE 3 – NEUROENDOCRINE AND
HEALTH COMPLEXITY AND BIPOLAR
DISORDER

42. Bipolar Disorder Is Like HavingTwo Serious Illnesses at Once
Nicole Foubister
Psychiatrist
Assistant Professor Child and Adolescent Psychiatry, NYU

45. Common
Mechanism
COMMON MECHANISM APPROACH
This approach there are different symptoms that both are impacted by a
mechanism of the medicine or intervention
Let’s Choose two
Symptoms that
can be effected by
one intervention
either biological,
psychological or
social
Chronic Pain
Different
Symptoms
PROBLEM BASED LEARNING BIPOLAR – II AND
PAIN
Bipolar - II

46. Common
Symptom
Intervention
Medication
Let’s Choose a
Symptom that
Overlaps Between
Chronic Pain and
Bipolar to develop
a medication,
social and
psychological
intervention.
Bipolar-II
Chronic
Pain
PROBLEM BASED LEARNING BIPOLAR – II AND
PAIN
COMMON SYPTOM APPROACH
Often it is possible to find an overlap in medication management that
addresses both mental health and health condition. Lets look at pain and
Bipolar-II .

48. Assessment Exercise

50. BIPOLAR DISORDER GENETICS
• World wide life time incidence of bipolar disorder is 2.4% in
the US it is 4.4%.
• Monozygotic co-twin 40-70%; first degree relative 5-10%;
unrelated person 0.5-1.5%.
• Gene X Environment: One study indicating BDNF gene
interacting with stressful life events to increase risk of
bipolar depressive episodes.
• Genome-wide association (GWAS) & Single nucleotide
polymorphisms (SNPs): SLC6A4,TPH2, DRD4, SLC6A3,
DAOA, DTNBP1, NRG1, DISC1 and BDNF.
Serretti, A., & Mandelli, L. (2008). The genetics of bipolar disorder: genome ‘hot regions,’genes, new potential candidates and future
directions. Molecular psychiatry, 13(8), 742.
Uher, R. (2014). Gene–environment interactions in severe mental illness. Frontiers in psychiatry, 5, 48.

51. EPIGENETICS OF BIPOLAR MEDICATION
• Lithium andValproic Acid: Increased methylation leading to amplification
of leptin via lepr gene.
• Mixed or manic state BDNF methylation levels near controls
• Patients in euthymic or depressed states higher BDNF methylation levels.
• Lithium and valproate both decreased BDNF methylation levels (non-sig).
• Mice treated with olanzapine showed increased methylation in multiple
genes higher number in hippocampus.
• Later study found: significant increase methylation at the hippocampal
dopamine-DARPP32 pathway.
Lockwood, L. E., & Youssef, N. A. (2017). Systematic Review of Epigenetic Effects of Pharmacological Agents for Bipolar Disorders. Brain sciences,
7(11), 154.

52. INFLAMMATION AND BIPOLAR
• Cox-2 inhibitor celecoxib (antarthritic medication) has antidepressant
effects in bipolar disorder (BD) patients during depressive or mixed
phases
• Bipolar disorder and inflammation are related through both gene
differences and genetic expressions. Episodes of Manic or Depressive
States show alterations in inflammatory markers.
• Individuals with bipolar disorders have higher disease burden and this
burden is impacted by inflammatory cytokines.
• Bio-behavioral links exist between inflation and exercise, sleep, EtOH,
Smoking,Artery Disease, Insulin Resistance, and Pain
• Multiple medications for bipolar disorder also have positive impact on
inflammation markers.
Goldstein, B. I., Kemp, D. E., Soyinka, J. K., & Mclntyre, R. S. (2009). Inflammation and the phenomenology, pathophysiology, comorbidity, and
treatment of bipolar disorder: a systematic review of the literature. The Journal of clinical psychiatry.

56. Öngür, D., Lundy, M., Greenhouse, I., Shinn, A. K., Menon, V., Cohen, B. M., & Renshaw, P. F. (2010). Default mode network abnormalities in
bipolar disorder and schizophrenia. Psychiatry Research: Neuroimaging, 183(1), 59-68.

57. Panda, R., Bharath, R. D.,
Upadhyay, N., Mangalore, S.,
Chennu, S., & Rao, S. L. (2016).
Temporal dynamics of the
default mode network
characterize meditation-induced
alterations in consciousness.
Frontiers in human neuroscience,
10, 372.
Temporal
Dynamics of
the Default
Mode Network
Characterize
Meditation-
Induced
Alterations in
Consciousness

58. Cumulative Incidence for Bipolar Disorder after age 15 years over Number of Early
Adverse Events.
Bergink, V., Larsen, J. T., Hillegers, M. H. J., Dahl, S. K., Stevens, H., Mortensen, P. B., ... & Munk-Olsen, T. (2016). Childhood adverse life events and
parental psychopathology as risk factors for bipolar disorder. Translational psychiatry, 6(10), e929.

59. Forty, L., Ulanova, A., Jones, L., Jones, I., Gordon-Smith, K., Fraser, C., ... & Rivera, M. (2014). Comorbid medical illness in bipolar disorder. The British
Journal of Psychiatry, 205(6), 465-472.

61. Common
Mechanism
COMMON MECHANISM APPROACH
This approach there are different symptoms that both are impacted by a
mechanism of the medicine or intervention
Let’s Choose two
Symptoms that
can be effected by
one intervention
either biological,
psychological or
social
___________
_
Different
Symptoms
PROBLEM BASED LEARNING BIPOLAR – II AND
HEALTH
Bipolar - II

62. Common
Symptom
Intervention
Medication
Let’s Choose a
Symptom that
Overlaps Between
Chronic Pain and
Bipolar to develop
a medication,
social and
psychological
intervention.
Bipolar-II
_______
PROBLEM BASED LEARNING BIPOLAR – II AND
HEALTH
COMMON SYPTOM APPROACH
Often it is possible to find an overlap in medication management that
addresses both mental health and health condition. Lets look at pain and PTSD.