This lecture explores some core issues in neuropharmacology of depression and anxiety. With a focus on general overview of treatment.

1. Neuropharmacology of
Depression and Anxiety

4. HPA-AXIS ANS
Core Biology of Anxiety

5. (Central AMY) Fear: Short-
term and conditioned
through classical
conditioning principals.
(BNST AMY) Anxiety: Long-
term, diffuse and activated in
the background. Does not
follow conditioned stimulus.
Video Hand Model: https://www.youtube.com/watch?v=gm9CIJ74Oxw

8. Medication Tx for Anxiety
SSRIs: Change serotonin and are the first line of treatment for anxiety.
SNRI’s: Change serotonin and norepinephrine
Wellbutrin: Change predominantly dopamine (Bupropion).
Benzodiazepines – Mechanism GABAergic enhance the effect of the neurotransmitter
gamma-aminobutyric acid (GABA-A).
Beta-blockers: control some of the physical symptoms of anxiety, such as trembling
and sweating.
Buspirone: A good treatment for GAD. Buspirone functions as a serotonin 5-
HT1Areceptor partial agonist. It is this action that is thought to mediate its anxiolytic
and antidepressant effects.
Antipsychotics: Studies as main treatment show effective tx for GAD and social anxiety
questions about Risperdal as a main treatment. Often used as adjunct tx for anxiety.
Has poor adherence due to side effects.

9. Benzodiazepines (BZD) Continued
Short-acting compounds have a median half-life of 1–12 hours.
◦ They have few residual effects if taken before bedtime, rebound insomnia may occur
upon discontinuation, and rebound anxiety with prolonged usage.
◦ Examples are brotizolam, midazolam, and triazolam.
Intermediate-acting compounds have a median half-life of 12–40 hours.
◦ They may have some residual effects in the first half of the day if used as a hypnotic.
Rebound insomnia more common for intermediate the long-acting
◦ Examples are alprazolam, estazolam, flunitrazepam, clonazepam, lormetazepam,
lorazepam, nitrazepam, and temazepam.
Long-acting compounds have a half-life of 40–250 hours.
◦ For those with slow metabolism and elimination they have risk of accumulation. but
they have a reduced severity of rebound effects and withdrawal.
◦ Examples are diazepam, clorazepate, chlordiazepoxide, and flurazepam.

11. Co-morbid IBS and anxiety correlates
with increased severity of GI
symptoms and more disability.
CBT has several studies but limited
double blind studies but is considered
effective.
Tricyclic antidepressants (TCAs) more
effective than SSRI (central analgesic
actions of norep.)
SSRIs are effective for underlying
anxiety and depression, and possibly
for IBS sufferers without psychiatric
disorders.
The benzodiazepines have some
studies showing efficacy for reducing
anxiety and limited for effecting the
IBS sympt. but due to tolerance and
addiction not recommended.
Buspar: May be effective but no clear
data exists to date.

16. Gelenberg, A. J. (2010). A review of the
current guidelines for depression treatment. J
Clin Psychiatry, 71(7), e15.
A Review of Current
Guidelines for Depression
Treatment
‘All major guidelines for the
treatment of depression
agree upon the need for a
biopsychosocial assessment
of stressors… Universal
recommendations include
individualizing treatment
according to patients’
profiles and needs, using
standardized measurement
tools to track sympt.,
prescribing an appropriate
dosage of a medication for
an adequate duration, and
treating patients to
remission…’

17. Neurotransmitters in Depression
◦ Norepinephrine: Effects behavioral activation, arousal
and mental filter aspect of attention. Absence leads to
lethargy poor attentional control.
◦ Dopamine: Pleasure, desire and motivation. Low levels
of dopamine lead to anhedonia symptoms.
◦ Serotonin: Satiation, here and now happiness, and
absence is guilt and worry.
◦ BDNF: Brain-derived neurotrophic factor (BDNF) is a
key protein in brain plasticity and is particularly
important for survival of dopaminergic neurons.

18. Other Theories of Depression
Cortisol: People with depression have altered levels of cortisol.
Cortisol changes levels of dopamine driving it down. High cortisol
increases Serotonin reuptake.
Vagal Nerve Tone: Vagal tone relates to depression and increased
tone relates to improved depression due to treatment.
Inflammation: Elevated inflammatory cytokines are related to
increased symptom of depression. In a study of > 14,000
individuals elevated C-Reactive Protein (CRP) was in a significant
amount of depression.
Microbiome: There are microbiota that are related to increased
risk and increased protection in people who are depressed.

20. Tracking the Stress Response
Karatsoreos, I. N., & McEwen, B. S. (2011). Psychobiological allostasis: resistance, resilience and vulnerability. Trends in cognitive
sciences, 15(12), 576-584.

21. Ethnopharmachology
1. The J mutation of the CYP2D6 is found in 47% to 70% of
Asian Americans.
2. Z mutation is found in 15% to 20% of non-Hispanic
African Americans and is responsible for CYP 2D6 and
slows down metabolism of antibiotics, cardiovascular
drugs, pain medication and antidepressants.
3. When considering prescription and dosages of SSRI’s for
African Americans of non-Hispanic descent, Puerto Rican
and Dominican adolescents one needs to take these
metabolic factors into account.

23. Post Stroke Depression

24. Stahl, S. M. (2013). Stahl's essential psychopharmacology: neuroscientific basis and practical applications. Cambridge university press.

25. Medication Tx of Depression
MAO-I: First anti-depressants. Rarely used Due to lethal effects. Work to enhance
dopamine, norepinephrine and serotonin.
Tricyclics: Second generation anti-depressant medications. These medications
effect serotonin and norepinephrine. They have limited to no effect on dopamine.
SSRI: Are focused at the reuptake process and specifically serotonin. They treat
anxiety and are used as adjunct treatment in multiple health and mental health
disorders (1–4 weeks while the body adapts to the drug and 6 to 8 weeks to full
effect).
SNRI: Are focused on the reuptake of serotonin and norepinephrine. They can be
activating.
NDRI/Wellbutrin: Works on dopamine and norepinephrine. Is activating, is used
to treat smoking and or weight loss. A common of label use is the treatment of
ADHD.

26. Medication Tx of Depression
Cortisol: Several drug targets have the effects of blocking cortisol. These
medications have limited effects on treatment of depression but in at least one trail
treated psychosis associated with depression and hallucinations.
Psychostimulant Treatments on changing dopamine and increase behavioral
activation but also at times can lead to disinhibition and loss of appetite. Effective
short-term significant reduction in symptoms but clinical significance is less clear.
◦ NRI (Norepinephrine Reuptake Inhibitors) – Strattera ADHD limited to no effects for
depression in double blind studies.
◦ NDRI (Norepinephrine Dopamine Reuptake Inhibitors) - Wellbutrin, Zyban
Ketamine: New drug target. Rapid symptom change (1 hour). Adaptation from
street drug “special K” caused hallucinations.
Inflammation Drug Targets
◦ TNF-Alpha (Infliximab): Some indications of efficacy in treatment resistant depression.
◦ Celecoxib – Effective in a 2006 placebo controlled piolet study.

27. SSRI Side Effects - 2005 Harvard
Mental Health Letter
Physical symptoms: Some patients taking SSRIs develop insomnia, rashes,
headaches, joint and muscle pain, stomach upset, nausea, or diarrhea. These
problems are usually temporary, mild, or both.
Bleeding problems: A more serious potential problem is reduced blood clotting
capacity that increases risk for stomach or uterine bleeding, if patients use
SSRIs and NSAIDs (aspirin, ibuprofen, naproxen, COX-2 inhibitors).
Sexual effects: For many patients, SSRIs diminish sexual interest, desire,
performance, satisfaction, or all four. (Viagra) can help.
Suicide: The risk that antidepressants will incite violent or self-destructive
behavior. When compared with a placebo, all antidepressants, including SSRIs,
seem to double the risk of suicidal thinking, from 1%–2% to 2%–4%, in both
children and adults.

28. SNRI Side Effects
1. Similar to SSRI.
2. Tend to be more stimulating due to norepinephrine component.
3. At times associated with anxiety, elevated pulse and blood pressure.
4. Sexual dysfunction: Lack of interest in sex and difficulty reaching climax
(anorgasmia).
5. Nausea is reduced in extended release formulation.

29. Biological Tx of Depression
Deep Brain Stimulation: An electrode is implanted in the subcallosal
cingulate and continuously stimulated. Effective in refractory
depression and as a treatment for Parkinson's disease. Video
ECT: Is used often to treat refractory depression. Unipolar is less
damaging. It can cause memory loss that mostly remits after four
weeks. Very few placebo control studies. A trial of CBT or other
psychotherapy is not included in criteria for “treatment resistant
depression.”
TMS (Transcranial Magnetic Stimulation): Sends a burst of magnetic
energy across the skull and stimulates an area of the brain. Has
shown effects in refractory depression in a placebo control study.
(Left dorsolateral prefrontal cortex)
Vagal Nerve Stimulation: Stimulates the valgus nerve
(parasympathetic – relaxation response) and has been found to have
some effects in moderate refractory depression.

32. Rush, A. J., Hirschfeld, R. M., Kahn, D. A.,
Charles DeBattista, D. M. H., Nelson, J.
C., & Nierenberg, A. A. (1999). The Texas
Medication Algorithm Project: report of the
Texas consensus conference panel on
medication treatment of major depressive
disorder. J Clin Psychiatry, 60(3), 142-156.
TMAP - Major
Depressive Disorder
“The Texas Medication
Algorithm Project
(TMAP) is the first
attempt to develop and
prospectively evaluate
consensus-based
medication algorithms
for the treatment of
individuals with severe
and persistent mental
illnesses.”

33. Recognizing and managing antidepressant discontinuation symptoms. Peter M. Haddad, Ian M. Anderson.
Advances in Psychiatric Treatment Oct 2007, 13 (6) 447-457; DOI: 10.1192/apt.bp.105.001966

34. Psychological Tx of Depression
Interpersonal Therapy (ITP): An evidence based treatment.
Holds that there are three areas of life disrupted in depression.
Personality, Social Functioning and Symptoms. Treatment
focuses on social functioning and pragmatic solutions to
symptoms.
Cognitive Behavioral Therapy (CBT): Addresses thoughts and
cognitions as well as behaviors that maintain symptoms. It
focuses on changing schema’s about the self, world and future.
Behavioral Therapy: Based on learned helplessness. Behavioral
theory holds that there is a lack of behaviors. This lack of
behaviors leads to lower levels of reinforces. Lower reinforces
leads to increased depression. Increase behavioral activation
leads to reduction of symptoms of depression.

35. Psychobiological Treatments
Massage and body work: Multiple studies exploring this
modality have found good symptom reduction.
Yoga Nidra: Preliminary data has found solid efficacy for
treatment of depression. Further Reading, “Yoga For
Depression.”
MBSR: Some indications of efficacy for depression
treatment (e.g. depression post-cancer dx). Mix results in
some studies. Particular reduction in rumination.