Kwame Nkrumah University of

Science & Technology, Kumasi, Ghana

PHADT 554 INTEGRATED PATHOPHYSIOLOGY AND PHARMACOTHERAPY OF

NEUROPSYCHIATRY SYSTEM

PSYCHOPHARMACOLOGY OF
ANXIETY DISORDERS J. Parkinson

Wonder Abotsi, PhD

Room C116, Tackie Building
Department of Pharmacology, College of Health Sciences,
KNUST
Email: wkmabotsi.pharm@knust.edu.gh
 Further Reading
▪Zeind CS, Carvalho MG. (2017). Applied Therapeutics: The Clinical
Use of Drugs (2017). 11th Edition. LWW
▪Boland R., Verdiun, M. & Ruiz, P. (2021). Kaplan & Sadock’s
Synopsis Of Psychiatry. 12th Edition. Philadelphia: Wolters Kluwer
▪Dodds LJ. (2013). Drugs in Use. 5th Edition. Pharmaceutical Press
▪Anderson IM, Mcallister-Williams RH (2016). Fundamentals of
Clinical Psychopharmacology. CRC Press/Taylor & Francis
▪Brunton, L. L., Hilal-Dandan, R. and Knollmann, B.C. (2018).
Goodman & Gilman's: The Pharmacological Basis of Therapeutics.
13th Edn., New York: McGraw-Hill.
▪UpToDate, Waltham, MA

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 Anxiety disorders - pathophysiology
▪Anxiety/fear regulating system in the brain
oPrefrontal cortex (vmPFC), anterior cingulate, amygdala, locus ceruleus,
hypothalamus, hippocampus, thalamus, etc
oThe system maintains a delicate balance of activation and
inhibition.
– This balance maintains optimal responsiveness (to threats) while also inhibiting
anxiety and fear in non-threatening situations
– Inhibition via GABA & serotonin (5-HT1A, 5-HT2A); Inhibition/activation via NE, CRH,
SP, NPY, CCK, vasopression
◊ Perturbation of one or more of these modulators may induce or maintain anxiety
disorders

▪Pharmacological treatments for anxiety disorders typically

activate or augment the natural neuronal inhibitory
mechanisms (via GABA, serotonin, etc).

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PHARMACOTHERAPY
▪Antianxiety medication is indicated for patients
experiencing symptoms severe enough to produce
functional disability.
▪Accurate diagnosis of the type of anxiety disorder
enables identification of the pharmacological
treatments with the best evidence-base.
▪8–12 weeks of pharmacotherapy at optimum doses
may be needed to assess efficacy.
▪Good evidence for the benefit of maintenance
treatment at least up to 6 months.

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 Pharmacotherapy

▪Antidepressants
▪Benzodiazepines —acute anxiety
▪Buspirone
▪Anticonvulsants
▪Atypical antipsychotics
▪β-blockers – to control physical symptoms

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 Pharmacotherapy
GAD PD SAD OCD PTSD
Escitalopram SSRIs Escitalopram Fluoxetine Paroxetine
Paroxetine Venlafaxine Fluvoxamine Fluvoxamine Sertraline
Sertraline Alprazolam Paroxetine Paroxetine Venlafaxine
Venlafaxine Clonazepam Sertraline Sertraline Fluoxetine
Duloxetine Clomipramine Venlafaxine Clomipramine Amitriptyline
Benzodiazepines Imipramine Clonazepam Escitalopram Imipramine
Buspirone Phenelzine Citalopram Mirtazapine
Imipramine VPA Pregabalin Prazosin
Pregabalin Gabapentin Phenelzine
Hydroxyzine Phenelzine
Quetiapine

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 ANTIDEPRESSANTS
▪Antidepressants (esp. SSRIs/SNRIs) are the recommended
first-line treatment for most patients with anxiety disorder
oSuperior efficacy for cognitive symptoms
oLack potential for abuse and dependence
▪Likely work by activating stress-adapting pathways, via
modulation of receptor activation of signal transduction
pathways connected to the neurotransmitters 5-HT, DA and
NE.
▪Selection among SSRIs/SNRIs is based on the medication
side effect profile, drug-drug interactions or patient
characteristics/treatment history/preference.

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 Antidepressants
▪Mostly one-daily dosing
▪The effects of ADs occur gradually during several weeks (2-4
weeks or longer).
▪BDZ (or hydroxyzine/gabapentin/pregabalin) as an initial adjunct while
AD is titrated to an effective dose, then tapered over few weeks
while AD is continued.
oAlso helps deal with early AEs of SSRI tx (agitation & insomnia) which
can often lead to discontinuation of the medication
▪Small initial daily doses of AD for 1st wk to limit development of
transient increased anxiety (jitteriness syndrome) – start low, go slow
▪MAOIs are reserved for the most refractory or difficult patients

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 BENZODIAZEPINES
▪The most effective and commonly prescribed drugs for the
rapid relief of acute anxiety symptoms (use usually limited to
2-4 weeks)
oparticularly useful for as-needed (PRN) use in individuals with acute
episodes and exacerbations of anxiety, including performance anxiety
and panic attacks
▪All benzodiazepines are equally effective anxiolytics
oSelection is based on PK considerations & patient’s clinical situation
▪Are more effective in treating the somatic and autonomic
symptoms

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 BENZODIAZEPINES
▪Diazepam (prototype) – 4-40 mg/d
▪Alprazolam – 0.5-6 mg/d (up to 10 mg/d for PD)
▪Chlordiazepoxide – 15-100 mg/d
▪Clonazepam – 0.5-12 mg/d
▪Clorazepate - 7.5-60 mg/d
▪Lorazepam – 2-6 mg/d
▪Oxazepam – 30-120 mg/d

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Benzodiazepines - Mechanisms
▪Ameliorate anxiety
through potentiation
of the inhibitory
activity of GABA
▪Act on a subset of
GABAA receptors

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Benzodiazepines - Mechanisms

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 Benzodiazepines - Pharmacokinetics
▪Benzodiazepines are readily absorbed from the GI tract and cross
all membranes and placenta
▪High lipid solubility; tend to accumulate in body fat
oLipid solubility varies, resulting in differences in rates of absorption and speed
of onset, as well as duration of clinical effects
▪Most are administered orally but some are also administered by
other routes
oLorazepam is the preferred agent when IM dosing is needed for quick control
of anxiety & agitation. Absorption following I.M. diazepam administration is
slow and erratic and should be avoided.
▪Highly protein-bound but have few drug interactions.
▪Metabolized primarily in liver and excreted in the urine.
▪Long-acting compounds have active metabolites
oE.g. N-desmethyldiazepam (nordiazepam) - t½≈60 h

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 Benzodiazepines - Pharmacokinetics

N-desmethyldiazepam accounts for tendency of many BDZs to produce cumulative effects and

long hangovers when they are given repeatedly.
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 Benzodiazepines – Adverse
effects

Falls in
▪CNS depression - drowsiness, sedation,
elderly psychomotor impairment, ataxia
oLong-acting BDZs taken the previous night may cause residual
daytime effects and pose a hazard while driving the next day.
▪Anterograde amnesia
▪Paradoxical effects
oIncreased anxiety, agitation, talkativeness, irritability,
aggression & hostility

Avoid in 1st trimester (Preg. Category D); nursing mothers

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 Tolerance
▪Decreased responsiveness to a drug following
repeated exposure
▪May result in the need for an increase in the dose
required to maintain symptomatic improvement
▪Develops to the sedative, muscle relaxant, and
anticonvulsant activities of BDZs
▪Does not appear to affect the anxiolytic or antipanic
efficacies???

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 BDZ abuse and dependence
▪Abuse - Use outside the therapeutic setting and implies
recreational use combined with continued use despite negative
consequences, dose escalation, and loss of control over use
operceived desirable properties of relief of anxiety, euphoria,
disinhibition, and promotion of sleep
oIndividuals with a history of multiple drug abuse (eg,
alcohol or sedatives) are at the greatest risk
oDiazepam, alprazolam, and lorazepam are reported to be
more likely to be abused
–quicker onset of effect, which may be associated with a subjective
euphoric sensation
oRelative risk of addiction =3 (1=nonaddictive; 5=highly addictive)

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 BDZ abuse and dependence
▪Dependence - appearance of a predictable abstinence syndrome
(withdrawal symptoms) on abrupt discontinuation of therapy
oMay appear within
–1-2 days and may be more intense and short-lived (short t ½ BDZs)
–4-7 days and may last several weeks (long t½ BDZs)

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 Management of BDZ withdrawal
▪Gradual taper
oE.g. 25% per week reduction in dosage until 50% of the original dose
is reached, and then dosage reduction by 10-12%/week until
discontinued
oLong-term use of benzodiazepines (i.e, 1 year or longer) requires a 2-
to 4-month slow taper
▪Switching from a short- to long-acting BDZ before gradual
taper??
▪Adjunctive use of pregabalin, carbamazepine, propranolol,
psychotherapy (CBT)
▪Tapering will not eliminate the emergence of withdrawal
symptoms entirely but will prevent severe withdrawal
Foetal/Newborn withdrawal

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 To minimize abuse and
dependence
▪Identification of patients who have a history of
alcohol or substance abuse and using
nonbenzodiazepine treatments in such cases
▪Patients should be counseled about the anticipated
duration of benzodiazepine use & the possibility of
withdrawal symptoms
▪Patients should be counseled about the importance
of gradual drug tapering when therapy is
discontinued.

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Drug interactions
▪Additive CNS & resp. depressant effects
oWith alcohol, barbiturates or other drugs with CNS
depressant properties (eg, opioids, antipsychotics,
antihistamines, etc)
▪Elevated Cpl./prolonged t½s
oCytochrome P450 3A4 inhibitors
▪ Decreased Cpl./medication ineffectiveness
oLiver enzyme inducers e.g. carbamazepine

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 Benzodiazepines Overdose
▪Acute overdose is rarely fatal unless combined with
other depressants (e.g., ethanol).
▪Characterized by respiratory and CNS depression
▪Treated with Flumazenil (benzodiazepine
antagonist)
oReverses BDZ-induced sedation or coma within 1 to 2
minutes after IV administration
oRespiratory function should be adequately supported and
carefully monitored.
oFlumazenil may induce seizures and cardiac arrhythmias

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 Benzodiazepines – other
indications

▪Sedative/hypnotics
▪Anticonvulsants
▪Muscle relaxants (antispastic)
▪Pre-anaesthetic medications
▪Alcohol withdrawal

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 BUSPIRONE
▪It is a partial agonist at 5-HT1A receptors
▪An effective treatment for GAD
oMore effective than BDZs against psychic symptoms of
anxiety
▪It has a more gradual onset than BDZ.
oInitial effects are observed within the first 7-10 days, but
3-4 weeks may be needed for optimal results.
oNot useful for immediate anxiolysis or for situations
requiring “as-needed” anxiolytic therapy
▪Usual dosage range: 15-60 mg/day

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 BUSPIRONE
▪Adverse effects are less troublesome than with BDZs
oDizziness, nausea, headache
oLacks depressant effects, sedation, cognitive or psychomotor
impairment, respiratory depression, sexual dysfunction and muscle
relaxant or anticonvulsant effects.
▪It has minimal potential for abuse and does not produce
physical dependence or withdrawal syndromes on
discontinuation, even after long-term therapy
▪It does not suppress the BDZ withdrawal syndrome
▪May reduce depressive symptoms (also evidence for modest
efficacy in treating major depression)

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ANTICONVULSANTS
▪Gabapentin – SAD
▪Pregabalin – GAD, SAD

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 ATYPICAL ANTIPSYCHOTICS
▪Quetiapine (or aripiprazole) is a useful agent,
either as monotherapy or as an augmentation
agent for both acute and maintenance
treatment of GAD.
▪Adverse effects potentially limit the usefulness

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BETA-BLOCKERS
▪Decrease the perception of anxiety by blunting the
peripheral autonomic symptoms of arousal (e.g.
rapid heart rate, sweating, blushing, and tremor)
▪Are often used to decrease anxiety in
performance-related situations.
oPropranolol (10-80 mg) or atenolol (25-100 mg) can be
taken 1 hour before a performance as needed.

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