Download Pharm 22, 23- Drugs for Affective Disorders Depression

Pharm 22, 23- Drugs for Affective Disorders
Depression
Pathophysiology
Monoamine hypothesis
Neurotrophic hypothesis
Neuroendocrine factors
 HPA axis abnormalities – dysregulation of the stress hormone axis
  cortisol
 Non-suppression of ACTH release in the dexamethasone suppression test
 Chronic  of corticotropin-releasing hormone
 Thyroid dysregulation
 Blunting of response of thyrotropin to TRH
  in circulating thyroxine
 Sex steroids
 Estrogen/testosterone deficiency
Pharm 22, 23- Drugs for Affective Disorders
Anxiety
 “Anxiety is a common emotion and an integral response to the vicissitudes of life.”
 “…adaptive when mild but may be incapacitating and terrifying when extreme.”
Neurochemical Models
Noradrenergic
 Autonomic nervous system is hypersensitive
 Locus ceruleus (LC) activates norepinephrine (NE) release
 stimulates the sympathetic and parasympathetic nervous system
 NE increases glutamate release
 Drugs with anxiolytic or antipanic effects inhibit LC firing and decrease noradrenergic activity
GABA receptor
 The GABAA chloride ion channel is a protein complex pentameric form that has varying combinations of α, β, and
γ subunits
 GABA is the major inhibitory neurotransmitter in the CNS
 Inhibitory effects on norepinephrine, dopamine, and 5-HT (serotonin)
 When GABA binds to GABAA , neuronal excitability is reduced
Serotonin
 5-HT is primarily an inhibitory neurotransmitter
 Abnormalities in serotonergic function may play a role in anxiety disorders
 Presynaptic receptors (5-HT1A/1D)
 Serotonin reuptake transporter (SERT)
 Postsynaptic receptors (5-HT1A, 5-HT2A, 5-HT2C)
 5-HT may reduce NE activity in the locus ceruleus
Pharm 22, 23- Drugs for Affective Disorders
Basic Pharmacology
SSRIs (Selective serotonin reuptake inhibitors)
 MOA: inhibition of the serotonin transporter (SERT)
 inhibit reuptake, enhancing serotonin activity within the synapse
 AEs:
 GI: nausea, diarrhea, cramping (early, transient)
 Sexual dysfunction: loss of libido, delayed orgasm
 Sleep disturbance
 Hyponatremia (SIADH)
Pregnancy Category
 Fluoxetine (Prozac)
C
 Sertraline (Zoloft)
C
 Paroxetine (Paxil)
D (cardiac septal defects)
 Fluvoxamine (Luvox)
C
 Citalopram (Celexa)
C
 Escitalopram (Lexapro)
C
Pharm 22, 23- Drugs for Affective Disorders
SNRIs (Serotonin/Norepinephrine Reuptake Inhibitors)
 MOA: Bind to the SERT and NET transporters
 enhance serotonin and norepinephrine activity in the synapse
 AEs: similar to SSRIs plus:
 CV: Dose-dependent increases in BP (venlafaxine)
 CNS: anxiety, insomnia, agitation
Pregnancy Category
 Venlafaxine (Effexor)
C
 Duloxetine (Cymbalta)
C
 Desvenlafaxine (Pristiq)
C
 Milnacipran (Savella)
C
Tricyclic Antidepressants
 MOA: Bind to the SERT and NET transporters
 enhance serotonin and norepinephrine activity in the synapse
 considerable variability in affinity for SERT v. NET
 antimuscarinic
**Remember AEs and some therapeutic uses for these
 antihistaminic (H1)
 block α-1 adrenergic receptors
 AEs
 Dry mouth, constipation: agitation, delirium, tachycardia, & urinary retention in aged persons
 Sedation, weight gain
 Orthostatic hypotension: counsel patient to rise slowly from recumbency or sitting, esp. in elderly
 Sexual dysfunction
 Toxicity
 Cardiac toxicity: quinidine-like effects; slowing of intracardiac conduction, prolongation of QRS and QT
intervals
 Acute overdoses of > 1g in adults and > 8mg/kg in children can be fatal
death results from arrhythmias, hypotension, or uncontrollable seizures
 Pregnancy Category C/D
Aminoketone: Buproprion (Wellbutrin)
 Resembles amphetamine in chemical structure
 has CNS activating properties
 MOA:  presynaptic release of norepinephrine and, to a lesser extent, dopamine
 No effects on the serotonin system
 May mimic nicotine’s effect on dopamine and norepinephrine and antagonize nicotine receptors
 AEs: agitation, insomnia, anorexia, dry mouth,  seizure threshold
 No sexual dysfunction
 Pregnancy Category C
Triazolopyridines: 5-HT2 Antagonists
 MOA: antagonists at the 5HT2A receptor and, to a lesser extent, SERT
 nefazodone also weakly inhibits NET
 antagonize 1-adrenergic receptors
 trazodone also inhibits H1 receptors
 AEs: sedation, esp. with trazodone, orthostatic hypotension, GI upset
 sexual side effects uncommon
 priapism – trazodone
 hepatotoxicity – nefazodone (1/250,000 – 300,000 patient years)
 Pregnancy Category C
Pharm 22, 23- Drugs for Affective Disorders
Trazodone: Priapism
 Injection of norepinephrine, epinephrine or dopamine may be successful in treating priapism
 In approximately one-third of the cases reported, surgical intervention was required
 in a portion of these cases, permanent impairment of erectile function or impotence resulted
 WARN all men of slow detumescence – D/C drug immediately
Tetracyclic: Mirtazapine
 MOA: Antagonizes the presynaptic α-2 receptor; enhances the release of NE and 5-HT
 antagonist at 5-HT2 and 5-HT3 receptors
 H1 antagonist
 AEs
 sedation - reported to be inversely proportional with dose; orthostatic hypotension - significant
 weight gain
 No sexual dysfunction
SSRI/5-HT1A Agonist (Viibryd)
 MOA: inhibition of SERT and 5-HT1A receptor partial agonist
 P’kinetics: food increases bioavailability; extensively metabolized by CYP450 3A4 and 3A5, 2C19 and 2D6
 AEs: same as SSRIs
 diarrhea, nausea, headache
 insomnia, decreased libido
 DIs: see above
MAOIs (Monoamine Oxidase Inhibitors)
 MOA: Bind irreversibly and nonselectively with MAO-A and –B
 Decrease the actions of monoamine oxidase in the neuron, thereby blocking degradation of NE, DA and
5-HT
 MAO-A metabolizes NE, 5-HT and DA
 MAO-B metabolizes dopamine selectively
 AEs: orthostatic hypotension, dizziness, headache, constipation, dry mouth
 Pharmacodynamic
o Serotonergic agent plus MAOI = serotonin syndrome
o Discontinue at least 2 weeks before starting an MAOI
OR
o Discontinue MAOI at least 2 weeks before starting a serotonergic agent
o Refer back to slide #20
 Drug - Food
 MAOI prevent breakdown of dietary tyramine in the gut  high serum levels
 Enhance peripheral adrenergic effects 
 Dramatic rise in blood pressure (stroke, MI)
 Drug-drug (CI)
 pseudoephedrine
 phenylpropanolamine
 Isocarboxazid (NS)*
 Phenelzine (NS)*
 Selegiline (MAO-B @ low doses)
 Tranylcypromine (NS)*
*NS - nonselective
Pharm 22, 23- Drugs for Affective Disorders
St. John’s Wort
 Hypericum perforatum - natural product, available over-the-counter, widely used for the management of
depression and anxiety
 Flower contains the active constituents
 MOA: SSRI-like
 P’kinetics: CYP3A4 inducer  DIs!
 AEs: SSRI-like; photosensitization causing rash
Antidepressant Discontinuation Syndrome
 Symptoms typically appear within 3 days
 Usually mild and resolves spontaneously within one to two weeks
Look for any behavioral changes upon initiation of therapy and dose changes. Document that the patient and
caregiver verbalized understanding of these instructions. Look for anxiety, agitation, panic attacks, insomnia,
irritability, hostility, impulsivity, akathisia (severe restlessness), hypomania, and mania. Also, warn the caregiver
not to stop the medication abruptly.
Algorithm for uncomplicated/Major Depression
Treatment-Resistant Depression
 Augmentation
 Thyroid hormone
 Lithium
Pharm 22, 23- Drugs for Affective Disorders
Anxiolytics
Anxiety Disorders
 Generalized Anxiety Disorder (GAD)
 Panic disorder
 Post Traumatic Stress Disorder (PTSD)
 Obsessive Compulsive Disorder (OCD)
 Social phobia
Treatment Principles
 Psychotherapy (CBT) is least invasive and most effective
 Lifestyle management:
 Stress management
 Exercise
 Healthy diet
 Work
 Interpersonal affairs
 Antidepressants 1st line of treatment (SSRI probably drug of choice)
Buspirone
 MOA: Partial serotonin agonist at the 5-HT1A receptors
 May cause up-regulation of postsynaptic serotonin receptors
 Does not exert any activity at the GABA receptors
 Indicated for the treatment of anxiety disorder but not acute anxiety states such as panic
 P’kinetics: rapidly absorbed; hepatic metabolism via CYP450 3A4; t ½ = 2 - 4 h
 AEs: nausea is most common
 DIs:
 CYP 3A4 inhibitors, e.g., erythromycin, ketoconazole, grapefruit juice, etc.
 Potential for serotonin syndrome in combination with other serotonergic drugs
 MAOIs
 Free of sedation
 No abuse potential
 Onset of effect:
 1 - 2 weeks for initial effects
 4 - 6 weeks for maximum effectiveness
 Pregnancy Category B
 Withdrawal: No cross-tolerance with benzodiazepines and other sedative/hypnotic drugs, including EtOH
Therefore, it will not block the withdrawal syndrome often seen with cessation of therapy with these drugs
Benzodiazepines
 Benzene ring (benzo) joined to a 7-member ring with two nitrogen molecules (diazepine)
 MOA: facilitate the activity of γ-aminobutyric acid (GABA), inhibitory neurotransmitter in the CNS; bind to α1
(BZ1) and α2 (BZ2) subunits of the GABA ionophore
 GABA regulates the excitability of neurons in almost every neuronal tract
 Dose-dependent depression of the CNS
 Given orally, low incidence of respiratory depression, coma or death unless administered w/another
CNS depressant
 Benzodiazepines bind to an allosteric site formed by the cleft between α and γ subunits
 This facilitates GABA binding & increases the frequency of chloride channel opening
 P’kinetics: well absorbed; distributed into the brain according to lipid solubility; extensively metabolized in the
liver; urinary elimination
Pharm 22, 23- Drugs for Affective Disorders
•
•
All benzodiazepines, including those with no
active metabolites, are eventually converted to
glucuronide compounds that are p’cologically
inactive & are excreted in the urine.
The benzodiazepines that have no active
metabolites include oxazepam, temazepam, and
lorazepam ("out the liver"); these may be the
safest benzodiazepines to use in treating elderly
patients.
Benzodiazepines: Indications
 Anxiety disorders
 Short-term relief of symptoms or stabilization of symptoms
 Hypnosis, anesthesia
 Anterograde amnesia – interfere w/formation of new memory
 Anticonvulsant - status epilepticus
 Decrease muscle spasm
 EtOH withdrawal
Adverse effects
 Motor incoordination
 Dizziness
 Drowsiness
 Impairment of concentration, judgment & planning
 Driving/psychomotor skills
 Disinhibition
 Physical dependence
 FDA CIV
Withdrawal syndrome
 Rebound anxiety
 Rebound sleep disorder
 Headache
 Insomnia
 Irritability
 Muscle twitches
 Seizures
 ALWAYS taper gradually!!!
Drug interactions
 Alcohol/other CNS depressants potentiate effects
 CYP450 inducers may decrease serum levels, e.g., rifampin
 CYP450 inhibitors may increase serum levels, e.g., ketoconazole
 Pregnancy category D
 Freely cross the placenta and accumulate in the fetal circulation
Pharm 22, 23- Drugs for Affective Disorders
Benzodiazepines
Treatment of Anxiety
Busipirone vs Benzodiazepines
 Slow onset
v. rapid onset
 No abuse potential v. abuse potential (CIV)
 Free of sedation v. significant CNS effects
Miscellaneous Anxiolytics
Hydroxyzine (Atarax, Vistaril) - probably works via its sedative effects, questionable anxiolysis
Second line agent due to inferior efficacy and sedative effects
Pregnancy Category C. Do not use during the first trimester due to lack of safety data
-Blockers - possibly helpful for social phobia or situational anxiety and PTSD
10-40mg propranolol prior to performance, public speaking engagement, etc.
Kava-kava (Piper methysticum) – hepatotoxicity limits its use
Mechanism of action is not clear
Ethanol consumption markedly increases the toxicity of kava
Treatment of Anxiety Disorders
*This can be tricky since benzodiazepines have an immediate effect and, for some people, pleasurable side effects.
Thus, the SSRI is often not taken and the benzodiazepine is difficult to discontinue.
Pharm 22, 23- Drugs for Affective Disorders
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Clinical Use of Antidepressants and Anxiolytics
Time to maximal effect: 6 – 8 weeks
Length of treatment: 4 – 9 months after remission
Combination therapy: common
Monitor for response, adherence and adverse effects
Elderly Patients
 Persons > 65 years have a high rate of suicidality
 Prior to antidepressant therapy, complete physical
 SSRIs generally first choice
 Start with ½ the recommended starting dose but titrate up to avoid under treatment
Pediatric Patients
 Consensus guidelines recommend fluoxetine (Prozac), citalopram (Celexa), and sertraline (Zoloft) as first-line
treatments for moderate to severe depression in children and adolescents
 ? risk suicidal ideation with antidepressants versus untreated adolescents successfully complete suicide
Pregnant and Lactating Women
 Risk of discontinuing antidepressant versus risk of drug therapy
 Untreated depression during pregnancy
 Poor maternal weight gain
 Low birth weight
 Suicidality
 Neglect of obstetric care
 Difficulty caring for other children
 Lack of data in breastfeeding