Venlafaxine Mirtazapine Buspirone asthenia

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                                                             • Topics to be covered for each
      Venlafaxine, Mirtazapine                                 medication:
            & Buspirone                                        – Indications & clinical use
                                                               – Pharmacodynamics & pharmacokinetics
                                                               – Efficacy
         Daniel Gorman, MD, FRCPC                              – Adverse effects
                                                               – Contraindications & drug interactions
                                                               – Monitoring
                                                               – Dosing                                2

                                                                Indications and Clinical Use
                                                             • In adults, venlafaxine is approved for the
                                                               treatment of MDD, GAD, and SP (Health
                                                               Canada and FDA)
                                                             • In children and adolescents, venlafaxine has
                                                               no approved indications (Health Canada and
                                                             • Clinically, venlafaxine has been used in pediatric
                                                               populations as an antidepressant, an anxiolytic,
                                                               and a treatment for ADHD

                                                         3                                                                 4

          Pharmacodynamics                                               Pharmacokinetics
• Inhibits reuptake of:                                      • Immediate release (IR) formulation of
   – Serotonin                                                 venlafaxine is not available in Canada
   – Norepinephrine                                          • Effexor XR (extended release):
   – (Dopamine, to a lesser degree)                            – Tmax=6 hrs for venlafaxine and 9 hrs for active
• Serotonergic reuptake is thought to be more                    metabolite O-desmethylvenlafaxine (ODV) in adults
  prominent at lower doses (<150 mg/day [?])                   – Rate of absorption is slower than rate of elimination;
                                                                 therefore, the effective adult elimination T1/2 of 15
• Noradrenergic reuptake is thought to be more                   hours is actually the absorption T1/2 rather than the
  prominent at higher doses (≥150 mg/day [?])                    true disposition T1/2 (5 hrs for venlafaxine and 11 hrs
• No significant affinity for cholinergic, histaminic,           for ODV) observed after administration of the IR
  or α1-adrenergic receptors                                     formulation
                                                         5                                                                 6

     Pharmacokinetics (cont.)                                   Efficacy: Depression
                                                       • Mandoki et al., 1997:
• Venlafaxine is metabolized by 2D6 and                  – 33 subjects, 8-17 years old, with MDD
  3A4 to ODV (active metabolite)                         – 6-week DBPC trial of venlafaxine+CBT vs.
• Weak inhibitor of 2D6                                    placebo+CBT
                                                         – Venlafaxine dose range: 12.5-75 mg/day
• Protein-binding of venlafaxine and ODV is              – Results:
  about 30%                                                 • Both groups improved, but no significant difference
• Taking with food has negligible effects on                  between groups
                                                            • Venlafaxine was generally well tolerated
  absorption or metabolism
                                                         – Limitations:
                                                            • Short duration of treatment
                                                            • Venlafaxine dose range may be too low
                                                  7                                                             8

   Efficacy: Depression (cont.)                        Emslie et al., 2007: Efficacy Results
• Emslie et al., 2007:                                 • No significant differences between
  – 2 DBPC trials of venlafaxine XR for up to 8          venlafaxine XR and placebo on the
    weeks in youth (7-17 years) with MDD
                                                         CDRS-R in either study
  – Total N=339
  – Mean daily dose=97.1 mg                            • Post-hoc age subgroup analysis of
     • Adolescents (12-17 years): 109.2 mg               the pooled data:
     • Children (7-11 years): 80.4 mg                    – Adolescents: VEN > PBO (-24 vs. -20;
  – Primary outcome: change in the Children’s              p=0.02)
    Depression Rating Scale-Revised (CDRS-R)
                                                         – Children: VEN = PBO
                                                  9                                                            10

         Emslie et al., 2007:
                                                        Efficacy: Resistant Depression
        Adverse Event Results
• Common:                                              • Recall the TORDIA Study:
  – anorexia, abdominal pain, dizziness                  – “Treatment of SSRI-Resistant Depression in
• Notable:                                                 Adolescents” (Brent et al., 2008)
  – Suicide-related: VEN=11 vs. PBO=1
  – Hostility: VEN=7 vs. PBO=2                         • Federally funded, multi-site RCT in a
  – Hallucinations: VEN=2 vs. PBO=0                      clinical sample of 334 youth (12-18 years)
                                                         with MDD who had not responded to 2-
• “Serious”:
                                                         month initial treatment with an SSRI
  – VEN=12 (7%) vs. PBO=3 (2%)
  – No completed suicides                         11                                                           12

     TORDIA: Randomization                                     TORDIA: Main Outcome Measures
• Randomized to 12 weeks of:                                  • “Adequate clinical response,” defined as a
  1. Switch to a second, different SSRI (PAR,                   CGI-Improvement score of “much” or “very
     CIT, or FLX)                                               much” improved and ≥50% ↓ in the
  2. Second SSRI + CBT                                          Children’s Depression Rating Scale-
  3. Switch to venlafaxine (VEN)
                                                                Revised (CDRS-R)
  4. VEN + CBT

• Medication assignment was double-                           • Change in CDRS-R over time
  blinded, and CBT was blinded to
  independent evaluators
                                                         13                                                               14

    TORDIA: Efficacy Results                                     TORDIA: Adverse Event Results
• Response rates:                                             • No differences among treatments regarding:
  – CBT + switch to either medication                           – Frequency of adverse events overall, serious adverse
                                                                  events, or removal from the study because of adverse
    regimen (55%) > medication switch                             events
    alone (41%)                                                 – Self-harm or suicide-related adverse events
  – VEN (48%) = 2nd SSRI (47%)                                • Psychiatric adverse advents:
                                                                – Sleep difficulties (5%) and irritability (5%) were the only
• No differential treatment effects on                            psychiatric adverse events that occurred in ≥5% (no
                                                                  group differences)
  change in the CDRS-R, CGAS, CGI-                              – Only 1 instance of hypomania during the first 12 wks
  Severity Subscale, or self-rated                              – 18 suicide attempts in 17 participants, but no completed
  depressive symptoms                                             suicides
                                                         15                                                               16

  TORDIA: Adverse Events (cont.)                                       TORDIA: Conclusions
• Nonpsychiatric adverse advents:                             • “For adolescents with depression not responding
  – Of nonpsychiatric adverse events that occurred in           to an adequate initial treatment with an SSRI,
    ≥5% of participants, only skin problems were                the combination of CBT and a switch to another
    significantly more common with VEN vs. a 2nd SSRI           antidepressant resulted in a higher rate of
    (8% vs. 2%)
                                                                clinical response than did a medication switch
  – Compared with a 2nd SSRI, VEN resulted in                   alone.”
    significantly greater ↑ in DBP (+3.3 vs. -1.6 mm Hg)
    and HR (+6.0 vs. -1.1 bpm)
  – CV changes associated with VEN were rarely                • “However, a switch to another SSRI was just as
    clinically significant                                      efficacious as a switch to venlafaxine and
  – Participants removed from the study for CV reasons:         resulted in fewer adverse effects.”
    4 for VEN vs. 1 for a 2nd SSRI (p=0.2)               17                                                               18

                                                    Rynn et al., 2007: Efficacy Results
               Efficacy: GAD
                                                    • Study 1:
                                                      – VEN > PBO on the primary outcome measure
• Rynn et al., 2007:                                  – VEN > PBO on all 8 secondary outcome measures
   – 2 DBPC trials of venlafaxine XR for 8            – VEN > PBO on response rate using primary outcome
     weeks in youth (6-17 years) with GAD               measure (38% vs. 17%)
                                                    • Study 2:
   – Total N=313                                      – Trend towards VEN > PBO (p=0.06) on the primary
   – Daily dose range: 37.5 to 225 mg                   outcome measure
                                                      – VEN > PBO on only 3 of 8 secondary outcome
   – Primary outcome: change in score on 9              measures
     items of the GAD section of the K-SADS           – VEN = PBO on response rate using primary outcome
                                                    • Pooled analysis:
                                                      – VEN > PBO on the primary outcome measure             20

          Rynn et al., 2007:
                                                           Efficacy: Social Phobia
        Adverse Event Results:
• Common:                                           • March et al., 2007:
   – Asthenia, pain, anorexia, somnolence             – DBPC trial of venlafaxine XR for 16 weeks in
• Notable:                                              youth (8-17 years) with social anxiety disorder
   – VEN > PBO for changes in height, weight, BP,     – N=293 across 48 (!) sites
     HR, and cholesterol levels                       – VEN or PBO was titrated from 37.5 mg/day to
   – Suicide-related: VEN=1, PBO=1                      a maximum of 225 mg/day
                                                      – Primary outcome measures:
• “Serious”:
                                                         • Social Anxiety Scale (child or adolescent version)
   – VEN=2 (1%), PBO=2 (1%)                              • Clinical response defined as “much” or “very much”
   – No completed suicides                                 improved on the CGI-I
                                               21                                                            22

                                                              March et al., 2007:
March et al., 2007: Efficacy Results
                                                             Adverse Event Results
• Social Anxiety Scale:                             • Adverse events: VEN=90%, PBO=81%
                                                      – Most common AEs associated with VEN: asthenia,
  – VEN > PBO (p=0.001)                                 anorexia, nausea, weight loss, abnormal behaviour,
                                                        pharyngitis, mydriasis
    • VEN: 59.5 @ week 1 → 40.6 @ week 16
                                                    • AEs during tapering: VEN=41%, PBO=23%
    • PBO: 61.3 @ week 1 → 47.7 @ week 16             – Most common taper-emergent AEs in the VEN group:
  – Effect size=0.46                                    nausea, headache, dizziness, and nervousness
                                                    • No suicides, suicide attempts, or hostility
• Clinical response:                                • Suicidal ideation: VEN=3, PBO=0 (NNH=47)
  – VEN (56%) > PBO (37%) (p=0.001)                 • VEN was associated with ↑ in HR (4 bpm) and
  – NNT=5                                             DBP, and 2 patients (1%) on VEN experienced
                                               23     sustained hypertension                                 24

            Adverse Effects                                           Adverse Effects (cont.)
• Nausea, abdominal        •   Irritability, hostility        • ↑ HR and BP (especially DBP)
  pain                     •   Asthenia                       • Suicidality:
• Anorexia, weight loss                                          – RR compared to placebo=4.97 (95% CI=1.09-22.72)
                           •   Dizziness                           (Hammad et al., 2006)
• ↑ appetite               •   Dry mouth                      • (?) Suppression of growth in height:
• Behavioural activation   •   Nasal congestion                  – Rynn et al., 2007: after 8 weeks, VEN ↑ 0.3 cm vs.
• Insomnia                 •   Skin problems                       PBO ↑ 1.0 cm (p<0.001)
• Sedation                                                    • (?) ↑ cholesterol:
                                                                 – Rynn et al., 2007
                                                              • (?) Priapism:
                                                         25      – Case report in a 16-year-old (Samuel, 2000)          26

           Contraindications                                               Drug Interactions
                                                              • MAOIs (serotonin syndrome)
• Hypersensitivity to venlafaxine
                                                              • Inhibitors/inducers of 2D6 and 3A4
                                                              • Venlafaxine will modestly increase levels of 2D6
• Concurrent MAOI (wait ≥2 weeks between                        substrates
  stopping one and starting the other)                        • Combination of venlafaxine 150 mg/day (steady-
                                                                state) and haloperidol 2 mg (single dose)
                                                                resulted in a 70% increase in haloperidol AUC
• Caution if history of hypertension
                                                                and an 88% increase in venlafaxine Cmax (T1/2
                                                                 – The mechanism that accounts for this finding is
                                                                   unknown                                              28

                 Monitoring                                             Dosing: General Info
• Blood pressure (especially diastolic)                       • No official guidelines for dosing
• Suicidality                                                   venlafaxine in children and adolescents
• Because of venlafaxine’s association with
  ↑ DBP and its prominent noradrenergic                       • Pharmacokinetic data obtained by Derivan
  activity at higher doses, some authorities                    et al. (1997 [abstract]) suggest that to
  recommend that EKG monitoring be                              achieve similar blood levels as in adults,
  considered for some patients                                  children and adolescents need weight-
                                                                adjusted venlafaxine doses approximately
                                                                1.5 times higher
                                                         29                                                             30

   Dosing: General Info (cont.)                                   Dosing Specifics (Suggested)
• Effexor XR is generally dosed once daily                    • Start with 37.5 mg po qam
  in the morning                                              • Gradually titrate up by 37.5-75 mg/day, waiting
                                                                at least a week between dose increases
                                                              • As with all antidepressants, clinical response
• Effexor XR capsules must be swallowed                         generally takes 4-6 weeks at a given dose
  whole (do not cut or chew)                                  • In adults, maximum recommended daily dose is
                                                                225 mg (HC and FDA)
                                                              • Note that the IR formulation of venlafaxine has
• Taking the medication with food may                           been studied in adults at doses up to 375
  reduce nausea, but has negligible                             mg/day
  pharmacokinetic effects                                31                                                   32

Dosing Schedule Used in Study by
        Rynn et al., 2007


                             (enlarged slide appended)   33                                                   34

   Indications and Clinical Use                                        Pharmacodynamics
• In adults, mirtazapine is approved for the                  •   “NaSSA”: Noradrenergic and Specific
  treatment of depression (Health Canada and                      Serotonergic Antidepressant
• In children and adolescents, mirtazapine has
  no approved indications (Health Canada and                  •   Like venlafaxine, mirtazapine is more
  FDA)                                                            serotonergic at lower doses and more
• Clinically, mirtazapine has been used in                        noradrenergic at higher doses
  pediatric populations as an antidepressant, an
  anxiolytic, a hypnotic, and an appetite stimulant

                                                         35                                                   36

      Pharmacodynamics (cont.)                                                                   Pharmacodynamics (cont.)
a) Antagonism of presynaptic α2-autoreceptors                                             b) Antagonism of presynaptic α2-
   on noradrenergic neurons                                                                  heteroreceptors on serotonergic
  –    This inhibits negative feedback, which in turn leads                                  neurons
       to increased release of NE
  –    ↑ release of NE results in ↑ firing of postsynaptic                                      – This inhibits negative feedback, which in
       noradrenergic neurons                                                                      turn leads to increased release of 5-HT
  –    ↑ release of NE also results in ↑ firing of
       postsynaptic serotonergic neurons, because of
       NE’s activity on α1-adrenoreceptors on the cell
       body of these neurons

                                                                                     37                                                       38

      Pharmacodynamics (cont.)                                                                   Pharmacodynamics (cont.)
c) Potent antagonism of postsynaptic 5-HT2 and
   5-HT3 receptors, but little effect on
                                                                                           d) Low affinity for D1 and D2 receptors
   postsynaptic 5-HT1 receptors
  –    This biases the activation of serotonin receptors in
       favour of 5-HT1 receptors and against 5-HT2 and 5-                                  e) Potent histaminergic (H1) antagonist
       HT3 receptors                                                                             –    Results in sedation and weight gain
  –    Activation of postsynaptic 5-HT1 receptors is
       thought to reduce anxiety and depressive symptoms
                                                                                           f)     Moderate α1-antagonist
  –    Antagonism of postsynaptic 5-HT2 and 5-HT3
                                                                                                 –    Moderate BP-lowering effect
       receptors is thought to reduce anxiety and
       depressive symptoms and also to reduce nausea
      •       Note: Activation of postsynaptic 5-HT2 and 5-HT3 receptors                   g) Moderate muscarinic (M1) antagonist
              (e.g., by SSRIs) may cause anxiety, insomnia, nausea, and
              sexual dysfunction
                                                                                                 –    Moderate anticholinergic side effects
                                                                         39                                                                   40

   A Picture’s Worth 1000 Slides
   (enlarged slide appended)                                                                                  Clinical Pearl
                                                                                                Given mirtazapine’s pharmaco-
                                          (a)                                                   dynamic profile and common side
                                                                                                effects, think of using it for:
                                                                                                a) Children with ADHD on stimulants who
                                                                                                     • Appetite suppression
                                                                                                     • Initial insomnia
                                                                                                     • Comorbid anxiety/depression
          Postsynaptic NA target neuron           Postsynaptic 5-HT target neurons
                                                                                     41                                                       42
            noradrenaline                 •serotonin               •••mirtazapine

          Clinical Pearl (cont.)                             Pharmacokinetics
                                                  • Well absorbed (taking with food reduces
    b) Medically ill children who may be            the rate but not the extent of absorption)
                                                  • Tmax=2 hrs (adults)
      •   Nausea
      •   Decreased appetite                      • T1/2=20-40 hrs (adults) with substantial
      •   Insomnia, agitation
                                                    individual variation, but generally longer
                                                    for women (mean=37 hrs) than men
      •   Anxiety/depression
                                                    (mean=26 hrs)
                                                  • Extensively metabolized by the liver and
                                                    eliminated via urine (75%) and feces
                                             43     (25%)                                         44

      Pharmacokinetics (cont.)                             Efficacy: Depression
• Metabolism involves demethylation and
  oxidation followed by conjugation               • 2 unpublished DBPC trials of mirtazapine
• Substrate for 2D6, 3A4, and 1A2                   for depression in children and adolescents
                                                    were negative (FDA website, 2001)
• Does not inhibit or induce any of the
  CYP450 systems
• Only one active metabolite, desmethyl-          • Response rates:
  mirtazapine, which has a similar                  – Study A (N=126): MIR (60%) = PBO (57%)
  pharmacokinetic profile as the parent             – Study B (N=124): MIR (54%) = PBO (42%)
• Protein-binding is approximately 85%       45                                                   46

              Adverse Effects                            Adverse Effects (cont.)
                                                  • Suicidality:
• Sedation (>50% of adults)                         – RR compared to placebo=1.58 (95% CI=0.06-
• ↑ appetite, weight gain                             38.37) (Hammad et al., 2006)

• Orthostatic hypotension, dizziness
                                                  • Neutropenia/agranulocytosis:
• Anticholinergic side effects (e.g., dry           – Pre-marketing (adult):
  mouth, constipation)                                 • 1.5% neutropenia (generally mild)
• Transient increases in LFTs (2% of adult             • 0.1% agranulocytosis (3 cases)
  patients)                                         – Postmarketing: 6 cases of agranulocytosis
                                                      reported out of >3 million treated
                                                    – All patients recovered after drug
                                             47       discontinuation                             48

            Contraindications                                        Drug Interactions
• Hypersensitivity to mirtazapine                         • MAOIs (serotonin syndrome)
                                                          • Inhibitors/inducers of 2D6, 3A4, and 1A2
• Concurrent MAOI (wait ≥2 weeks                          • Synergistic depressant effects on motor
                                                            and cognitive performance when used in
  between stopping one and starting                         conjunction with benzodiazepines or
  the other)                                                alcohol (Kuitunun, 1994)

                                                     49                                                        50

                 Monitoring                                          Monitoring (cont.)
• Suicidality                                             • For children, no official guidelines for lab
• HR and BP                                                 monitoring exist, but…
• For adults, no routine lab monitoring is                  – Some recommend CBC at baseline, after 2
  required, but…                                              months, and then every 6-12 months
  – If patient develops clinical evidence of                – Consider baseline and repeat LFTs as well
    infection, check CBC to assess for                      – As with adults, if child develops clinical
    neutropenia/agranulocytosis                               evidence of infection or liver toxicity, check
  – If patient develops clinical evidence of liver            CBC and LFTs, respectively
    toxicity, check LFTs

                                                     51                                                        52

         Dosing: General Info                               Dosing Specifics (Suggested)
• No official guidelines for dosing in children and       • Start 7.5-15 mg or 0.8 mg/kg QHS
• Generally given once daily at HS
                                                          • If child is ≥40 kg, consider starting with 30
• Purportedly causes greater sedation and                   mg QHS to minimize sedation and appetite
  appetite increase at lower doses                          increase
• Remeron RD (fruit-flavoured, orally                     • Titrate to initial target dose of 0.8
  disintegrating tablets) may be useful for children        mg/kg/day
  who have trouble swallowing pills
• Remember that mirtazapine has a relatively long         • If no response after 4-6 weeks and WBC is
  half-life, especially in females; consequently, it        stable, can ↑ to 1 mg/kg/day or maximum
  may take 1-2 weeks to reach steady state                  of 45 mg QHS
                                                     53                                                        54

                                                                    Indications and Clinical Use
                                                                 • In adults, buspirone is approved for short-
                                                                   term (up to 4 weeks) treatment of anxiety
                     Buspirone                                     in individuals with GAD (Health Canada
                                                                   and FDA)
                                                                 • In children and adolescents, buspirone
                                                                   has no approved indications (Health
                                                                   Canada and FDA)
                                                                 • Clinically, buspirone has been used in
                                                                   pediatric populations to treat anxiety
                                                            55                                                   56

            Pharmacodynamics                                        Pharmacodynamics (cont.)
• Serotonergic effects:
  – Partial agonist or mixed agonist/antagonist at 5-            • Noradrenergic effects:
    HT1A receptors                                                 – 1-pyrimidinylpiperazine (1-PP), the main
  – Predominantly agonistic activity at the presynaptic              metabolite of buspirone, has central α2-
    5-HT1A autorereceptors, which are present in high                adrenergic blocking activity
    concentrations in the dorsal raphe nucleus:                    – Blocking of presynaptic α2-adrenergic
     • ↑ negative feedback, which results in ↓ release of            autoreceptors ↓ negative feedback and results
       serotonin in the dorsal raphe nucleus                         in ↑ noradrenergic activity in the locus
     • This, in turn, is thought to result in anxiolysis             ceruleus
  – Partial agonistic activity at the postsynaptic 5-              – This may account for buspirone’s potential
    HT1A receptors, which are present in high                        usefulness as an augmentation strategy for
    concentrations in the hippocampus and cortex:                    depression and for treatment of SSRI-induced
     • This may account for antidepressant effects          57
                                                                     sexual dysfunction                          58

     Pharmacodynamics (cont.)                                              Pharmacokinetics
 • Dopaminergic effects:
    – Moderate antagonist of presynaptic D2 autoreceptors,       • Almost completely absorbed within 1 hr of
      and thus ↑ dopaminergic neurotransmission through            oral administration
      inhibition of negative feedback
    – Buspirone’s dopaminergic effects are probably
                                                                 • Oral bioavailability is reduced, however, by
      clinically unimportant in general                            substantial first-pass metabolism, which is
    – However, in an open study of buspirone in youth with         even greater at higher doses
      PDD, one child developed an orofacial-lingual
      dyskinesia after 10 months of treatment, and this
                                                                 • Taking with food does not affect
      resolved completely within 2 weeks of discontinuing          absorption, but ↓ first-pass metabolism
      buspirone (Buitelaar et al., 1998)
                                                                 • >95% protein-bound
 • GABA system:
    – No direct effects                                     59                                                   60

      Pharmacokinetics (cont.)                                         Pharmacokinetics (cont.)
• Tmax=40-90 min (children and adults)
                                                                • CYP 3A4 substrate
• T1/2=2-4 hrs in adults and older children, but 1-2
  hrs in children 4-6 years old (Edwards et al.,                • Not known to inhibit or induce any of the
  2006)                                                           CYP450 systems, but this has not been
• Extensively metabolized to 1-PP:                                well studied
   – Pharmacologically active
   – Present in concentrations several times higher than        • Excreted mostly in the urine, but also in
     the parent compound                                          feces
   – T1/2=3-4 hours in children and adults
• Cmax of both buspirone and 1-PP is higher in
  children compared to adults (Salazar et al.,
                                                           61                                                     62

              Efficacy: Anxiety                                                Adverse Effects
• No DBPC trials of buspirone for pediatric                     • Most studies of buspirone in youth report only
  anxiety have been published                                     mild side effects, which usually improve within a
                                                                • Common side effects include:
• Simeon et al., 1994:
                                                                  –   Dizziness, lightheadedness
   – 15 children (mean age=10 years) with various anxiety
                                                                  –   Headache
                                                                  –   Nausea, vomiting, dyspepsia
   – Single-blind PBO x 2 wks, then buspirone x 4 wks
                                                                  –   Nervousness
   – Dose range: 5-10 mg BID (mean=18.6 mg/day)
                                                                  –   Insomnia
   – Outcome measure: CGI
                                                                  –   Sedation
   – Results: no subjects improved on PBO, and all
     improved on buspirone (3 “marked,” 10 “moderate,” 2          –   Agitation
     “minimal”)                                         63        –   Euphoria                                    64

             Contraindications                                               Drug Interactions
• Hypersensitivity to buspirone                                 • 3A4 inhibitors/inducers

• Severe hepatic or renal impairment                            • Buspirone ↑ levels of haloperidol, likely
                                                                  because of competitive inhibition of the
                                                                  oxidative dealkylation of haloperidol
• Concurrent MAOI
                                                                • MAOIs (hypertension)

                                                           65                                                     66

              Monitoring                                  Dosing: General Info
                                                  • No official guidelines for dosing in children
• No specific medical monitoring is                 and adolescents
  recommended in adults                           • Dose BID-TID because of short T1/2
                                                  • Maximum daily dose in adults: 45 mg (HC)
                                                    or 60 mg (FDA)
                                                  • Studied and found to be safe in children
                                                    and adolescents at doses up to 30 mg BID
                                                    (Salazar et al., 2001)
                                                  • Usual optimal doses in adult clinical trials:
                                                    20-30 mg/day
                                             67                                                    68

   Dosing: General Info (cont.)                              Dosing: Specifics
                                                  • Adult dosing (CPS):
• May take 1-2 weeks at a given dose to             – Start 5 mg BID-TID, and ↑ by 5 mg q2-3 days
  achieve anti-anxiety effect (Sussman,               to a maximum of 45 mg/day
• Further symptom improvement may                 • Suggested pediatric dosing (modified
  continue for at least 4 weeks at a given          slightly from Coffey, 1990):
  dose, with psychic symptoms of anxiety            – Children: start 2.5-5 mg/day, and ↑ by 2.5 mg
  improving sooner than somatic symptoms              q3-4 days to a maximum of 20 mg/day
  (Feighner & Cohen,1989)                           – Adolescents: start 5-10 mg/day, and ↑ by 5-
                                                      10 mg q3-4 days to a maximum of 45-60
                                             69       mg/day                                       70

Dosing Schedule Used in Study by
        Rynn et al., 2007

A Picture’s Worth 1000 Slides




 Postsynaptic NA target neuron           Postsynaptic 5-HT target neurons
   noradrenaline                 •serotonin               •••mirtazapine

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Description: Venlafaxine Mirtazapine Buspirone asthenia