The Use of Risperidone in PTSD

Michelle WidholmPharm.D Candidate 2016

25th, June 2015MCHPS University

Objectives Discuss the normal stress response system

and compare it to the response in patients with PTSD

Identify the pharmacology and mechanism of action of risperidone

Discover how risperidone is used therapeutically for PTSD

Evaluate the safety and efficacy of risperidone for PTSD patients.

Apply these findings to a patient case

Normal Stress Response

Dopamine and NorEpi

Biological impact of PTSD People with PTSD have chronic stress

› This leads to prolonged HPA axis activation and biochemical changes.

Dopamine and norepinephrine levels increase.

There is a up regulation of 5HT2 receptors and a downregulation of 5HT1A receptors

Alterations in the GABA receptor complex also occur

Risperidone Pharmacology Risperidone Has…

› Strong affinity for 5HT2 receptors› Slightly weaker affinity for D2 receptors› And a small affinity to:α-1, α-2, H1, 5-HT1A,

5-HT1C, 5-HT1D, and D1

Risperidone works as an antagonist at all of these receptors

How Risperidone Works in PTSD

Risperidone acts as a competitive antagonist at the D2 and D1 receptors thus blocking elevated dopamine.

Upregulated 5-HT2 receptors are also blocked.

This allows the patient to have more normalized response to catecholamines.

Reich et al (2004) Selected women had a history of sexual,

physical, verbal or emotional abuse and were 18-65 years old.

This was an 8 week randomized, monotherapy, placebo controlled trial.

Patients were assessed on the CAPS-2 at weeks 1,2,4 and 8.

9 patients were in the placebo group and 12 patients were in the risperidone group.

Reich et al (2004) Risperidone was dosed at 0.5mg/day for

3 days, increased to 1mg/day and then titrated up to 4mg/day if tolerated. By week 5, if patients had some relief they were allowed to go up to 8mg/day in 2-3 divided doses.

Average risperidone dose at 8 weeks was 2.05mg/day. They noted that no specific dose correlated with decreases in symptoms.

Reich et al (2004) CAPS-2 scores decreased by 29.6

points, and only 18.6 points in the placebo group. (P<0.001)

The number of patients who experienced a 50% reduction in CAPS-2 scores, in the risperidone group, was significant (P<0.015), no N given.

Common ADRS: Increased prolactin levels, sedation, dry mouth, tremors, apathy and poor concentration

Padala et al (2006) Women ages 19-65 who experienced

domestic violence or sexual assault were enrolled.

This was a 12 week monotherapy, double-blind comparison of flexible dosed risperidone and placebo.

Patients were assessed on the following scales: TOP-8, HAM-A, HAM-D, and CAPS-2.

20 patients enrolled, 11 were in the risperidone group.

Padala et al (2006) Target does were between 4-6mg/day in

2 divided doses. Doses were titrated from 0.5mg twice day for 1 week, 1mg twice a day for the next week then to 2mg twice a day by week three.

Average risperidone dose was 2.62mg/day at week 12

Padala et al (2006) CAPS scores were significantly lower than baseline

and placebo scores. (no p-value or scores given) TOP-8 scores were significantly lower than baseline

at follow-ups during weeks 6-11. (no p-value or scores given)

HAM-A scores were significantly lower at the second and third administration. (no p-value or scores given).

HAM-D Scores were significantly lower, compared to baseline, a visits 7, 11, and 13. (no p-values or scores given.)

Subjects had improved sleep, decreased anxiety & reduction in intrusive memories

Rothbaum et al (2008) This study enrolled male and female

subjects This trial tested the efficacy and safety of

risperidone augmentation to sertraline. All the patients that were enrolled had

civilian trauma including sexual abuse, physical abuse, domestic violence, accidents, witness killings, and other types of stressors.

Rothbaum et al (2008) This was a randomized placebo-controlled

trial.› Open label phase one portion:

Patients were given sertraline 200mg/day (titrated from 25mg up 50mg each time to the max dose). If the subjects did not achieve a 70% reduction in CAPS scores they were put into phase II.

› Double-blinded phase II portion: During phase II subjects were started on

0.5mg/day and titrated up weekly by 0.5mg/day to a max dose of 2mg/day. On a case by case basis some patients were increased to 3mg/day.

Rothbaum et al (2008) Patients were assessed on the CAPS, DTS,

PANSS, BDI and CGI-I on weeks 1, 2, 4, 6, 8, 9, 10, 12, 14, and 16.

45 patients entered phase I, 34 completed phase I, and 25 were randomly assigned to phase II.

20 patients completed phase II (risperidone N=9) Mean dose of risperidone was 2.1mg at the end

of week 16. Mean sertraline dose was 147mg in the risperidone group and 177mg in the placebo group.

Rothbaum et al (2008) CAPS scores decreased by 51.6 points between

baseline and phase II, however risperidone was not significant to placebo.

55% reduction in DTS scores (baseline: 75, week 16: 33.5) was significant (p=0.03)

PANSS, BDI and CGI-C were not significant. All 5 patients that discontinued were in the

risperidone group. These adverse events were possibly due to the

study drugs. › Patients discontinued due to tachycardia, increased liver

enzymes, intermittent chest pain (patient was a heavy smoker and obese) and probable dystonic reaction. No other ADRs were mentioned.

Patient CasePlease refer to the handout that was

provided.

Patient characteristics Alcohol use and abuse

› Alcohol is a GABA agonist Unsupportive family Trauma Number of years with the illness Adjunctive medications

› Citalopram› Lorazepam

Other Considerations Dose of risperidone

› Most of the studies have an average dose around 2mg.

› Dosed once a day to three times a day depending on the patient.

Adverse effects› Weight increase and tardive dsykinesia

Length of treatment› Want to achieve a full year of sobriety and

remission before removing risperidone therapy. Pregnancy category- Cat. C

Recommendations Patient needs to set up an appointment

with a new PCP to get a physical. Increase risperidone to 1mg once daily.

› Dose should be increased based on current trials. Dosing it once a day will make it easier for the patient.

› Half life is 3-20 hours. Once a day dosing is potentially appropriate. Metabolite half live is 8 days.

Discontinue lorazepam.› Benzodiazepines are not recommended for

PTSD patients due to it exacerbating symptoms.

Recommendations Re-initiate trazodone, but at 100mg at

bedtime.› To help the patient sleep at night and help

her discontinue the lorazepam. Increase citalopram to 40mg daily.

› We want to max out the dose before determining it to be ineffective. Also trials with citalopram used 40mg/day.

Re-initiate nicotine replacement therapy if she is still smoking.

Recommendations We also want to talk to the patient about

alcohol consumption. Patient should be educated on her disease

state and the important of compliance.

Any Questions?

References1. Stephens MA and Want G. Stress and the HPA Axis. Role of Glucocorticoids in Alcohol

Dependence. National Institute of Alcohol Abuse and Alcoholism. http://pubs.niaaa.nih.gov/publications/arcr344/468-483.htm. Accessed June 22nd, 2015.

2. Risperidone. Micromedex Solutions. http://www.micromedexsolutions.com.ezproxy.mcphs.edu/micromedex2/librarian/PFDefaultActionId/evidencexpert.DoIntegratedSearch#. Accessed June 22nd, 2015.

3. Sherin et al. Post-Traumatic Stress Disorder: The Neurobiological Impact of Psychological Trauma. Dialogues Clin Neurosci. 2011; 13:263-278.

4. Clinician Administered PTSD Scale (CAPS). International Society for Traumatic Stress Studies website. http://www.istss.org/assessing-trauma/clinician-administered-ptsd-scale-(caps).aspx. Accessed June 22nd, 2015.

5. Weathers Et al. Clinician-Administered PTSD Scale: A Review of the First Ten Years of Reaserch. Dep and Anxiety. 2001; 13: 132-156.

6. Reich et al. A Preliminary Study of Risperidone in the Treatment of Posttraumatic Stress Disorder Related to Childhood Abuse in Women. J Clin Psychiatry. 2004; 65: 1601-1606.

7. Padala et al. Risperidone Monotherapy for Post-Traumatic Stress Disorder Related to Sexual Assault and Domestic Abuse in Women. Int Clin Psychopharmacol. 2006; 21: 275-280

8. Routhbaum et al. Placebo-Controlled Trial of Risperidone Augmentation for Selective Serotonin Reuptake Inhibitor-Resistant Civilian Posttraumatic Stress Disorder. J Clin Psychiatry. 2008; 69: 520-525.

References Cont.1. Davidson J. DTS, Davidson Trauma Scale. MHS.

http://www.mhs.com/product.aspx?gr=cli&id=overview&prod=dts. Accessed June 22nd, 2015

2. Bardi JS. One Night in San Diego: Tragedy of Alcohol Abuse Drives TSRI Researcher's Work. The Schipps Reaserch institute. https://www.scripps.edu/newsandviews/e_20020225/koob2.html. Accessed June 22nd, 2015.

3. Bobo WV, Warner CH, Warner CM. The Management of Post Traumatic Stress Disorder (PTSD) in the Primary Care Setting. South Med J. 2007; 100(8): 797-802 https://msrc.fsu.edu/system/files/Bobo%20et%20al%202007%20The%20management%20of%20post%20traumatic%20stress%20disorder%20PTSD%20in%20the%20primary%20care%20setting.pdf. Accessed June 22nd, 2015.

4. Dissociative Experiences Scale. The Colin A Ross Institute for Psychological Trauma web site. http://www.rossinst.com/dissociative_experiences_scale.html Accessed June 22nd, 2015.

5. Kay et al. PANSS, Positive Negative Syndrome Scale. MHS. http://www.mhs.com/product.aspx?gr=cli&id=overview&prod=panss. Accessed June 22nd, 2015.

6. Soraya et al. Open trial of citalopram in adults with post-traumatic stress disorder. Int J Neuropsy. 2000; 3:135-140

Thank you for listening