Table 2.
Survey of non-SSRIs evaluated for clinical efficacy in treating PTSD: Non-monoamine mechanisms.
| Drug | Primary mechanism | Pavlovian FC Process* | Population | Trial Type/#Enrolled | Effect on symptoms‡ | Comment |
|---|---|---|---|---|---|---|
| Morphine | Opiate: μ agonist | # FC | Acute trauma, military-related | Historical /696 | #[192] | Reduced risk of developing PTSD following traumatic injury |
| $ Consolidation | ||||||
| # Retrieval | ||||||
| # Extinction | ||||||
| Acute trauma, civilian | Historical /155 | #[193] | Lower morphine dose associated with increased risk of PTSD | |||
| Acute trauma, children | Historical /70 | #[194] | Higher doses of morphine reduced subsequent PTSD symptoms | |||
| Acute trauma, children | Historical /24 | #[195] | Higher doses of morphine reduced subsequent PTSD symptoms | |||
| Nalmefene | Opiate antagonist | Untested | Chronic PTSD | OL /18 | #[196] | Thought to block endogenous opiate effect thereby reducing emotional avoidance |
| Naltrexone | Opiate antagonist | ” FC | Chronic PTSD | OL /8 | #[197] | Reduction in hyperarousal symptoms but at doses producing side-effects |
| $ Consolidation | ||||||
| $ Extinction | ||||||
| D-Cycloserine | NMDA partial agonist (developed as broad spectrum antibiotic) | ” Consolidation | Chronic PTSD | DBPC | $[198,199] | No benefit vs. placebo when combined With CBT. Several other clinical trials in PTSD are ongoing. |
| $ Retrieval | ||||||
| ”Reconsolidation | ||||||
| ” Extinction | ||||||
| Ketamine | GLU: NMDAR antagonist | # Acquisition | Acute stress disorder following trauma | Historical /50 | ”[200] | Ketamine increased symptoms of dissociation, reexperiencing, hyperarousal and avoidance |
| # Retrieval | ||||||
| Acute trauma, military-related | Historical /147 | #[201] | Patients who received ketamine had lower rates of PTSD than those who did not | |||
| Hydrocortisone | Glucocorticoid Receptor: agonist | ” Acquisition | Trauma-exposed, with and without PTSD | OL | #[152] | Decreased fear-potentiated startle in PTSD patients |
| ” Generalization | 100 | |||||
| # Cond. Inhib. | ||||||
| # Retrieval | ||||||
| ” Extinction | ||||||
| Veterans, with and without PTSD | DBPC /63 | #[153] | Decreased fear-potentiated startle in both PTSD and non-PTSD participants | |||
| Chronic PTSD, military-related | DBPC /20 | #[157] | Used in combination with memory reactivation; effect is significant at 1 week but diminished after 1 month | |||
| Cardiac surgery patients | DBPC /28 | #[154] | Hydrocortisone given at time of surgery decreased chronic stress symptoms | |||
| Chronic PTSD | OL /3 | #[151] | Reduced recall of traumatic memories | |||
| Cardiac surgery patients | Randomized 48 | #[155] | Hydrocortisone given at time of surgery decreased chronic stress symptoms | |||
| Septic shock patients | DBPC /20 | #[156] | Decreased development of PTSD | |||
| Topiramate | Anticonvulsant; Multiple effects | untested | Chronic PTSD | DBPC /38 | #[202] | Monotherapy significantly reduced reexperiencing symptoms and Treatment Outcome PTSD scale. |
| Chronic PTSD, military-related | DBPC /40 | $[203] | Augmentation to standard pharmacotherapy and psychotherapy. Higher dropout rate in topiramate group due to CNS adverse events prevented definitive assessment. | |||
| Chronic PTSD | OL /35 | #[204] | Monotherapy and augmentation. Decreased nightmares and other PTSD symptoms. | |||
| Lamotrigine | Anticonvulsant; Na+ channel inhibitor | # FC | Chronic PTSD | DBPC /14 | #[205] | Reduced reexperiencing and avoidance/numbing symptoms |
| Tiagabine | Anticonvulsant; GABA uptake blocker | Untested | Chronic PTSD | DBPC /232 | $[206] | |
| Chronic PTSD | OL/DBPC /18 | #[207] | Responders identified in OL trial had greater incidence of relapse when switched to placebo (p = 0.08) | |||
| Divalproex | Anticonvulsant; GABA enhancer | ” FC | Chronic PTSD, military- related | DBPC /85 | $[208] | |
| ” Generalization | ||||||
| ” Reconsolidation | ||||||
| ” Extinction | ||||||
| Gabapentin | Anticonvulsant: calcium channel a2d subunit | Untested | PTSD | Historical /30 | #[209] | Adjunctive therapy with gabapentin improved sleep and decreased nightmares |
| Levetiracetam | Anticonvulsant; unknown mechanism | Untested | Chronic PTSD | Historical /23 | #[210] | Adjunctive therapy in PTSD patients with partial or no response to antidepressant therapy |
| Eszopiclone | GABA: GABAA PAM (BZD site) | Untested | Chronic PTSD | DBPC /24 | #[211] | 3 weeks treatment improved sleep and overall PTSD symptoms |
| Alprazolam | GABA: GABAA PAM (BZD site) | # Retrieval | PTSD in recent trauma survivors | OL /26 | $[212] | Clonazepam (n = 10) |
| Alprazolam (n = 3) | ||||||
| Chronic PTSD | DBPC /10 | $[213] | Cross-over design. Modest reduction in anxiety with alprazolam. | |||
| Clonazepam | GABA: GABAA PAM (BZD site) | Untested | Chronic PTSD, military-related | Randomized 6 | $[214] | |
| Temazepam | GABA: GABAA PAM (BZD site) | Untested | Acute trauma, civilian | Randomized 21 | $[215] | Treatment for 1 week following trauma; follow-up at 6 weeks |
| GR205171 | NK1 Receptor Antagonist | # Retrieval | Chronic PTSD | DBPC /39 | $[216] |
*
Effects of drugs on Pavlovian FC processes: ” enhanced, #impaired, $mixed results. No entry means either the drug has not been tested for that process or available tests show null effects. Both preclinical and clinical studies were considered, but only if drugs were evaluated on explicit FC paradigms. Acquisition: refers to a clear learning effect (either within-session or STM effect, or effect with pre-training but not post-training administration); Consolidation: refers to a clear consolidation effect (drug given post-training but washed out before fear retrieval test). FC is used when data aren't available to distinguish between acquisition and consolidation effects (Note: Pavlovian FC Processes column excludes findings from instrumental avoidance studies).
zEffects of drugs on Symptoms: $ No significant effect; # improved symptoms; ” worsened symptoms.
DBPC: Double Blind Placebo-Controlled; FC: Fear conditioning; OL: Open Label; Historical: Retrospective chart review.