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Ronald C. Albucher and Israel Liberzon^,

Department of Psychiatry/PCT 116C, Veterans Administration Medical Center, University of Michigan, 2215 Fuller Road, Ann Arbor, MI, 48105, USA

Received 31 July 2001; revised 7 August 2002; accepted 14 August 2002. Available online 16 October 2002.

1. Introduction

In the past 20 years psychology and neuroscience began to elucidate the intricate interplay between the underlying biological substrate of the individual and the complex human experience of trauma. This more recent progress allowed the delineation of a biological diathesis for posttraumatic stress disorder (PTSD), and clarified the potential importance of psychopharmacological interventions in this condition, (Davidson; Friedman and Grillon).

Clinical presentation in PTSD is often very heterogeneous, with symptoms varying in intensity from patient to patient. According to the DSM-IV-TR, the essential features of PTSD are the development of characteristic symptoms following exposure to an extreme traumatic stressor (American Psychiatric Association, 2000). The person's response to the event must involve intense fear, helplessness, or horror, while the characteristic symptoms resulting from the exposure to the extreme trauma include persistent re-experiencing of the traumatic event (Criterion B), persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (Criterion C), and persistent symptoms of increased arousal (Criterion D).

The diversity of these symptoms (flashbacks, nightmares, hyperarousal, avoidance, numbing, anxiety, anger, impulsivity or aggression) suggest the involvement of multiple neurobiological systems. In addition, the disorder has a high degree of comorbidity with other psychiatric disorders such as depression, substance abuse, and panic disorder. Given the complex interaction between biology and individual experience, it is not surprising that the development of pharmacological treatments for PTSD is quite challenging. Yet, despite this complexity, advances in neurobiology have shed some light on the relevant neurobiological systems which might have been altered by the exposure to severe stress, and in turn contribute to PTSD phenomenology.

Current findings implicate a number of neuroanatomical circuits, neurotransmitter systems, and neuronal mechanisms in PTSD pathophysiology. Central catecholamines, serotonin and extrahypothalamic CRF are implicated in the modulation of stress response, fear, anger, arousal and aggression (functional domains often impaired in PTSD). Pharmacological interventions target these systems in an attempt to alleviate PTSD symptoms. Similarly, mechanisms of kindling and sensitization are implicated in the regulation of mood and emotional memory, opening the possibility that "antikindling" agents might prove therapeutic in specific aspects of PTSD symptomatology. Thus, abnormalities in a variety of neurobiological systems might lead to the formation of some PTSD symptoms, but a single abnormality in one system cannot account for them all.

Below we present the treatment outcome literature for several different classes of medications that have been used in the treatment of PTSD. Reports of clinical trials of psychotropic agents, carried out with PTSD patients and published in peer-reviewed journals, in English, between 1966 and 2001, were identified by searching the Medline and PILOT data bases and through cross-referencing. Proceedings of national meetings (ISTSS, Biological Psychiatry, ADAA, ACNP, and Society for Neuroscience) were searched for relevant information. Where possible, we emphasize results from randomized controlled trials (these data are summarized in Table 1), and augment this information with less controlled research clarifying the limitations along the way. In the descriptions that follow, drug doses in parentheses refer to mean daily maximum doses used in that study.

Table 1. Summary of double-blind randomized pharmacotherapy trials for PTSD
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2. Antidepressants

Originally developed to treat depression, these agents are effective in a range of psychiatric disorders including panic disorder, obsessive compulsive disorder, chronic pain, and eating disorders. Given the high degree of comorbidity between PTSD and depression, and the common clinical features of PTSD and other anxiety disorders (anxiety, agoraphobia, panic attacks), it is not surprising that the majority of early research studies have focused on the efficacy of antidepressants for PTSD.

3. Tricyclic antidepressants (TCAs)

The TCAs block the reuptake of norepinephrine and serotonin to varying degrees. Most of the side effects are due to the blockade of receptor sites often considered "secondary" to antidepressant action such as the muscarinic, histaminergic, and adrenergic systems. Central catecholamines and serotonin are involved in modulating arousal level, stress response, mood regulation and anxiety (McEwen, 2000). Multiple aspects of the PTSD syndrome (such as enhanced fear, anger, arousal, and aggression) suggest dysregulation in one or more of these functions in PTSD patients ( Kosten and Yehuda), that in turn provides neurobiological rationale for the efficacy of pharmacological interventions that affect these systems in PTSD ( Maes; Newport; Southwick; Southwick and Spivak). Since the majority of TCAs are active in a number of neurotransmitter systems, their efficacy in PTSD could be mediated by their effect in increasing serotoninergic transmission, modulating alpha-2 adrenergic function, affecting monoamine transporters, influencing secondary messenger systems or some combination of the above.

Three controlled trials and several uncontrolled studies examined efficacy of the TCAs for PTSD symptoms, including studies of imipramine, desipramine, and amitriptyline. In one of the larger TCA studies, imipramine (225 mg) was compared to phenelzine (68 mg) in a placebo-controlled, 8-week trial with 60 combat veterans (Kosten et al., 1991). Treatment retention to 8 weeks was relatively low (52%) and endpoint analysis was utilized in this study. Here, post-treatment time points varied across subjects (i.e. for subjects that dropped out prior to week 8, scores from their last week in treatment were carried forward). While intrusive symptoms decreased on imipramine relative to placebo, no imipramine benefit was observed for avoidance or depressive symptoms.

Another large, double blind placebo-controlled, 8-week trial compared amitriptyline (200–300 mg) and placebo in 46 combat veterans (Davidson et al., 1990). Treatment retention was considerably better in this study (72%), and improvement was noted for amitriptyline relative to placebo for depression, anxiety, and both intrusive and avoidance symptoms on self-reported, but not observer-rated measures. Avoidance symptoms improved more than intrusions.

Reist and colleagues examined the efficacy of desipramine (165 mg) in a placebo-controlled crossover design in 18 inpatients with combat-related PTSD (Reist et al., 1989). Each arm of the study was 4 weeks in duration with a 2-week washout period between phases. In this brief trial, desipramine was superior to placebo for improving depressive, but not anxiety or PTSD-specific symptoms.

Two uncontrolled trials also reported relative efficacy of TCAs for PTSD, finding improvement in both intrusive and depressive symptoms (Burstein and Kauffman). Finally, a retrospective chart review of 17 combat veterans treated with various TCAs reported that 82% were "much improved" on medication ( Falcon et al., 1985).

In sum, available data suggest that TCAs can be effective in treating PTSD symptoms, with the most convincing evidence coming from two large placebo-controlled trials (Davidson and Kosten). The third controlled trial of desipramine had less promising results, but the brevity of treatment duration could have contributed to negative findings. Finally, neither imipramine and amitriptyline stand out as more effective than the other, though the controlled study using desipramine showed no improvement for PTSD symptoms.

Not surprisingly, given the broad side effect profiles of these drugs, dropout rates with TCAs tend to be high (28–48%), suggesting that these medications are often difficult to tolerate for PTSD patients. All of the controlled trials, and all but one of the uncontrolled trials, of TCAs were completed using combat veterans with chronic PTSD, who are known to be a particularly treatment refractory population (van and Zisook). Thus, the evidence of moderate efficacy obtained in these studies should be accepted with greater enthusiasm. In general, it appears that for those patients who are able to tolerate TCAs, these medications are likely to offer some improvement to their PTSD symptoms.

4. Monoamine oxidase inhibitors (MAOIs)

MAOIs inhibit the neuronal enzyme monoamine oxidase, and consequently increase the concentration of amines in the cell's cytoplasm and in the synaptic terminals. It was initially believed that this accumulation of amines was responsible for the therapeutic action of this medicine. In this context, the therapeutic effects of MAOIs, might be mediated by the same mechanisms that are responsible for the efficacy of the tricyclic agents. Consequently, it was thought that elevated levels of catecholamines and serotonin may correct abnormalities in the central nervous system altered by trauma. Now, researchers are looking at secondary adaptive mechanisms as an explanation of their efficacy.

The MAOIs are especially effective in the treatment of depression and some anxiety disorders, like social phobia. However, their clinical utility is limited by the need for patients to follow a low tyramine diet in order to avoid a potentially life-threatening hypertensive crisis. MAOIs that reversibly bind to the MAO enzyme are not currently available in the USA, but may represent a safer way in the future to use this class of medication.

Four controlled trials and at least six uncontrolled reports demonstrate MAOIs efficacy for the treatment of PTSD, including trials with phenelzine, brofaromine, and moclobemide. Kosten and colleagues compared phenelzine (68 mg) and imipramine (225 mg) in a double-blind, placebo-controlled trial in combat veterans with PTSD (see the previous section on TCAs) (Kosten et al., 1991). Dropout rates were high, with only 52% of the original 60 patients completing the full 8 weeks of treatment. Phenelzine decreased intrusive, but not avoidance or depressive symptoms relative to placebo, and symptom reduction was slightly greater for phenelzine than imipramine.

Shestatzky and colleagues similarly studied phenelzine (60 mg) using a within-subject, placebo-controlled crossover design, in patients with non-combat PTSD (Shestatzky et al., 1988). The dropout rate was very high, the number of subjects small, and the trial duration was brief in this study. Although designed as a 5-week crossover trial, only six (46%) of the original 13 patients completed the full 5 weeks, so results were reported for the 10 patients completing at least 4 weeks on each arm. In contrast to Kosten's promising results, Shestatzky found that phenelzine was not superior to placebo in reducing PTSD, depression, or anxiety symptoms. The lack of efficacy against depressive symptoms in this study is contraintuitive, and might suggest that depressive symptoms within PTSD syndrome are more difficult to treat, are driven by a different mechanism, or that the study did not have enough power to detect change.

More recently, two large placebo-controlled trials for PTSD have been published using brofaromine, a combined MAO-A/serotonin reuptake inhibitor. In one report, Baker and colleagues studied brofaromine (150 mg) versus placebo over 12 weeks in 113 patients with PTSD due to various traumas (Baker et al., 1995). Dropout rate was 30%, and despite the relatively long duration of the study, brofaromine was not superior to placebo in reducing PTSD symptoms. However, the placebo response in this study was notably greater than that in other reported medication trials for PTSD (26%), thus potentially obscuring positive results. The authors attributed this to potentially therapeutic patient–interviewer attention received in repeated interview assessments.

In the other brofaromine trial, Katz and colleagues compared brofaromine (up to 150 mg) to placebo, in 68 diverse trauma patients participating in a 14 week, multi-site- trial (Katz et al., 1994). The dropout rate was 34%, quite similar to the one reported by Baker and colleagues. Katz et al. reported that brofaromine significantly reduced PTSD symptoms relative to placebo among those patients with chronic PTSD (symptoms present for at least 1 year). Findings for specific PTSD symptom clusters were not reported. While some patients improved notably, nearly half of brofaromine-treated patients continued to meet criteria for PTSD at the end of the trial. Unfortunately the manufacturer has withdrawn brofaromine from the market, and it is currently not available to clinicians for further study.

Several open trials and case reports have been published that examine the efficacy of MAOIs, showing benefit for PTSD symptoms, sleep, and depression (Davidson; DeMartino; Hogben; Lerer and Milanes). More recently, Neal and colleagues reported results from a 12-week open trial of moclobemide (600 mg), a reversible inhibitor of MAO-A, not available in the USA ( Neal et al., 1997). Among their 20 patients with PTSD due to diverse traumas, moclobemide significantly reduced intrusions, avoidance, and hyperarousal symptoms of PTSD as well as depression relative to placebo, with improvement being most marked for avoidance/numbing symptoms.

In summary, the controlled research examining the efficacy of MAOIs in the treatment of PTSD revealed some mixed findings; however, PTSD patients using this class of medication showed greater global improvement than those treated with TCAs. Of the four placebo-controlled trials conducted with MAOIs, there is one positive and one negative phenelzine report and one partly positive and one largely negative brofaromine report. As is often the case, the uncontrolled reports are more promising, with three of four open trials and several case reports demonstrating positive results with MAOIs. These medications appear to be helpful for at least some PTSD patients, but the difficulty using the MAOIs currently available in the USA may prohibit their future use, especially in an impulsive patient population.

Treatment dropout rates on MAOIs are quite high (30–54%), perhaps even greater than rates observed with TCAs. However, dropout seems to be lower with the newer, reversible MAOIs, brofaromine and moclobemide (20–34%), than with phenelzine (40–54%). This is likely due to the fact that a restricted diet and potential hypertensive crisis are less of a concern with the newer drugs due to their pharmacological selectivity and reversibility. As with the TCA studies, most MAOI studies were conducted with combat veterans known to be treatment-refractory, and therefore represent a stringent test to the efficacy of these agents as general treatments for PTSD.

5. Selective serotonin reuptake inhibitors (SSRIs)

Problems in serotonin functioning in the central nervous system have been posited to underlie disturbances in mood, anxiety, aggression, sexual drive and other areas. Serotonin is synthesized locally in the central nervous system, since it cannot cross the blood–brain barrier. After it is released into the synapse, it is then degraded either by monoamine oxidase or by reuptake and vesicular restorage.

SSRIs both enhanced and tremendously simplified the treatment of many psychiatric disorders when they were introduced in the late 1980s. These medications while as effective as the TCAs and MAOIs in the treatment of depressive disorders, have less prominent effects outside the central nervous system (for instance on cardiac function), and are much safer in drug overdose. Their major side effects are gastrointestinal complications (diarrhea or nausea) and sexual dysfunction. The latter may be a very pertinent issue for survivors of sexual abuse.

Decreased serotonin levels in animal models and human studies have been associated with increased impulsivity, aggression, fear and sadness/depression (Hashimoto; Lesch; Maes; Mann and Ressler). Normal function of serotonin 5HT_1A receptors is essential to the regulation of anxiety responses as has been demonstrated in mouse knock-out models (Parks and Ramboz). Thus, SSRIs and non-selective SRI efficacy in PTSD symptoms are likely to stem from their enhancement of serotonergic function, with subsequent improvement in modulation of anxiety, anger, mood and impulsivity.

The research literature examining SSRIs in the treatment of PTSD already exceeds that of the TCAs and MAOIs, and there are several other large, double-blind, placebo-controlled clinical trials underway. To date, eight completed, controlled SSRI trials have been reported.

A double-blind, placebo-controlled 5-week trial of 64 outpatients with combat and non-combat PTSD compared the efficacy of 40 mg fluoxetine to placebo (van der Kolk et al., 1994). A high number (36%) of fluoxetine-treated patients failed to complete this brief trial. Among completers, fluoxetine was superior to placebo for treating PTSD symptoms and depression, particularly the numbing and hyperarousal symptoms of PTSD. Though both veteran and non-veteran patients benefited, fluoxetine response was greater among the non-veteran patients.

In another trial, fluoxetine was used to treat PTSD in 53 civilians for 12 weeks, using doses of up to 60mg per day (Connor et al., 1999b). Fluoxetine was more effective than placebo observed as early as week two, in terms of PTSD symptom severity and overall disability. Interestingly, the placebo group had a higher drop out rate than the treatment group.

A large double-blind, placebo controlled, multicenter trial followed 187 outpatients at 14 centers over 12 weeks using doses of sertraline ranging from 50 to 200 mg/day (Brady et al., 2000). At the endpoint, patients treated with sertraline demonstrated significant improvement on PTSD symptoms on three out of four outcomes measures. Symptom clusters including avoidance, numbing and increased arousal improved, while, the re-experiencing and intrusion subscale achieved only trend significance. Furthermore, the presence of either depression or another anxiety disorder did not diminish the efficacy of sertraline. The dropout rate was not significantly different from placebo (31% vs. 27%). The majority (76%) of patients in this trial were women. Post hoc exploratory analyses revealed a significant difference between sertraline and placebo on several measures in women, regardless of a baseline diagnosis of comorbid depression. However, there was no significant effect in the relatively smaller number of men in this study. The clinical significance of this apparent gender interaction is unknown at this time; however, the apparent gender effect for sertraline may simply be an artifact of the small number of men enrolled in this trial, since the study was not designed to demonstrate gender effects. Based on these studies, sertraline was approved by the FDA as the first pharmacological agent indicated for the treatment of PTSD.

In a study by Davidson et al., 208 PTSD outpatients were randomized to 12 weeks of double-blind treatment with either sertraline (50–200 mg per day) or placebo (Davidson et al., 2001). Improvement according to the Clinician-Administered PTSD Scale (CAPS-2), Impact of Event Scale (IES), and other measures showed significant improvement for the sertraline group (60% responder rate for sertraline versus a 38% placebo response). Sertraline treatment was well tolerated.

A recent, very large double-blind, randomized, placebo-controlled fluoxetine study, conducted in Europe, Israel, and South Africa also showed promising results (Martenyi et al., 2002). Three hundred and one patients were randomly assigned to 12 weeks of treatment with fluoxetine (20–80 mg/day) or placebo. The primary outcome measurement was the Treatment Outcome PTSD rating scale (TOP-8). Other measures included the CAPS and the Davidson Trauma Scale (DTS). Statistically significant improvements were found with fluoxetine in weeks 6–12.

Finally, the largest double blind, placebo controlled trial compared paroxetine in 20–50 mg per day doses to placebo in 307 PTSD patients in a 12 week, multicenter trial (Tucker et al., 2001). The most common trauma type was either physical or sexual assault in a mostly female cohort. Active medication at both doses resulted in improvements in each of the three PTSD clusters: re-experiencing, avoidance/numbing, and hyperarousal. Other outcome measures like the TOP-8, DTS, and the Sheehan Disability Scale (SDS) all showed significant improvement with paroxetine over placebo. The 40 mg daily dose did not demonstrate better efficacy compared to the 20 mg dose.

In one of two double-blind, controlled trial which showed no benefit, Hertzberg et al. tested 12 combat veterans over 12 weeks with fluoxetine up to 60 mg/day versus placebo (Hertzberg et al., 2000). Only one fluoxetine patient responded, compared to two of the six placebo patients, in a small sample of combat veterans with severe and chronic PTSD. Factors contributing to the negative outcome might include the small sample size, comorbidity, chronicity or other bias.

Zohar also found no improvement in a study of outpatients with PTSD (Zohar et al., 2002). Forty-two Israeli military veterans were randomized to 10 weeks of double-blind treatment with sertraline (50–200 mg/day). There was a 13% dropout rate due to side events. The baseline CAPS-2 total severity score was high (94.3±12.9), and sertraline showed a non-statistically significant advantage compared with placebo on the CAPS-2 total severity and symptom cluster outcomes.

A substantial number of open trials report efficacy for fluoxetine (Davidson; March; McDougle; Nagy and Shay), fluvoxamine ( Davidson; De; Marmar and Tucker), sertraline ( Brady; Kline and Rothbaum), paroxetine ( Marshall et al., 1998), and even citalopram ( Seedat and Seedat) in PTSD.

In summary, six published, controlled trials and many open trials now indicate that SSRIs are effective in the treatment of PTSD and related symptoms, with improvement generally similar to or better than that reported in the TCA and MAOI studies. The two smallest controlled trials, one with sertraline, the other with fluoxetine, showed no advantage of these medications over placebo.

Most of the SSRI reports suggest that effects are not limited to a particular symptom domain, but can be seen in all three symptom clusters. There appears to be no difference yet between fluoxetine, fluvoxamine, sertraline, paroxetine and citalopram in terms of outcomes; however, fluvoxamine and citalopram have only been studied in less rigorous open trials. The dropout rates reported in the SSRI trials resemble (or are lower than) rates reported in the TCA and MAOI trials. In fact, with the exception of one open trial of fluvoxamine that had unusually good treatment retention of 91% (Marmar et al., 1996), dropout ranged from 13 to 64%. We were somewhat surprised about the range of dropout rates, since clinically the SSRIs are usually tolerated better than the older, less specific antidepressants (at least in regards to the treatment of depression). It is possible that PTSD patients have all together higher discontinuation rates, or alternatively are more sensitive to SSRI specific side effects. Alternatively, dropouts may be due to other factors aside from side effect to the tested medication.

6. Other antidepressants

The atypical structure of trazodone makes it a somewhat unique antidepressant. Mainly it acts as a serotonergic agent by mildly inhibiting reuptake, antagonizing some 5-HT receptors, and, through its active metabolite m-chlorophenylpiperazine, or m-CPP, acting as a serotonin agonist. Trazodone has a less pronounced side effect profile than TCAs or MAOIs; however, it can cause sexual dysfunction and is fairly sedating. Thus, many patients have difficulties tolerating the higher doses of trazodone that are necessary to achieve an antidepressant effect. Yet, this medication does seem useful to treat insomnia, and perhaps agitation. Only one report in the literature addresses the efficacy of trazodone in PTSD. Hertzberg and colleagues studied trazodone (300 mg), using a multiple baseline design over four months in six patients with combat-related PTSD (Hertzberg et al., 1996a). Although trazodone decreased PTSD symptoms, the overall symptom score reduction was only 13%. If therapeutic doses can be tolerated, trazodone might constitute a viable alternative treatment for some PTSD symptoms. In its lower dose range (50–150 mg) it is a valuable supporitic (sleep inducing) agent without addictive potential.

Nefazodone is a primarily presynaptic serotonin reuptake inhibitor as well as postsynaptic 5-HT₂ receptor antagonist. Lacking ₁ adrenergic receptor activity, it does not cause significant orthostatic hypotension, and is less sedating than trazodone. To date, several open label studies show nefazodone benefits PTSD (Davidson; Hertzberg; Hertzberg; Hidalgo and Sajatovic). These studies noted improvement in sleep, anger, and nightmare measures. There is also some preliminary evidence that nefazodone may treat general anxiety symptoms as well. Davis et al. followed 36 PTSD veterans through an 8 week open trial, with 31 and 26 patients making it to 4 and 8 weeks respectively ( Davis et al., 2000). CAPS scores decreased significantly throughout the study, with most of the improvement occurring in the first 4 weeks. Zisook et al. treated 19 refractory PTSD patients with nefazodone for 12 weeks ( Zisook et al., 2000). The authors reported noticeable improvements in intrusive symptoms, avoidance and hyperarousal, as well as in depression, sleep and sexual functioning.

Venlafaxine is another structurally novel antidepressant which inhibits serotonin and norepinephrine reuptake and weakly inhibits dopamine reuptake. There is one case report of benefit in a depressed PTSD patient who had failed to respond to SSRI therapy (Hamner & Frueh, 1998).

Mirtazapine and bupropion both demonstrate limited efficacy in treating PTSD through open label trials with small numbers of patients (Canive and Connor).

7. Buspirone

Buspirone is an anxiolytic agent that binds at the 5-HT_1A receptor binding site, acting as an agonist at presynaptic receptors, and a partial agonist at postsynaptic receptors. In one open trial, three patients with PTSD were successfully treated with buspirone with maximum dosages ranging from 35 to 60 mg daily (Wells et al., 1991). In a more recent open trial, Duffy and Malloy examined eight patients with PTSD. Seven out of eight patients exhibited a significant reduction in symptoms, with a dose ranging from 5 to 30 mg per day ( Duffy and Malloy, 1994).

8. Mood stabilizers

8.1. Lithium

Lithium is an element that has many interactions within the central nervous system such as augmenting serotonin function, modifying dopamine transmission, facilitating the release of norepinephrine, and impacting other neurotransmitters such as acetylcholine, and -aminobutyric acid (GABA) (Schatzberg and Nemeroff, 2001).

Lithium has been used effectively in the augmentation of antidepressants (Bauer and Bauer), and in patients with impulse control problems and aggression ( Campbell; Forster and Yehuda), but the literature on lithium's effectiveness in PTSD is limited. In one open trial, lithium (300–600 mg) improved anxiety, anger, irritability, and insomnia in five treatment-resistant combat veterans with PTSD, with one case responding best to a combination of lithium and 10 mg of propranolol ( Kitchner and Greenstein, 1985). Lithium is effective within a narrow range of serum blood levels, above which toxicity prevails, thus kidney, thyroid, and cardiac functions have to be monitored regularly during lithium treatment. It is possible that these constraints contributed to the paucity of research on lithium in PTSD, a disorder often complicated by comorbidities and poor compliance.

8.2. Anticonvulsants

Anticonvulsants were introduced into the psychiatric pharmacopoeia for the treatment of manic-depressive illness (as a mood stabilizer) and to decrease the frequency of impulsive or violent behaviors. With the development of the kindling model as a possible pathophysiological abnormality underlying mood oscillations, these medications were found to have antikindling properties, offering a possible explanation for their pharmacological effects (Weiss and Post, 1998). Kindling is traditionally defined as an increase in seizure activity when a subthreshold stimulus is applied repeatedly to certain brain structures. In the kindling model repeated electrical stimulation "sensitizes" the cell to respond to less and less potent stimuli, or even to start firing independently without external stimulation ( Goddard et al., 1969). Kindling phenomena have been demonstrated in limbic structures like the amygdala ( Adamec and Cullen), that are implicated in stress response, fear, and potentially in PTSD symptoms. The mechanism of kindling may contribute to an exaggerated reaction to stressors, or consequently less stress might be needed to induce a major pathological response ( Adamec and Kalynchuk). Thus, it has been suggested that after exposure to traumatic events, limbic structures like the amygdala may become kindled or sensitized as a result of exaggerated noradrenergic input from locus ceruleus ( Post et al., 1997), producing exaggerated fear responses, mood instability, anger and aggression. Consequently, drugs known to have anticonvulsant and anti-kindling effects have been considered potential treatments for PTSD.

Only one controlled trial has been published, thus far, on the use of anticonvulsants in the treatment of PTSD. In a small sample study of 15 patients, lamotrigine was compared to placebo in a double blind fashion for a 12-week period (Hertzberg et al., 1999). The active medication was twice as effective, especially in the areas of re-experiencing, avoidance and numbing symptoms. Four open trials and several case reports have suggested the efficacy of carbamazepine, valproic acid, gabapentin and vigabatrin in treating some PTSD symptoms, although the sample sizes in these studies were small, ranging from one to 16 subjects ( Berigan; Brannon; Fesler; Ford; Lipper; Looff; Macleod and Wolf). Doses of carbamazepine in these reports were generally between 800 and 1000 mg, while valproic acid doses ranged from 1000 to 1500 mg. Both carbamazepine and valproic acid have side effects such as gastrointestinal disturbance, possible bone marrow suppression, pancreatitis and hepatitis, requiring periodic laboratory tests.

In sum, anticonvulsants may improve intrusive symptoms and emotional lability, while reducing hypervigilance and startle response. Agents like gabapentin that have been recently approved for the treatment of chronic pain, might be particularly useful in PTSD patients with chronic pain problems (a frequent comorbidity in subgroups of PTSD patients). Furthermore, since chronic pain mechanisms potentially involve amygdaloid pathways (which convey the emotional component of the pain) it is possible that these agents target pathophysiological processes involved both in PTSD and chronic pain. Novel anti-epileptic agents like topiramate that have been shown to inhibit kindling in animal models may also be effective in the treatment of PTSD.

8.3. Benzodiazepines

In the last 30 years, benzodiazepines replaced barbiturates as first line sedative and anxiolytic agents. They are safer, especially in overdose and, although they can be addictive, they have less abuse potential than the barbiturates. They are active in the widely distributed -aminobutyric acid (GABA) system which is a major inhibitory neurotransmitter system in the brain, where they potentiate GABA-ergic neuronal circuits.

These medications are possibly effective in the treatment of depression, but their anti-anxiety effect has a more rapid onset of action than any of the antidepressants. Dependence can develop in some patients, especially when the medication is used chronically leading to withdrawal which may be indistinguishable from the original symptoms, upon abrupt discontinuation. Benzodiazepine use in patients with past histories of substance abuse problems must be weighed against the potential benefit of the treatment.

One controlled trial was conducted using benzodiazepines in the treatment of PTSD. In that study, alprazolam (3.75 mg) was compared to placebo in a 5-week crossover design, with a 2-week washout between drug and placebo phases (Braun et al., 1990). Although overall anxiety ratings decreased on drug relative to placebo, no changes in core PTSD symptoms were observed. Shalev and colleagues have also reported a failure of clonazepam and alprazolam to suppress auditory startle responses in PTSD patients ( Shalev and Shalev) as well as a failure of early administration of these drugs (2–18 days post-trauma) to alter the course of PTSD symptoms over 6 months ( Gelpin et al., 1996). Mellman randomized 21 patients with PTSD symptoms to a 7-day course of temazepam or placebo within a month of sustaining traumatic injuries. Temazepam had no long term impact on sleep or PTSD symptoms after its discontinuation ( Mellman et al., 2000). Limited data suggest that clonazepam may be useful in the treatment of the severe dissociative symptoms often present in refractory PTSD ( Lowenstein et al., 1988); however, no other reports provided further support for this specific area of efficacy.

In sum, although benzodiazepines may seem a logical choice for the treatment of pervasive anxiety, there is little empirical support for their efficacy for specific PTSD symptoms. Furthermore, several factors suggest that initiation of benzodiazepine treatment in PTSD might require careful consideration, including the risk of abuse and the possibility that withdrawal from benzodiazepines can exacerbate PTSD symptoms (Risse et al., 1990). On the other hand, the abuse potential in other anxiety disorders has been overstated in the past ( Shader and Greenblatt, 1993), and should not constitute an absolute contraindication, thus depriving PTSD patients of a potentially helpful pharmacological agent. In fact, a recent study examined outcomes in PTSD patients who had a prior history of substance abuse. It found that while there was no clinical improvement in symptoms, patients treated with a benzodiazepine, did report a decrease in overall health care utilization ( Kosten et al., 2000).

9. Antipsychotic agents or neuroleptics ("major tranquilizers")

The typical antipsychotics (like haloperidol and chlorpromazine) were originally thought to improve psychotic symptoms by blocking D₂ receptors followed by decreasing dopamine activity in the CNS. Atypical antipsychotics, like olanzapine, clozapine or risperidone, differ from the older compounds, since they produce minimal or no extrapyramidal side effects, and at least in the case of clozapine, demonstrate improvement for both positive and negative symptoms of psychosis. More recently, neurobiological studies examined the role of the dopamine in amygdala and other limbic structures implicated in PTSD symptomatology, suggesting that dopaminergic transmission might have modulatory role in the function of these structures (Rosenkranz and Rosenkranz).

Typical neuroleptics have been readily used in the past in PTSD patients, due to a lack of diagnostic clarity and a lack of other efficacious pharmacological agents. Given few data supporting their benefit and their potentially serious side-effect profile, especially tardive dyskinesia, typical antipsychotic medication should probably not be considered a first-line treatment. Having stated this, these agents might be helpful for a particular symptom profile or patient subtype. For example, PTSD patients with extreme suspiciousness or aggressive paranoia, intense anger, self-destructive behavior, and frequent hallucinatory flashbacks may respond to a typical neuroleptic trial (Dillard and Walker). Mueser and Butler reported on five Vietnam veterans with PTSD and auditory hallucinations whose symptoms improved on typical anti-psychotics ( Mueser and Butler, 1987).

Given the advantages of the atypical neuroleptics, the use of these compounds in PTSD has been reexamined. In clinical situations where PTSD is comorbid with psychosis, these newer antipsychotics may represent a good pharmacological option. Hamner presented unpublished data from a 5-week double blind randomized control trial with 40 PTSD patients using risperidone (2.5 mg) versus placebo (Hamner et al., 2000). The Positive and Negative Syndrome Scale (PANSS) was the primary outcome measure, showing significant reduction in psychosis. The CAPS re-experiencing symptom subscale scores also improved.

Risperidone has been used to successfully treat four male patients with vivid flashbacks and nightmares, allowing them to participate in psychotherapeutic treatment (Leyba and Wampler, 1998). In addition, Krashin reported on risperidone's effectiveness in two case reports ( Krashin and Oates, 1999). Finally, Hamner also reported on a Vietnam veteran with both PTSD and Psychotic Disorder NOS whose psychotic and PTSD symptoms improved on 600 mg per day of clozapine ( Hamner, 1996).

Currently, there are ongoing studies examining the efficacy of both olanzapine and risperidone in the treatment of PTSD. An initial 10-week, double-blind study of 15 patients who were randomized to either olanzapine (5–20 mg/day) or placebo showed no between-group differences in treatment response (Butterfield et al., 2001). This might have been due to the small sample size (only 11 patients completed the study), the high placebo response in this sample which obscured any medication benefit, the chronicity in this cohort, or simply olanzapine is not effective in PTSD. Further study must be done to sort this out.

10. Adrenergic agents

The principle pharmacological action of adrenergic agents used in psychiatry is to modulate noradrenergic tone associated with arousal, anxiety, and panic symptoms. While often not a primary or "first line" psychopharmacological treatment, these agents can supplement and augment other psychiatric medications in the treatment of generalized anxiety, essential tremor and performance anxiety. In general, they are effective in anxiety disorders if the somatic symptoms are not too severe (Emilien and Maloteaux, 1998). Several open trials and case reports suggest their potential utility. One multiple-baseline case report on 11 sexually or physically abused children with PTSD found that propranolol (up to 2.5 mg/kg) was effective in decreasing PTSD symptoms ( Famularo et al., 1988). Similarly, van der Kolk reported that propranolol (120–160 mg) improved PTSD symptoms in 11 of 12 combat veterans and clonidine (0.2–0.4 mg), an ₂ agonist, improved PTSD symptoms in 8 of 9 combat veterans (van der Kolk, 1983). Other reports indicated similarly positive results with clonidine ( Harmon; Horrigan; Horrigan and Kinzie). Finally, prazosin, a centrally active ₁ antagonist improved combat trauma nightmares in 20 veterans and 5 civilians with PTSD (Raskind and Raskind)

In sum, several reports suggest efficacy of adrenergic agents in treating some PTSD symptoms, particularly nightmares and hyperarousal symptoms. Even more exciting are the very preliminary reports on the potential usefulness of adrenergic agents (like propranolol) for the prevention of PTSD in the early aftermath of traumatic events (Pitman et al., 2002). This study randomized recently traumatized patients to receive either 160 mg per day of propranolol or placebo for 10 days, and assessed these patients at follow-up one and three months after treatment. Although the CAPS score was lower in the treatment group, the results did not achieve statistical significance perhaps due to the small sample size of the study. Nonetheless, this is an important study, since the prevention of PTSD is an important therapeutic goal. There is a clear improvement in early hyperreactivity of physiologic measures which could result in a preventive effect on the future development of PTSD. With a number of other controlled studies currently underway, the use of adrenergic agents in PTSD treatment is likely to receive more attention in the near future.

11. Opiate antagonists

Originally used to treat opioid addiction or overdose, these medications may have a role in treating a number of psychiatric disorders, including PTSD. A number of investigators suggested that abnormalities in the endogenous opioid system might underlie PTSD symptomatology (Pitman et al., 1990) and high comorbidity between PTSD and substance abuse might also suggest involvement of common pathways in the pathophysiology of these disorders. These considerations raise the possibility that opioid antagonists might have a role in the treatment of PTSD . Preliminary evidence provides empirical support to these arguments with two studies reporting improved symptoms using nalmefene and naltrexone ( Bills and Glover). Clearly additional data is needed to assess the potential usefulness of opioidergic compounds in this condition.

12. Conclusion

The past decade brought new appreciation for the complexity and the heterogeneity of the clinical picture found in PTSD, as well as for the need for continued research to integrate effective treatments and to improve outcomes. While achieving complete remission or "cure" from PTSD symptoms through pharmacotherapy alone appears out of reach currently, numerous pharmacological agents are clearly effective in alleviating symptoms and facilitating recovery. To date the antidepressants appear to demonstrate the best overall efficacy for the treatment of PTSD, especially in patients with depression, sleep disturbance, or intrusive and hyperarousal symptoms. They might be less effective in the treatment of avoidance behavior; however, this has to be further studied. No data is available for differential efficacy between the SSRIs, the MAOIs or the TCAs. It is reasonable, therefore, to advocate the use of the SSRIs as a first line treatment, given positive results from several large controlled trials, their greater ease of use, lower risk in overdose, and perhaps fewer side effects. The mood stabilizers also show significant promise, especially for the treatment of impulsivity, irritability, and mood fluctuation. Although numerous case reports advocate their use either alone or in combination with antidepressants, additional controlled studies of these agents in PTSD are clearly needed. Benzodiazepines, commonly used in clinical practice for sleep problems, panic symptoms, and residual anxiety in PTSD patients have not been studied enough to draw conclusions regarding their efficacy for specific PTSD symptoms. In the little research available, they have not been shown to be effective. Similarly, there is very little data demonstrating efficacy of the newer or atypical neuroleptics in the treatment of PTSD; however they may provide an effective treatment strategy in patients with PTSD and psychosis. Given the potential serious side effects of typical neuroleptics, their use should be carefully considered, and, when possible, avoided. Adrenergic agents might hold some promise for the treatment of hyperarousal symptoms, in combination with other agents or alone, and they might prove beneficial during the early stage following the trauma. The other agents mentioned in this review should still be considered "experimental."

The future of psychopharmacology for PTSD holds much hope. Research will further clarify the efficacy and the utility of medications like the mood stabilizers, atypical neuroleptics, and newer antidepressants. Meanwhile, innovative treatments, for example, inositol and cyproheptadine (a serotonin/histamine antagonist), are already being tested (Guptae and Kaplan). Finally, a better understanding of the pathophysiology of PTSD and its risk factors like the effects of early trauma on corticotrophin releasing factor containing neural circuits, will ultimately allow the development of more specific pharmacological agents (like CRF antagonists) and even of early intervention and prevention strategies ( Heim et al., 1997).

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