Psychiatric Annals

CME Article 

A New Treatment Algorithm for Posttraumatic Stress Disorder

Jonathan Davidson, MD; Marcio Bernik, MD, PhD; Kathryn M. Connor, MD; Matthew J. Friedman, MD, PhD; Kenneth O. Jobson, MD; Yoshiharu Kim, MD, PhD; Yves Lecrubier, MD; Hong Ma, MD; Frank Njenga, MD; Dan J. Stein, MD, PhD; Joseph Zohar, MD

Abstract

Posttraumatic stress disorder (PTSD) is characterized by symptoms of intrusive thoughts and recollections, avoidance of reminders of the trauma, emotional numbing, and hyperarousal. The disorder occurs in approximately 8% of the United States population and follows a chronic course in up to 50%.1–3 According to the most recent major US epidemiological survey, active PTSD can last more than 20 years.3,4 Receipt of treatment is associated with an overall shorter course of PTSD.1

Existing PTSD treatment guidelines are based on reviews of the extent to which levels of evidence support particular treatments, but they do not address the all-important matter of treatment sequencing, or “what to do next” when the first treatment has failed to bring about remission or good response. Neither do they address the management of PTSD with comorbidities. Six major PTSD treatment guidelines are those published by the Expert Consensus Group,5 the International Society of Traumatic Stress Studies (ISTSS),6 the International Consensus Group for Depression and Anxiety,7,8 the American Psychiatric Association,8 the US Department of Veterans Affairs and Defense Joint Clinical Practice Guidelines,9 and the United Kingdom's National Center of Clinical Excellence (NICE).10

To address issues of treatment management, for which the levels of evidence typically diminish as one travels down the sequence or considers using drug combinations, there is need to develop treatment algorithms. Accordingly, we present this algorithm for the pharmacologic management of PTSD. At the outset, it is acknowledged that two distinct approaches are of proven benefit in PTSD: the pharmacologic and the psychosocial. Thus, the first choice to be made is whether to offer medication, psychotherapy, or both. Psychosocial treatments, if not used initially, can be added to or replace pharmacotherapy. However, with one exception,11 we are unaware of any empirical data to support the augmentation of medication with a psychosocial treatment.

In this algorithm, we provide a sequenced approach to the pharmacotherapy of PTSD, taking into account salient symptomatology and diagnostic comorbidity, levels of evidence (LOE; Table 1, see page 889), and extent of response. We also address special issues, including suicidality, comorbidity, ongoing trauma, treatment nonadherence, cultural considerations, issues relevant to women of childbearing potential, legal system involvement, and psychosocial treatment.

A range of traumas may precede PTSD (eg, interpersonal violence, motor vehicle accidents, natural disasters), and many are highly prevalent throughout the world. Given data that a significant number of cases of PTSD are underdiagnosed and undertreated, it is important to inquire about exposure to trauma and to maintain a high level of awareness of the disorder. Receipt of treatment is associated with an overall shorter course of PTSD (LOE 3).1

PTSD is associated with significant morbidity and comorbidity. Recent studies show greater levels of disability, use of welfare, use of prescription medication, and healthcare visits, as well as work impairment, with loss of as many as 4 working days per month.3,13,14 People with PTSD also demonstrate impaired resilience, exhibiting greater difficulty coping with stress and adversity when compared with the general population, primary care outpatients, and those with depression or other anxiety disorders.15 Increased rates of attempted suicide have been noted in PTSD, and the adverse physical health consequences related to PTSD are enormous.16,17 There also is mounting evidence that PTSD is a risk factor for medical illness.18 Among all anxiety disorders, PTSD was found to be the most costly with, among other things, substantial work loss or cutback.14

PTSD is poised to become a major public health problem worldwide.19 Projections from the World Health Organization suggest that, during the next 20 years, the global burden associated with PTSD will increase dramatically. Road traffic accidents, war-related injuries, and other violence…

Posttraumatic stress disorder (PTSD) is characterized by symptoms of intrusive thoughts and recollections, avoidance of reminders of the trauma, emotional numbing, and hyperarousal. The disorder occurs in approximately 8% of the United States population and follows a chronic course in up to 50%.1–3 According to the most recent major US epidemiological survey, active PTSD can last more than 20 years.3,4 Receipt of treatment is associated with an overall shorter course of PTSD.1

Existing PTSD treatment guidelines are based on reviews of the extent to which levels of evidence support particular treatments, but they do not address the all-important matter of treatment sequencing, or “what to do next” when the first treatment has failed to bring about remission or good response. Neither do they address the management of PTSD with comorbidities. Six major PTSD treatment guidelines are those published by the Expert Consensus Group,5 the International Society of Traumatic Stress Studies (ISTSS),6 the International Consensus Group for Depression and Anxiety,7,8 the American Psychiatric Association,8 the US Department of Veterans Affairs and Defense Joint Clinical Practice Guidelines,9 and the United Kingdom's National Center of Clinical Excellence (NICE).10

To address issues of treatment management, for which the levels of evidence typically diminish as one travels down the sequence or considers using drug combinations, there is need to develop treatment algorithms. Accordingly, we present this algorithm for the pharmacologic management of PTSD. At the outset, it is acknowledged that two distinct approaches are of proven benefit in PTSD: the pharmacologic and the psychosocial. Thus, the first choice to be made is whether to offer medication, psychotherapy, or both. Psychosocial treatments, if not used initially, can be added to or replace pharmacotherapy. However, with one exception,11 we are unaware of any empirical data to support the augmentation of medication with a psychosocial treatment.

In this algorithm, we provide a sequenced approach to the pharmacotherapy of PTSD, taking into account salient symptomatology and diagnostic comorbidity, levels of evidence (LOE; Table 1, see page 889), and extent of response. We also address special issues, including suicidality, comorbidity, ongoing trauma, treatment nonadherence, cultural considerations, issues relevant to women of childbearing potential, legal system involvement, and psychosocial treatment.

Levels of Evidence (LOE)*

Table 1:

Levels of Evidence (LOE)

The PTSD Algorithm Flowchart and are essential accompaniments to this article. The flowchart's basic structure is shown in the Figure (see page 890); the full interactive version may be downloaded from http://www.ipap.org/ptsd. The flow chart contains 30 informational nodes; clicking on a given node provides detailed information describing the treatment indications, response, and alternatives. A text file that includes the content of all nodes also is available in PDF format from the Web site. The is provided on pages 899–900.

The basic PTSD treatment algorithm flowchart.

Figure.

The basic PTSD treatment algorithm flowchart.

A list of the medications discussed in this article, with appropriate dosage ranges,12 is provided in Table 2 (see page 891).

Dose Increment Recommendations12

Table 2:

Dose Increment Recommendations12

Node 1

Diagnosis of PTSD

A range of traumas may precede PTSD (eg, interpersonal violence, motor vehicle accidents, natural disasters), and many are highly prevalent throughout the world. Given data that a significant number of cases of PTSD are underdiagnosed and undertreated, it is important to inquire about exposure to trauma and to maintain a high level of awareness of the disorder. Receipt of treatment is associated with an overall shorter course of PTSD (LOE 3).1

PTSD is associated with significant morbidity and comorbidity. Recent studies show greater levels of disability, use of welfare, use of prescription medication, and healthcare visits, as well as work impairment, with loss of as many as 4 working days per month.3,13,14 People with PTSD also demonstrate impaired resilience, exhibiting greater difficulty coping with stress and adversity when compared with the general population, primary care outpatients, and those with depression or other anxiety disorders.15 Increased rates of attempted suicide have been noted in PTSD, and the adverse physical health consequences related to PTSD are enormous.16,17 There also is mounting evidence that PTSD is a risk factor for medical illness.18 Among all anxiety disorders, PTSD was found to be the most costly with, among other things, substantial work loss or cutback.14

PTSD is poised to become a major public health problem worldwide.19 Projections from the World Health Organization suggest that, during the next 20 years, the global burden associated with PTSD will increase dramatically. Road traffic accidents, war-related injuries, and other violence — traumas widely associated with PTSD — are predicted to be among the top 12 causes of disability worldwide.20

The particular response to any traumatic event involves multiple factors, including the subjective reaction of the person and consequent symptom severity. Therefore, patients require individual assessment for exposure to trauma and response to the event.

The diagnostic criteria for PTSD, as put forth by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV),21 and by the International Classification for Disease, 10th edition (ICD 10),22 are presented in Sidebars 1 and 2 (see page 892).

Sidebar 1.

DSM-IV Diagnostic Criteria for PTSD21

  1. Traumatic stressor

    • An event, or events, in which an individual experiences, witnesses, or is confronted with life endangerment, death, or serious injury or threat to self or others; and
    • The individual responds to the experience with feelings of intense fear, horror, or helplessness.
  2. Re-experiencing symptoms (one or more)

    • Intrusive recollections; distressing dreams; flashbacks; dissociative phenomenon; psychological and physical distress with reminders of the event.
  3. Avoidance and numbing symptoms (three or more)

    • Avoidance of thoughts, feelings, or conversations associated with the event; avoidance of places, situations, or people that are reminiscent of the event; inability to recall important aspects of the event; diminished interest; estrangement from others; restricted range of affect; sense of a foreshortened future.
  4. Hyperarousal symptoms (two or more)

    • Sleep disruption; impaired concentration; irritability or anger outbursts; hypervigilance; exaggerated startle reaction
  5. Minimum symptom duration of 1 month

  6. Symptoms cause distress or functional impairment

Diagnostic Criteria for PTSD

  Specifiers:

Acute:  Symptom duration from 1 to 3 months

Chronic:  Symptom duration greater than 3 months

Delayed onset:  Symptom onset at least 6 months after the stressor

Sidebar 2.

ICD-10 Classification of Mental and Behavioral Disorders for PTSD22

  1. The patient must have been exposed to a stressful event or situation (either short- or long-lasting) of exceptionally threatening or catastrophic nature, which would be likely to cause pervasive distress in almost anyone.

  2. There must be persistent remembering of ‘reliving’ of the stressor in intrusive ‘flashbacks’, vivid memories or recurring dreams, or in experiencing distress when exposed to circumstances resembling or associated with the stressor.

  3. The patient must exhibit an actual or preferred avoidance of circumstances resembling or associated with the stressor which was not present before exposure to the stressor.

  4. Either of the following must be present:

    1. Inability to recall, either partially or completely, some important aspects of the period of exposure to the stressor;

    2. Persistent symptoms of increased psychological sensitivity and arousal (not present before exposure to the stressor), shown by any two of the following:

      1. Difficulty in falling or staying asleep.

      2. Irritability or outbursts of anger.

      3. Difficulty in concentrating.

      4. Hypervigilance.

      5. Exaggerated startle response.

  5. Criteria B, C, and D must all be met within 6 months of the stressful event or of the end of a period of stress. (For some purposes, onset delayed more than 6 months may be included, but this should be specified clearly.)

Classification of Mental and Behavioral Disorders for PTSD

Node 2

Other Clinical Considerations

At the initial assessment and at intervals during treatment, the clinician should consider other issues relevant to the patient with PTSD (as listed under “Consider at Each Stage” in the Figure). These issues are discussed in more detail in the article by Connor and Stein (see page 902).

Node 3

SSRI, SNRI, or TCA

Following a diagnosis of PTSD, the recommended first-line pharmacologic intervention is an SSRI (eg, sertraline, paroxetine, fluoxetine), based on strong Level 1 evidence.23–30 The starting dose can be low (eg, fluoxetine, 10 mg; sertraline, 25 mg; paroxetine, 10mg), reflecting a subset of patients with exaggerated sensitivity to somatic anxiety cues or the doses used in trials (eg, fluoxetine, 20mg.; sertraline, 25 to 50 mg; paroxetine, 20mg). While other drugs in these categories may be beneficial, there is a lack of controlled trials of citalopram31–32 and fluvoxamine33,34 (LOE 3) and, to date, no evidence on escitalopram (LOE 4). Paroxetine and sertraline are the only two approved, in some countries, for the treatment of PTSD.

Based on published data, statistically and clinically significant improvement often is seen with the SSRIs by weeks 2 to 4 in the major studies. One study noted a marked improvement in anger/irritability after one week on sertraline,35 which may be a useful prognosticator of eventual response (LOE 1).36 An adequate trial requires 6 to 12 weeks, although the early part may be at a subtherapeutic dose while tolerance to side effects is being established. The clinician should expect to see some response after 4 to 6 weeks at an adequate dosage.

Two recent large trials suggest promise for the SNRI venlafaxine. The results are published as of this date only as abstracts.37,38 Hypertensive and other cardiovascular side effects, particularly at high doses, may be a limitation. Small trials of the noradrenergic and specific serotonergic antidepressant (NaSSA) agent mirtazapine (LOE 2, 3)39,40 also show efficacy in PTSD. However, a study of bupropion (LOE 2) showed no difference between the drug and placebo.41

The older antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), are of demonstrated efficacy in combat veterans with PTSD (LOE 2).42,43 In locations where formulary or cost considerations preclude the use of SSRIs or SNRIs, the tricyclics imipramine or amitriptyline may be considered first-line treatments in adults. Aside from two trials of reversible MAOIs with mixed results in civilians and combat veterans (LOE 1),43,44 the TCA and MAOI drugs have not been studied in controlled trials in civilian samples, in part because of the advent of the SSRIs in recent years. Issues of toxicity also have been a concern with these drugs, in terms of cardiotoxicity, seizure risk, and anticholinergic effects with the TCAs and dietary restrictions and risk of hypertensive crisis with the MAOIs. Considering the levels of evidence in the face of their safety profiles, we do not recommend MAOIs as first-line treatments.

One clear advantage of the antidepressants is their well-established efficacy in treating major depression and other anxiety disorders, which frequently are comorbid with PTSD. However, as noted above, these drugs can be associated with troublesome side effects. For example, common side effects with the SSRIs include nausea, loose stools, headache, insomnia, and agitation with initial treatment, as well as weight gain and sexual dysfunction over the long term.

However, when there is a partial response despite an optimum trial of medication, it may be useful to consider an augmenting agent. At least in depression, even among responders residual symptoms are common and are associated with greater likelihood of relapse. Few controlled studies have compared augmentation strategies with switching medications directly,46 although both seem effective in around 50% of cases.47,48 Augmentation offers the advantage of retaining any possible gains from the first agent but the potential disadvantages of polypharmacy (eg, more side effects, drug interactions).47 The addition of psychotherapy to pharmacotherapy for depression also may be considered in this context.49,50

Node 4

Response

Response to treatment after a 12-week trial is described as adequate, partial, or nonresponse. These levels of response are defined as follows:

  • Adequate response: at least a 50% improvement in symptoms or a rating of 2 (much improvement) or better on the Clinical Global Impressions of Improvement scale (CGI-I).51
  • Partial response: 25% to 50% reduction in symptoms.
  • Nonresponse: minimal (less than 25%) or no improvement; very little reduction in symptoms.

After 3 to 6 months of treatment or longer, many patients will attain a state of remission, indicated by at least a 70% reduction in symptom severity relative to pretreatment (ie, “70% better”) and is considered to be the treatment goal for PTSD. Clinical remission would correspond to a CGI-I score of 1.

After 12 weeks of treatment, many patients will experience improvement, with at least a 50% reduction in symptoms. However, further improvement often is noted with continued treatment, with additional improvement in the core PTSD symptoms, disability, and overall functioning. Three studies have demonstrated robust relapse-prevention effects for sertraline52 and fluoxetine53,54 when these treatments are continued for 1 year (LOE 1). After 6 months, a 70% reduction in symptoms is expected, representing a state of remission. If symptoms persist and this goal is not attained, refer to subsequent nodes, according to the symptoms present. Because chronic PTSD has a tendency to relapse or deteriorate in as many as 50% of patients if treatment is stopped, we recommend continuation of medication for at least 1 year (LOE 1).

Node 5

Do Some Symptoms Remain Unresponsive?

At this stage, the clinician is advised to assess whether only certain symptoms remain unresponsive or if all symptoms are still partially nonresponsive. If the former, then augmentation may be appropriate (see Node 7). If the latter, then Node 6 applies. If there is complete non-response, then Node 8 applies.

Node 6

Adjust to Maximum Tolerated Dose

If there is a partial response to an adequate dose of an SSRI (eg, 150 mg sertraline, 40 mg fluoxetine), suggesting that the initial treatment was somewhat helpful but the clinical response was less than adequate, the dose should be titrated to the maximum suggested dose (eg, 200 mg sertraline, 50 mg paroxetine, 60 mg fluoxetine) (Table 2).

Node 7

Augment According to Salient Symptoms

After 4 to 6 weeks of treatment with an appropriate dose of an SSRI, if there is a partial response, the clinician should assess ongoing symptoms and treat accordingly with augmentation by a second agent. For example, insomnia or nightmares may be treated with prazosin (LOE 2), trazodone (LOE 3), nefazodone (LOE 2),55 imipramine (LOE 2), or amitriptyline (LOE 2) in low doses. Any of these treatments can benefit not only sleep disturbance but also other aspects of PTSD (LOE 2). Additional information for managing persistent insomnia is given in Node 15. In some instances, while there are no published guidelines, the clinician may choose to increase the dose and augment simultaneously. It is important to establish that symptoms are not due to anxiogenic effects of treatment, however.

Most clinical trials with medication for PTSD have tested the efficacy of monotherapy. Indeed, with the exception of trials with atypical antipsychotics and prazosin, no clinical trials have systematically evaluated the relative effectiveness of different augmentation strategies. Therefore, our recommendations for augmentation strategies for partial responders are extrapolations from monotherapy trials. An alternative option would be to persist at the same (therapeutic) dose, in the expectation that response may eventually occur beyond 12 weeks.

Node 8

Switch Within SSRI Class or Between Classes

After failure of response (ie, less than 25% improvement) to an SSRI, with core PTSD symptoms persistent after 4 to 6 weeks with an adequate dose, the clinician should switch to another SSRI, SNRI, NaSSA, TCA, or prazosin (an α-1 adrenergic antagonist). An alternative would be to augment the same medication with another pharmacotherapeutic agent, even though there are very limited data on augmentation and none on switching to SNRI/NaSSA or SNRI to NaSSA (all LOE 4). Further, data are not available regarding whether a sequential trial of a second SSRI is as effective as switching to an SNRI or NaSSA after the first unsuccessful SSRI trial. Depending on the severity of the clinical situation, some clinicians may decide to increase the dose and wait longer before switching to another class or augmenting.

Node 9

Response After 6 to 12 Weeks?

If the dosage is already at the maximum and symptoms persist after 6 to 12 weeks, it may be appropriate to introduce a second treatment, while maintaining the initial medication as prescribed. The next course of action will be determined by the presence or absence of specific symptoms and comorbidities, including the persistence of core PTSD symptoms (eg, intrusion, avoidance, numbing, hyperarousal), sleep disturbances, psychotic symptoms, bipolar spectrum disorder, and substance abuse. Sometimes the choice of an augmentation agent may be driven more by clinically significant symptoms, as illustrated by the recommendations for insomnia, psychosis, and substance abuse (Nodes 15, 20, and 24).

Here, the empirical basis for choosing one agent over another is not very solid. Therefore, the following suggestions are based more on clinical lore and known pharmacologic actions. For example, patients exhibiting excessive arousal, hyperreactivity, and, possibly dissociation, might benefit from the addition of an antiadrenergic agent. Patients exhibiting aggressive, impulsive, or labile behavior might benefit from an anticonvulsant or mood stabilizer. Fearful, paranoid, hypervigilant, and psychotic patients might benefit from an atypical antipsychotic. Treatment success (or failure) will be determined by the adequacy of the clinical response and side effects.

Node 10

Inadequate Response of Core PTSD Symptoms

If there is inadequate response of core PTSD symptoms to 6 to 12 weeks of treatment with a maximum recommended and tolerated dose of an SSRI (eg, 60 mg fluoxetine, 200 mg sertraline; Table 2), the clinician should switch, for example, to another SSRI or to an SNRI, or from an SNRI to an NaSSA, or to a tri-cyclic drug or prazosin. However, at present, there are no published data on any of these strategies (LOE 4). Further, data are not available as to whether a sequential trial of a second SSRI is as effective as switching to an SNRI or NaSSA after the first unsuccessful SSRI trial.

Node 11

Response (See Node 4 for definitions)

Node 12

Augmentation With Medication or CBT

Most clinical trials with medication for PTSD have tested the efficacy of monotherapy with one pharmacologic agent or another. Indeed, with the exception of trials with atypical antipsychotics, no clinical trials have systematically evaluated the relative effectiveness of different augmentation strategies. Therefore, our recommendations for augmentation strategies for partial responders are extrapolations from monotherapy trials. For example, if a patient fails to respond to an SSRI, we recommend augmentation with an agent that has proven itself as an effective monotherapy or augmentation agent. As a result, our first recommended set of options for augmentation includes TCAs, prazosin, and atypical antipsychotics. Lack of responsiveness to such medications might suggest further augmentation with an agent for which the level of evidence is less strong, such as anticonvulsants, clonidine, guanfacine, or propranolol.

Sometimes the choice of an augmentation agent will depend on the presence of comorbid disorders. The presence of comorbid affective or anxiety disorders would suggest use of a medication that is effective for both PTSD and for that disorder (eg, an antidepressant for comorbid PTSD and depression).

Partial response may be managed by augmentation, particularly for aggression, with prazosin (LOE 2), divalproex sodium (LOE 3), risperidone (LOE 2), or lamotrigine (LOE 2), for insomnia/nightmares, or by atypical antipsychotics such as trazodone (LOE 3) risperidone (LOE 2), olanzapine, or quetiapine (LOE 3); buspirone (LOE 3); tiagabine (LOE 4); beta-blockers (LOE 4); or α2 adrenergic agonists (LOE 4) for anxiety/agitation. Benzodiazepines can be used cautiously for panic in patients without substance abuse histories (LOE 4). No data exist as to the effects of benzodiazepines in augmentation treatment, although some data exist suggesting lack of efficacy for monotherapy with alprazolam in chronic PTSD (LOE 2).56 Nonetheless, on occasion, benzodiazepines may be used adjunctively with other pharmacotherapy (LOE 4). Tiagabine monotherapy was also no different from placebo in one study (LOE 2),57 but its use in augmentation or for sleep disturbance may be considered (LOE 4). Bupropion appears to be ineffective (LOE 2).41 Trazodone may be effective (LOE 3),58 and if all else fails, phenelzine can be considered in certain cases (LOE 2).43 Addition of cognitive-behavior therapy and prolonged exposure (PE) were found to enhance response in patients who had shown only partial improvement on sertraline (LOE 2).11

Node 13

Response (See Node 4 for definitions)

Node 14

Switch to TCA or MAOI, Add Third Medication, or Re-evaluate Diagnosis; Consider Psychosocial Treatment

If the patient has failed to achieve an adequate response, there are other options to consider, although data to support all of these recommendations are not available (LOE 4). These include switching to a TCA (LOE 2)42 or MAOI (LOE 2)43 or adding a third medication from the list in Node 12. Note that before initiating treatment with an MAOI, attention should be paid to the need for the appropriate medication-free period, if the patient has been receiving another antidepressant.

Efficacy also has been shown for repetitive transcranial magnetic stimulation (rTMS) to the right dorsolateral prefrontal cortex in PTSD (LOE 2).59

For psychosocial therapy, see the article by Connor and Stein (page 902).

Node 15

Inadequate Response With Persistent Insomnia, Nightmares

Sleep disruption characterized by insomnia and nightmares is a core symptom of PTSD. The sleep disturbance or nightmares often persist despite treatment with some SSRI agents and may even be exacerbated by these medications.35,60 Under such circumstances, we recommend first assessing lifestyle factors, such as over-the-counter medications or heavy caffeine use, that may be contributing to the sleep disturbance. The addition of the α1-adrenergic antagonist prazosin can be quite effective in ameliorating nightmares and insomnia in PTSD (LOE 2, 3).61,62 Hypotension, syncope, and tachycardia are potential side effects with prazosin; therefore, the patient's predisposition to and risk from hypotension should be considered and blood pressure should be monitored. In addition, it may take some time to build up to a therapeutic dose (4 to 9 mg), and little is known about the metabolism of prazosin or its effects on the cytochrome P450 isoenzyme system.

Other pharmacologic options for which there is considerably less evidence (all LOE 4) but which may be of benefit include trazodone, low-dose sedating tricyclics, mirtazapine, olanzapine, quetiapine, or zolpidem; tiagabine at night also is an option.42,63–67 The role of the benzodiazepines here is less clear, and while they may be helpful in reducing hyperarousal symptoms during treatment, they do not appear to confer any additional benefit with respect to the course of PTSD when given in the immediate post-trauma period for acute stress disorder (LOE 2, 3).68,69

One nonpharmacologic approach that has shown promise in decreasing nightmares and in improving overall PTSD symptom severity is imagery rehearsal therapy (LOE 1).70

Node 16

Response (See Node 4 for definitions)

Node 17

Switch Within Group or Switch to Atypical Antipsychotic

If the response remains inadequate, consider switching to another augmenting agent within the same class or to an atypical antipsychotic (LOE 4).

Node 18

Response (See Node 4 for definitions)

Node 19

Consider Obstructive Sleep Apnea, Restless Leg Syndrome, or Other Sleep Disorders and Re-evaluate Diagnosis; Consider Psychosocial Therapy

In the event of continued poor response, polysomnography may be indicated to evaluate for suspected sleep-related breathing disorders and periodic limb movement disorders.71 If obstructive sleep apnea is confirmed, then treatment with continuous positive airway pressure is indicated (LOE 4). If the test does not reveal an obvious cause, an alternative drug may be selected from the above list.

For psychosocial therapy, see the article by Connor and Stein (page 902).

Node 20

Inadequate Response With Comorbid Psychosis

It is important to distinguish between psychotic symptoms that are part of the PTSD complex versus those that signify a comorbid psychotic disorder. For the former, antiadrenergic, SSRI, and anticonvulsant drugs often are beneficial (LOE 4). Failure to respond would then call for addition of an atypical antipsychotic. Indeed, fearful, paranoid, hyper-vigilant and psychotic patients might benefit from atypical antipsychotics. If, on the other hand, PTSD is comorbid with a psychotic disorder, then augmentation with atypical antipsychotics should be considered from the beginning.

Psychotic features may be found in as many as 40% of PTSD patients,72 with commonly reported symptoms including hallucinations, delusions, and paranoid ideation. In many cases, these individuals may not respond adequately to SSRIs. As a result, much of the work done in the area has focused on augmentation of SSRIs with atypical antipsychotics.

The presence of psychotic symptoms that are part of PTSD would call for addition of an atypical neuroleptic, with evidence being limited so far to risperidone (LOE 2), olanzapine (LOE 3), and quetiapine (LOE 3), studies of which appear largely limited to combat veterans,65,66,73,74 with only one study in civilians.72 Further, the evidence is mixed, in that some drugs may have not always separated from placebo76 or have done so only on limited dimensions (eg, psychotic symptoms74 or sleep and mood65).

Inadequate response to the first atypical antipsychotic could be followed by switching to a different medication in the same class. If that fails, then diagnostic re-evaluation is suggested. The specific atypical neuroleptic should be chosen after considering the risk of side effects such as weight gain, aggravation of diabetes, metabolic syndrome, hyperlipidemia, or hyperprolactinemia. Flashbacks, hypervigilance/paranoia, and dissociation can all manifest with psychotic features. For these, antiadrenergics and anticonvulsants are believed to be beneficial (LOE 4).

PTSD remains a very challenging disorder to treat effectively and often requires the use of more than one psychotropic medication, with atypical antipsychotics being used increasingly. Mellman77 found that 17% of a statewide Medicaid PTSD population had received this form of treatment, a rate which was even higher when depression was also present. There is also growing evidence for efficacy of atypical antipsychotics as adjunctive treatments in PTSD (LOE 3). Thus, it is important to recognize their role in managing the disorder. While the new-generation antipsychotics are less likely to produce extrapyramidal and acute cardiovascular side effects, as compared with the older generation drugs, there is concern about other problems, in particular weight gain, hyperglycemia, hyperlipidemia, diabetes, and long-term cardiac effects via the metabolic syndrome. Careful monitoring is therefore essential, and attention to recently published guidelines on the use of these drugs is recommended.78

Node 21

Response (See Node 4 for definitions)

Node 22

Change Antipsychotic or Add Mood Stabilizer or Anticonvulsant

If the response remains inadequate, consider switching to another antipsychotic or adding a mood stabilizer or anticonvulsant (LOE 4).

Node 23

Response (See Node 4 for definitions)

Node 24

Inadequate Response With Comorbid Depression, Anxiety, or Stable Bipolar Disorder

Comorbid depression, anxiety, and bipolar disorder are found commonly in association with PTSD. Common presentations in bipolar patients with PTSD may include mood lability, irritability, and aggression. In addition, in some instances, antidepressants used to treat PTSD may precipitate hypomania or mania in those predisposed to bipolar disorder. If the symptom picture suggests bipolar spectrum disorder, which also can be associated with PTSD, we recommend addition of either a mood stabilizer or anticonvulsant or an atypical neuroleptic.

In terms of anticonvulsants and mood stabilizers, divalproex sodium/valproic acid, carbamazepine, topiramate or lamotrigine have been reported as efficacious in PTSD without comorbid bipolar features,7,58,79–83 again largely in combat veteran populations. There is no evidence (LOE 4) for their use in PTSD with comorbid bipolar disorder. Alternatively, we would consider the use of atypical antipsychotics at this stage, even in the absence of supportive literature (LOE 4), given that the drugs separately are of benefit in bipolar disorder and in PTSD when associated with psychosis or mood disorder. Of note, some mood stabilizers and atypical neuroleptics may require periodic laboratory monitoring (eg, blood levels of carbamazepine and valproic acid, and, for certain atypical neuroleptics, fasting lipid profile and fasting blood sugar).

The sequence of treatment will depend upon which syndrome is clinically the most salient. For stabilized bipolar disorder, untreated PTSD will need addressing. Unstable bipolar disorder will need treatment first. For persistent PTSD with severe depression, it also is possible that electroconvulsive therapy may have value (LOE 4).

For persistent PTSD with other anxiety disorders, we recommend augmentation with treatments of proven or suggested efficacy in the specific disorder. Examples include hydroxyzine, buspirone, trazodone, or benzodiazepines for generalized anxiety disorder (LOE 4); clonazepam, olanzapine, or levetiracetam for social anxiety disorder (LOE 4); and clomipramine or atypical antipsychotics for obsessive-compulsive disorder (LOE 4).

Node 25

Response (See Node 4 for definitions)

Node 26

Switch or Add from Within Group

If the response remains inadequate, consider switching to another drug within this group or to adding another drug within this group (see Node 24; LOE 4).

Node 27

Response (See Node 4 for definitions)

Node 28

Re-evaluate Diagnosis; Consider Psychosocial Therapy

If response remains inadequate, consider diagnostic re-evaluation.

For psychosocial therapy, see the article by Connor and Stein (page 902).

Node 29

Continuation for At Least 1 Year If Good and Stable Response

Node 30

Psychosocial Treatment May Be Considered at Any Time

Summary

Treating PTSD requires selecting an appropriate first-line treatment, deciding on length of treatment, and knowing when and how to change to another approach. The algorithm presented in this article provides sequential choices to decide whether to persist longer at the highest tolerated dose, augment with a second agent, or switch to another treatment. There is a need to evaluate levels of response (full, partial, or nonresponse), as well as to decide whether partial response is generalized to all PTSD symptoms or limited to select symptoms. Treatment strategies may then be based on which scenario is present. Issues of comorbidity and diagnostic reevaluation must be considered as well.

References

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Addendum. International Psychopharmacology Algorithm Project PTSD Algorithm

GENERAL PRINCIPLES

  • Initial and Repeated Evaluations (Sidebar 2)

    1. PTSD is common and often goes undiagnosed. Given the high prevalence of exposure to trauma (including domestic violence), a trauma exposure history is important.

    2. The initial evaluation should use DSM-IV or ICD-10 criteria. Given that most research on PTSD in general, and on pharmacotherapy in particular, has used DSMIV criteria, these may be especially useful.

    3. The initial evaluation should include a thorough psychiatric assessment, medical history, and, when appropriate, referral for laboratory or medical evaluation.

    4. Initially and repeatedly (at any time of inadequate responses), consider ongoing trauma, key symptoms associated with PTSD that change management (eg, suicide risk, psychotic symptoms, insomnia, nightmares), comorbid psychiatric illness (eg, depression, bipolar disorder, other anxiety disorders, substance abuse), other possible diagnoses, treatment nonadherence, and litigation issues.

    5. Patients with bipolar disorder should be stabilized before introducing an antidepressant for PTSD. Similarly, other comorbid disorders (eg, psychotic disorders) may need to be addressed first before treatment for PTSD is begun. In other cases, however, the treatment for PTSD may also be effective for the comorbid disorder and can be begun at the same time.

    6. Standardized symptom rating scales are useful tools for baseline and later assessment.

  • Choice of Treatment: Medication, Psychosocial, or Both

    1. Initial treatment can be either pharmacotherapy or psychotherapy. Patient preference or special skills of the clinician should influence this choice. Comorbidity may influence the type of medication or psychotherapy prescribed and may also influence the choice of whether to use medication versus psychotherapy.

    2. Both approaches have been shown to be efficacious, and each has certain advantages and disadvantages.

  • Acute Stress Disorder Versus PTSD

    In the immediate aftermath of a traumatic event, the vast majority of the population will exhibit significant distress. For most, such symptoms will subside within the first 4 weeks, and often within the first 10 to 14 days. Therefore, pharmacologic (or psychosocial) treatment generally should be withheld from all but the most symptomatic and incapacitated people within this period. Supportive measures and psychological first aid are the treatments of choice for such distress during the immediate posttraumatic aftermath.

    1. Treatment of chronic PTSD is better understood than is treatment of acute stress disorder or acute PTSD.

    2. While many clinicians are likely to believe that the same types of treatment benefit acute stress disorder and acute PTSD (ie, less than 3 months), there are very few studies of treatment in these conditions. With respect to acute stress disorder, there is good evidence that cognitive-behavior therapy is effective for both symptom amelioration and prevention of the later onset of PTSD. Only a few preliminary studies on pharmacological interventions for acute stress disorder have been done. With respect to acute PTSD, there is no reason to delay treatment for people who meet diagnostic criteria.

  • Medications and Adequacy of Response (Sidebar 1)

    1. Patients with PTSD who are going to be treated with medication should, with few exceptions, be prescribed an SSRI or SNRI as their first medication.

    2. The response time for treatment of PTSD with an SSRI is generally 4 to 12 weeks. One expects at least a partial response by 4 to 6 weeks with adequate dosage. It is assumed that an adequate or maximally tolerated dose will have been given throughout this recommended period or time. In our present state of knowledge, we cannot say whether it is better to increase the dose, augment, or switch when there has been insufficient response. Clinicians may wish to keep their options open as to their preferred approaches. It is also the case that response can take longer than 12 weeks, as was noted for a cohort of subjects treated with sertra-line, in whom 55% of partial responders at 12 weeks had converted to full responders by 35 weeks.84

    3. Some patients may demonstrate an initial worsening when starting treatment. In some cases this may be due to activating/anxiogenic effects of the SSRIs. In other instances, it may be related to discussion of the trauma and uncovering previously unaddressed feelings and thoughts associated with the trauma.

    4. The patient who has an excellent response to the SSRI should generally be treated for a minimum of 1 year.

    5. Benzodiazepines are not recommended as monotherapy and can be harmful in the first few months after trauma. Because a number of antidepressants have been shown to be effective for generalized anxiety and panic, they should be considered before prescribing benzodiazepines. Furthermore, there are no published studies demonstrating efficacy of benzodiazepines in PTSD. If a clinician chooses to prescribe these medications as augmentation for residual comorbid anxiety (eg, generalized anxiety disorder, panic), they should be used as adjuvants only when there is not a history of substance abuse.

    6. At each point of evaluating nonresponse, we recommend diagnostic re-assessment, as well as checking for treatment nonadherence.

  • Managing Side Effects

    1. Patients with anxiety disorders, including those with PTSD, often experience greater sensitivity to medication side effects and may need a slower dosage titration than used in other patients, such as in depression.

    2. When patients only respond partially or fail to respond, it is important to consider whether the symptom presentation represents an inadequate response to the drug or medication side effects.

    3. Metabolic and general cardiovascular side effects can occur from antipsychotic medication, as may be the case for some patients with chronic PTSD who are receiving these drugs. This includes glucose dysregulation leading to type II diabetes or worsening of previously controlled diabetes, weight gain, abdominal adiposity, increased triglycerides, or increased total cholesterol and LDL cholesterol. Appropriate monitoring of the metabolic profile is recommended, in accordance with current recommendations.

    4. There is the possibility of untoward drug–drug interactions, for example, those mediated by inhibition or induction of the cytochrome P450 enzyme system. With increased rates of comorbid medical illness, there is greater likelihood that a patient with PTSD will be taking other medications. Clinicians are therefore encouraged to become familiar with the more important interactions as they apply to the medications prescribed to treat PTSD.

  • Social Support

    1. Social support is considerably reduced in PTSD,16 and attention should be paid to this as an important element in the recovery process.85 Brewin et al.86 have noted lack of social support to be the single most important predictor of risk for developing PTSD after trauma.

  • Placebo response

    1. Sometimes an initial rapid response that fades may be indicative of a “placebo” or “nonspecific” response, as has been suggested in the depression literature. We do not know to what extent this is the case for PTSD, or how it would be best managed. Some hold that under these circumstances, a medication switch would be preferable to augmentation, but there are no data to inform on this issue.

  • Cost–benefit considerations

    1. Cost is often an important consideration in drug selection. However, cost of medication must be viewed more broadly as part of a cost–benefit equation, as “cheaper” drugs may have more frequent side effects that bring additional cost burdens. Because of the variability in medication costs from one country to another, we do not make any specific recommendations about this issue. Related is the issue of risk–benefit, which should also be a consideration in drug selection.

Levels of Evidence (LOE)*

1More than one adequately powered placebo-controlled trial (n = 30 per group or greater).
2One or more small placebo-controlled trials of monotherapy, combination, or augmentation therapy.
3Case series or open-label trials.
4Either no published evidence or presence of clinical consensus.

Dose Increment Recommendations12

DrugStarting Dose (mg/day)Maximum Dose (mg/day)Dose Increments*
Selective serotonin/norepinephrine reuptake inhibitors
Sertraline25200Increase to 50 mg within a week; subsequently, 25 or 50 mg every 1 to 2 weeks
Paroxetine IR+10 to 205010 to 20 mg every 2 weeks
Venlafaxine XR37.5300Increase to 75 mg within 1 week; subsequently, 37.5 or 75 mg every 2 weeks
Fluoxetoine+106010 or 20 mg every 2 weeks
Fluvoxamine+5030050 or 100 mg every 2 to 4 weeks
Citalopram206020 mg every 2 weeks
Escitalopram5 or 10205 or 10 mg every 2 weeks
Tricyclic antidepressants
Amitriptyline+25 or 50300Increase to 50 mg by 1 week; subsequently, 25 or 50 mg every 1 to 2 weeks
Imipramine+25 or 50300Increase to 50 mg by 1 week; subsequently, 25 or 50 mg every 1 to 2 weeks
Other antidepressants
Mirtzazpine156015 mg every 2 weeks
Trazodone+50 or 100400Increase to 100 mg after 1 week; subsequently, 50 or 100 mg every 2 weeks
Phenelzine3090Increase to 45 mg after 1 week; subsequently, 15 mg every 2 weeks
Mood stablizers/anticonvulsants
Valproic acid/divalproex+5002,000500 mg every 2 weeks according to toxicity or plasma level (where available)
Carbamazepine+4001,600200 mg every 2 weeks and by plasma level (where available)
Lamotrigine25400Increase to 50 mg after 2 weeks; subsequently, 50 mg every 2 weeks (see product label for recommended schedule in the presence of valproic acid or other anti-convulsants)
Topiramate12.5 or 2550025 mg every 2 weeks (or 50 mg at the upper dose ranges)
Atypical antipsychotics
Olanzapine2.5 or 5202.5 or 5 mg every 1 to 2 weeks
Risperidone0.530.25 or 0.5 every 1 to 2 weeks
Quetiapine2530025 or 50 every 1 to 2 weeks
Adrenergic Inhibitors
Clonidine0.10.60.1 or 0.2 mg every 1 to 2 weeks
Guanfacine131 mg every 2 weeks
Prazosin1 to 2
Propranolol20 to 4016020 to 40 mg every 3 to 4 days

Sidebar 1.

DSM-IV Diagnostic Criteria for PTSD21

  1. Traumatic stressor

    • An event, or events, in which an individual experiences, witnesses, or is confronted with life endangerment, death, or serious injury or threat to self or others; and
    • The individual responds to the experience with feelings of intense fear, horror, or helplessness.
  2. Re-experiencing symptoms (one or more)

    • Intrusive recollections; distressing dreams; flashbacks; dissociative phenomenon; psychological and physical distress with reminders of the event.
  3. Avoidance and numbing symptoms (three or more)

    • Avoidance of thoughts, feelings, or conversations associated with the event; avoidance of places, situations, or people that are reminiscent of the event; inability to recall important aspects of the event; diminished interest; estrangement from others; restricted range of affect; sense of a foreshortened future.
  4. Hyperarousal symptoms (two or more)

    • Sleep disruption; impaired concentration; irritability or anger outbursts; hypervigilance; exaggerated startle reaction
  5. Minimum symptom duration of 1 month

  6. Symptoms cause distress or functional impairment

Diagnostic Criteria for PTSD

  Specifiers:

Acute:  Symptom duration from 1 to 3 months

Chronic:  Symptom duration greater than 3 months

Delayed onset:  Symptom onset at least 6 months after the stressor

Sidebar 2.

ICD-10 Classification of Mental and Behavioral Disorders for PTSD22

  1. The patient must have been exposed to a stressful event or situation (either short- or long-lasting) of exceptionally threatening or catastrophic nature, which would be likely to cause pervasive distress in almost anyone.

  2. There must be persistent remembering of ‘reliving’ of the stressor in intrusive ‘flashbacks’, vivid memories or recurring dreams, or in experiencing distress when exposed to circumstances resembling or associated with the stressor.

  3. The patient must exhibit an actual or preferred avoidance of circumstances resembling or associated with the stressor which was not present before exposure to the stressor.

  4. Either of the following must be present:

    1. Inability to recall, either partially or completely, some important aspects of the period of exposure to the stressor;

    2. Persistent symptoms of increased psychological sensitivity and arousal (not present before exposure to the stressor), shown by any two of the following:

      1. Difficulty in falling or staying asleep.

      2. Irritability or outbursts of anger.

      3. Difficulty in concentrating.

      4. Hypervigilance.

      5. Exaggerated startle response.

  5. Criteria B, C, and D must all be met within 6 months of the stressful event or of the end of a period of stress. (For some purposes, onset delayed more than 6 months may be included, but this should be specified clearly.)

Classification of Mental and Behavioral Disorders for PTSD

Educational Objectives

  1. Describe the first choice for treatment of posttraumatic stress disorder (PTSD).

  2. Discuss the sequencing of treatment for PTSD in the context of level of response.

  3. Explain the sequencing of treatment for PTSD in terms of symptomatology.

Authors

Dr. Davidson is director, Anxiety and Traumatic Stress Program, Department of Psychiatry, Duke University School of Medicine, Durham, NC. Dr. Bernik is director, Anxiety Disorders Program, Sao Paulo University, Sao Paulo, Brazil. Dr. Connor is research director, Anxiety and Traumatic Stress Program, Duke University School of Medicine. Dr. Friedman is executive director, National Center for Post-Traumatic Stress Disorder, Veterans Administration Medical Center, White River Junction, VT, and professor of Psychiatry and of Pharmacology, Dartmouth Medical School, Hanover, NH. Dr. Jobson is chairman, International Psychopharmacology Algorithm Project (IPAP), and clinical faculty member, Department of Psychiatry, University of Tennessee, Memphis, TN. Dr. Kim is director, Department of Adult Mental Health, National Institute of Mental Health of Japan, National Center of Neurology and Psychiatry, Tokyo, Japan. Dr. Lecrubier is director of research, French National Institute of Health and Mental Research, Paris, France. Dr. Ma is deputy director, National Center for Mental Health, China Center for Disease Control and Prevention, Beijing, China. Dr. Njenga is chairman, Kenya Psychiatric Association, and president, African Association of Psychiatrists and Allied Professions, Nairobi, Kenya. Dr. Stein is chairman, Department of Psychiatry, Cape Town University School of Medicine, Cape Town, South Africa. Dr. Zohar is director, Israeli PTSD Committee, and professor of psychiatry, Tel Aviv University Medical School, Tel Aviv, Israel.

Address reprint requests to: Jonathan Davidson, MD, Box 3812, Duke University Medical Center, Durham, NC 27710.

Dr. Davidson receives grant/research support from, serves on the Speaker's Bureau for, and serves as a scientific advisor to Pfizer, Solvay, GlaxoSmithKline, Wyeth, and Forest; receives grant/research support from and serves as a scientific advisor to Eli Lilly, Organon, AstraZeneca, Johnson & Johnson, Janssen, Bristol Myers Squibb, and UCB; receives grant/research support from PureWorld, Allergan, Nutrion 21, Cephalon, Parke Davis, Pharmacia, Upjohn, Schwabe, and Merck; and serves as a scientific advisor to Ancile, Roche, MediciNova, Jazz, Novartis, Boehringer Ingelheim, MedTap, Boots, Sanofi-Synthelabo, Alexza, and Brain Cells. Dr. Bernik receives grant/research support from Wyeth and Roche. Dr. Connor receives grant/research support from Eli Lilly, Forest, and GlaxoSmithKline; serves on the Speakers' Bureau for Ortho-McNeil, Pfizer, Wyeth, Cephalon, Predix, and Jazz; serves as a consultant to Ortho-McNeil, Pfizer, Schwarz Pharma, King, Cephalon, Predix, and Jazz; and receives other financial/material support from Schwabe, Nutrition 21, Cephalon, Nordic, Solvay, and Allergan. Dr. Zohar receives grant/research support from Lundbeck and Pfizer and serves as a scientific advisor to Pfizer. Dr. Lecrubier serves as a consultant to Eli Lilly, Sanofi, GlaxoSmithKline, Pfizer, and Pierre Fabre. Dr. Stein receives grant/research support from and/or serves as a consultant to AstraZeneca, Eli Lilly, GlaxoSmithKline, Lundbeck, Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo, and Wyeth. Drs. Friedman, Jobson, Kim, Ma, and Njenga have no industry relationships to disclose.

10.3928/00485713-20051101-04

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