Pharmacological Treatments for PTSD

(1)

U.S. Department of Veterans Affairs, National Center for PTSD, White River Junction, VT, USA

(2)

Departments of Psychiatry and Pharmacology & Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA

Keywords

Human stress (fight-or-flight) responseGeneral adaptation syndromeAmygdalaAdrenergic systemSerotonergic systemHypothalamic–pituitary–adrenocortical (HPA) systems

This chapter answers the following

How does the human stress response occur?—This section details the neurobiology involved in the “Fight, Fright, or Freeze” reaction as well as in the “General Adaptation Syndrome.”
What psychobiological abnormalities occur in those with PTSD?—This section covers abnormalities in the brain function and structure as well as alterations in the adrenergic, HPA, and serotonergic systems.
How can medications best be used to treat PTSD?—This section discusses specific medications available for PTSD treatment and their efficacy as well as treatment strategies.

Medical treatments for PTSD target abnormalities in the multiple biological systems involved with a person’s response to stress. This section reviews:

Psychobiology of the body’s general response to stress

Abnormalities in the human stress response associated with PTSD

Specific medication treatments that target these abnormalities

Corresponding efficacy research

How Does the Human Stress Response Occur?

Through evolution, humans have acquired a number of biological mechanisms for coping with the many different kinds of stressors normally encountered in the course of a lifetime. The most important brain structures involved in the stress response are the amygdala, hippocampus, and prefrontal cortex.

The amygdala is the part of the brain that processes emotional input, especially the strong emotional reactions associated with exposure to a traumatic event. It is the ignition switch that plays a key role in coordinating the response to threat or stress. It mobilizes a number of cortical and subcortical brain mechanisms, initially through activation of corticotropin releasing factor (CRF). CRF activates two major components of the human stress response—the “Fight, Flight, or Freeze” reaction and the “General Adaptation Syndrome.”

The hippocampus plays a major role in learning and memory and is involved in converting short-term to long-term memory. It provides a mental map or context for remembering traumatic events.

The medial prefrontal cortex (mPFC) regulates emotion and arousal. It is the major brain structure that can exert restraint on the amygdala.

Key Definitions

Adrenergic response—Neuronal activation mediated by either norepinephrine (noradrenaline) or epinephrine (adrenaline)

Amygdala—Principal nucleus in the brain for appraising emotional input and threatening stimuli and then mobilizing protective, defensive, or escape behavior

Cortisol—A hormone that increases energy by raising blood glucose levels, decreases immune processes, and causes other metabolic and neurobiological actions

HPA axis—Three anatomic structures that participate collectively in the hormonal response to stress: the hypothalamus (in the brain), the pituitary gland, and the outer layer (cortex) of the adrenal gland

Neurotransmitters—Chemical messengers that transmit signals from one nerve cell to another to elicit physiological responses

Postsynaptic neuron—The downstream neuron that is the target of neurotransmission

Presynaptic neuron—The neuron that initiates neurotransmission by releasing the neurotransmitter into the synaptic cleft

Receptors—Membrane-bound protein molecules with a highly specific shape that facilitates binding by neurotransmitters or medications

Selective serotonin reuptake inhibitors (SSRIs)—Medications that enhance serotonergic activity, some of which have proven effective in PTSD treatment.

Sympathetic nervous system (SNS)—Part of the autonomic nervous system that regulates arousal functions such as heart rate and blood flow

Synaptic cleft—The space between one neuron and the next that must be traversed by neurotransmitters

Fight, Flight, or Freeze Reaction

This reaction refers to the amygdala’s mobilization of the brain’s adrenergic system and the SNS. SNS mechanisms are activated in response to a threat [1]. During this reaction, the heart pumps more blood to the muscles, which enables them to perform defensive (“fight”), escape (“flight”), or hiding (“freeze”) movements necessary for survival. This reaction begins in the brain via a complex array of neurobiological mechanisms that have evolved to detect danger, experience fear, and to set off a sequence of adaptive, defensive, escape, and hiding responses.

Several important brain and SNS chemicals ( neurotransmitters) that relay signals from one neuron to the next mediate the fight, flight, or freeze response, called an adrenergic response because norepinephrine and epinephrine are also called noradrenaline and adrenaline. Adrenergic agents augment or attenuate such responses in the brain, heart, blood vessels, and elsewhere.

Although the fight, flight, or freeze response was described more than 80 years ago with regard to the SNS and muscle activity, we now understand how the amygdala, hippocampus, mPFC, and other brain structures react to threat and activate other neurobiological responses. When faced with a dangerous or stressful situation, the amygdala releases CRF, which activates the neurons in the locus coeruleus—a small cluster of nerve cells that contain most of the brain’s adrenergic neurons. Locus coeruleus neurons activate brain centers (such as the hypothalamus, hippocampus, and cerebral cortex) that mediate arousal, emotional reactivity, and memory as well as the SNS, which instigates the fight, flight, or freeze response [2–5]. This same hormone (CRF) activates an additional response to stress—the General Adaptation Syndrome.

The General Adaptation Syndrome

The general adaptation syndrome is the second major system that responds to stress [6]. It is a hormonal rather than a neurotransmitter response and focuses on the HPA axis.

The hypothalamus—A small, midline nucleus on the underside of the brain—releases CRF into the bloodstream, which carries it rapidly to the nearby pituitary gland, provoking the release of adrenocorticotropic hormone (ACTH). ACTH is then carried by the blood stream to the adrenal gland (perched atop the kidney), which releases cortisol. Cortisol has been called the “stress hormone” because blood cortisol levels are elevated during the normal human response to stress.

Many other neurobiological systems also participate in the human stress response, including the immunological system, the thyroid system, and other neurotransmitter and hormonal systems [2–5, 7].

The neurotransmitter, serotonin, is intimately involved in both adrenergic and HPA activity. It also facilitates inhibition of amygdala activity. Primarily located in the brainstem raphe nuclei, which have abundant reciprocal interactions with the adrenergic and many other brain neurotransmitter HPA systems, serotonin can facilitate the human stress response. Figure 5.1 depicts major brain areas involved in this response.

Fig. 5.1

Human stress response. These areas of the brain mediate the human stress response diagrammed below. CRF corticotropin releasing factor, NE norepinephrine, LC/NE locus coeruleus-norepinephrine, ACTH adrenocorticotropic hormone. Source: Diagram adapted from and reprinted with permission of Chrousos and Gold (1992)

As we come to increase our understanding of alterations in the human stress response associated with PTSD, it opens up the realistic possibility that newer and more effective pharmacological agents will be identified that target the unique psychobiological abnormalities associated with PTSD. Such medications will most probably not be traditional antidepressants or anxiolytics, but pharmacological agents that act on key components of the human stress response. For example, CRF antagonists might be expected to be effective; we look forward to research with such medications. Another possibility is a medication that enhances neuropeptide Y, a neuropeptide produced in the brain that antagonizes the actions of CRF. Its actions suggest another class of medications to test, as are other neuropeptides that affect these mechanisms [8, 9].

Since the systems affected by PTSD are key psychobiological mechanisms, advances in our basic understanding of human learning, memory, coping, and adaptation will accompany progress in this field.

What Psychobiological Abnormalities Occur in Those with PTSD?

In the normal stress response, the amygdala becomes acutely activated in reaction to threat. It mobilizes adrenergic, HPA, and other stress-induced activity. Later, when the danger has passed, the amygdala returns to its normal baseline functioning, probably due, in part, to mPFC restraint. Our current model of PTSD, however, is a stress response that doesn’t know when to quit. It is like a perfect storm in which the amygdala remains in a state of excessive arousal while the mPFC is unable to exercise its usual restraint (see Fig. 5.2). This model predicts that any medication that either reduces amygdala activity or increases mPFC activity would be expected to be effective for treating PTSD.

The psychobiology of PTSD is complicated. Research indicates that adrenergic HPA and serotonergic systems as well as CRF function abnormally in people with PTSD. Other PTSD-related psychobiological abnormalities involve thyroid, opioid, immunological, and other neurotransmitter, neuropeptide, or neurohormonal systems. This chapter focuses only on the major systems altered PTSD on which currently utilized pharmacological agents have the most influence. As we learn more about different brain mechanisms that PTSD affects, new medications will evolve to act on systems other than the adrenergic and serotonergic. Indeed, some medications, traditionally used to treat seizure disorders (e.g., antiepileptic drugs) have also been tested in PTSD. These medications exert their actions on the glutamatergic and GABA systems which are the brain’s major excitatory and inhibitory systems, respectively (see below). More detailed information on the psychobiology of the human stress response can be found elsewhere [2–5].

Adrenergic System

For those with PTSD, it appears that the adrenergic (and SNS) system is much more active than in normal individuals. The most dramatic illustrations of this finding are experiments with psychological and pharmacological probes.

Psychological probe—A visual or auditory stimulus reminiscent of a traumatic experience to which a person with PTSD is exposed

Pharmacological probe—A drug that can activate psychobiological mechanisms involved in the stress response

A typical psychological probe for a motor vehicle accident survivor with PTSD (such as Mary T. described in Chapter 2) may be the sound of a large truck or the squeal of brakes, the sight of a truck crashing into a car, or someone reciting details of a similar accident [10, 11]. Under such conditions, Mary T. would experience excessive SNS activation exhibited by a rise in blood pressure, a racing heart rate, and other physiological indications of heightened SNS physiological activity. She also experiences excessive amygdala and adrenergic activity in her brain.

From the Patient’s Perspective

I’ve been on the medication for 3 weeks now. I really didn’t want to take it, but Dr. Owen convinced me that it might help me function better. It’s really getting a lot easier to get behind the wheel of the car. I still don’t like the trucks, but at least I can deal with them now. Therapy is really helpful. I can handle the memories a lot better and have begun to discover things that happened after the crash that I had completely forgotten. It’s also easier to concentrate, and I can sit at the computer for a few hours. Dr. Owen wants me to consider easing back to work on a part–time basis. I don’t think I’m ready, but I’ll give it a try if she thinks I should.

Such physiological abnormalities can also cause abnormal elevations of blood or urinary norepinephrine as well as increased activation of the amygdala, locus coeruleus, and other brain centers. Mary T. may also experience abnormalities in the brain’s normal blood flow; these include increased blood flow to the amygdala and reduced circulation to the mPFC and hippocampus. Motor vehicle accident survivors who do not develop PTSD do not exhibit this heightened reactivity of adrenergic mechanisms in the SNS and brain.

A typical pharmacological probe is yohimbine, which causes excessive firing of adrenergic neurons [12]. Research with yohimbine has shown that the adrenergic system is abnormally sensitive in PTSD. Indeed, giving an intravenous dose of yohimbine to Mary T. might provoke a panic attack or even a flashback of the truck crashing into her car. Yohimbine does not produce such a response in people without PTSD. Yohimbine can even affect blood flow in the brain, thereby demonstrating the abnormal adrenergic sensitivity of those with PTSD [13].

HPA System

People with PTSD have shown a variety of HPA abnormalities, including elevated cerebrospinal CRF levels and abnormal serum and urinary cortisol levels (although study results are mixed) [2, 3, 5].

Although there is general agreement that those with PTSD have a significantly altered HPA system, there are a number of scientific controversies regarding the precise nature of HPA abnormalities. There is also evidence that people who develop PTSD have vulnerable HPA systems and that the traumatic event unmasked a biological abnormality that impairs their capacity to cope with catastrophic stress [14].

Serotonergic System

Research with the serotonergic system in PTSD is at a much more preliminary stage than that with adrenergic or HPA mechanisms. It appears, however, that serotonin plays an important modulatory role on both systems, and is a key component of the human stress response. Clinical studies show abnormalities in serotonergic mechanisms in PTSD patients [2, 3, 5].

Neurotransmission

Medications used to treat PTSD modify neurotransmission in serotonergic and adrenergic neurons. Neurons communicate by releasing neurotransmitters into the synaptic cleft. The presynaptic neuron packages, releases, and delivers the neurotransmitter into the synapse, where it can diffuse across to the postsynaptic neuron. Neurotransmitters attach to a specific postsynaptic receptor. The neurotransmitter forms a temporary binding complex with the receptor, analogous to a “lock-and-key” formation. The binding of the neurotransmitter to the receptor results in a chemical change that leads to a biological response, such as a behavior, thought, or reaction.

After their presynaptic release, most neurotransmitters are subsequently reabsorbed by a specialized reuptake site located on the presynaptic neuron. The reuptake mechanism is selective for serotonin, or norepinephrine, respectively. Various medications affect different parts of the neurotransmitter system. These include:

SSRIs
Tricyclic antidepressants ( TCAs)
Venlafaxine
Monoamine oxidase inhibitors ( MAOIs)

A recent chapter entitled, “Pharmacotherapy for PTSD,” offers a comprehensive review of PTSD pharmacology [15].

Fig. 5.2

Key brain structures in fear conditioning and PTSD

Figure 5.3, below, illustrates how the most common antidepressants work and what effects they produce. For more detailed information on these and other medications used to treat PTSD, review the following section.

Fig. 5.3

Mechanisms of action for different medications

How Can Medications Best Be Used to Treat PTSD?

In view of the great success of cognitive behavioral therapy ( CBT) (see Chap. 4), pharmacotherapy is only one of several treatment options for PTSD patients. Medication may be a good choice when [16]:

Patient acceptability of such an approach is high.
Comorbid conditions are present that are responsive to pharmacotherapy (e.g., depression, panic disorder, social phobia, obsessive-compulsive disorder).
CBT treatment is unavailable.

Figure 5.4, on the following pages, summarizes the current clinical literature on pharmacological trials. It provides information on medication class, specific medication, therapeutic dose range, clinical indications, and contraindications.

Fig. 5.4

Medications for PTSD—indications and contraindications (^aModified from Friedman and Davidson (2014) [15])

Of all medications tested, only two, both Selective Serotonin Reuptake Inhibitors (SSRIs) are approved by the FDA for the treatment of PTSD ( paroxetine and sertraline). SSRIs are considered the first-line treatment for PTSD because they [17–20]:

Have broad-spectrum effects against all PTSD symptom clusters
Are effective against many comorbid disorders
Are effective against associated symptoms, such as impulsivity, aggression, and suicidal thoughts

Venlafaxine which produces presynaptic blockade of both serotonin (like an SSRI) and norepinephrine, is also a first-line treatment for PTSD. It is a serotonin/norepinephrine reuptake inhibitor (SNRI) [21, 22].

Second-line medications include mirtazapine, prazosin, MAOIs, and TCAs, Evidence favoring the use of these agents is not as compelling as evidence for using SSRIs or venlafaxine because of the lower number of participants tested.

Other medications included in the Fig. 5.4 include antiadrenergic agents and atypical antipsychotics. Laboratory research indicates a strong rationale for considering antiadrenergic agents; however, only the postsynaptic alpha-1 receptor antagonist, prazosin, has been shown to be effective so far and there remain questions about whether this effectiveness is limited to reduction of traumatic nightmares and improvement of insomnia or whether it is effective against all PTSD symptoms. There will need to be more extensive testing to establish the usefulness of other antiadrenergic agents for PTSD patients [15, 23].

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