3 курс / Фармакология / Essential_Psychopharmacology_2nd_edition

FIGURE 9 — 3. One theory about the biological basis of panic disorder is that there is an excess of norepinephrine, causing intermittent and chaotic discharge of noradrenergic neurons from the locus coeruleus.

of yohimbine administration is an exaggerated response in panic disorder patients, including the precipitation of overt panic attacks. Caffeine is also panicogenic. That is, caffeine is an adenosine antagonist and can be synergistic with norepinephrine. When panic patients are given the caffeine equivalent of four to six cups of coffee, many experience a panic attack, whereas most normal subjects do not panic. On the other hand, panic patients have a blunted physiological response to postsynaptic adrenergic agonists, perhaps as a consequence of an overactive noradrenergic system. Thus, there may be a dysregulation in the noradrenergic system, with changes in the sensitivity of noradrenergic neurons and their receptors altering their physiological functioning and contributing to the pathophysiology of panic attacks.

GAMMA AMINOBUTYRIC ACID (GABA) The neurotransmitter GABA and its allosteric modulation by benzodiazepines have also been implicated in the biological basis of panic disorder. That is, it appears that the ability of benzodiazepines to modulate GABA is out of balance. This may be due to changes in the amounts of endogenous benzodiazepines (i.e., "the brain's own Xanax" or "Valium-like compound"), or to alterations in the sensitivity of the benzodiazepine receptor itself.

Very little is known about endogenous benzodiazepine ligands, so most of the emphasis has been placed on investigating the responsivity of the benzodiazepine receptor in panic disorder patients. Nevertheless, it is possible that the brain makes less than the necessary amount of an endogenous full agonist and thus has less ability to decrease anxiety on its own owing to a postulated deficiency in a naturally occurring benzodiazepine full agonist. Alternatively, it is possible that the brain is producing an excess in anxiogenic inverse agonists, causing the panic disorder patient

350Essential Psychopharmacology

to have more anxiety and panic attacks due to such a postulated and unwanted increase in a naturally occurring benzodiazepine inverse agonist.

These are just theoretical possibilities, but some data do actually suggest an abnormality in the benzodiazepine receptor in panic disorder patients, in which the "set point" is shifted toward the inverse agonist conformation (Fig. 9—4). Conceptually, the resting state of the GABA-A—benzodiazepine—chloride channel receptor complex is shifted to the left in the agonist spectrum already discussed (see Fig. 7 — 25). Thus, chloride channel conductance is already too diminished due to an altered sensitivity of the benzodiazepine receptor site (Fig. 9—4). Evidence for this comes from the fact that such patients require administration of exogenous benzodiazepine ligands (i.e., real Xanax [alprazolam] or real clonazepam) to reset the receptor complex's set point back to normal. Also, flumazenil, which is neutral and without behavioral effects in normal subjects because it acts as a relatively pure antagonist, can act differently in panic disorder patients. In these patients, some but not all studies suggest that flumazenil acts as an inverse agonist, perhaps via an abnormal shift of the set point to the right, toward an inverse agonist conformation. Thus, whereas flumazenil acts as an antagonist with no behavioral effects in normal subjects, it acts as a partial inverse agonist in panic patients and provokes panic attacks in these patients.

CHOLECYSTOKININ (CCK) The tetrapeptide CCK causes more panic attacks when infused into patients with panic disorder than it does in normal volunteers, which suggests increased sensitivity of the brain type of CCK receptor, known as CCK-B. Unfortunately, in early investigations CCK-B antagonists did not appear to be effective for panic disorder. Nevertheless, agents with novel pharmacological mechanisms of action are sometimes evaluated for their potential antipanic actions by testing whether they can block CCK-induced panic attacks.

Respiratory hypotheses

CARBON DIOXIDE AND LACTATE HYPERSENSITIVITY Another theory regarding

the biological substrate for panic disorder proposes that panic attacks are a result of abnormalities in respiratory function. This theory is based on observations that panic disorder patients experience panic attacks more readily than normal control subjects after exercising, when breathing carbon dioxide, or when given lactate. This has generated a theory of carbon dioxide hypersensitivity or lactate hypersensitivity in panic disorder patients, with a corollary hypothesis that panic patients demonstrate these findings because they are chronic hyperventilators. Lactate may induce panic because it is a potent respiratory stimulant, and panic disorder patients may be more sensitive to agents that promote respiratory drive.

FALSE SUFFOCATION ALARM THEORY This theory proposes that panic disorder patients have a suffocation monitor located in the brainstem, which misinterprets signals and misfires, triggering a "false suffocation alarm" (panic attack). Many factors are consistent with this hypothesis, including the above-mentioned theory ot chronic hyperventilation and carbon dioxide hypersensitivity. The disorder of Ondine's curse (congenital central hypoventilation syndrome) appears to be virtually the opposite of panic disorder and is characterized by a diminished sensitivity of the

FIGURE 9—4. Another theory about the biological basis of panic disorder is an abnormality in the set point for benzodiazepine receptors. Perhaps the sensitivity of these receptors is switched to the left in this spectrum, rendering the receptors less sensitive to full agonists and experiencing antagonists as inverse agonists.

suffocation alarm, causing sufferers from this disorder to lack adequate breathing, especially when asleep. These various observations support the existence of a distinct suffocation monitor, which is overly sensitive in panic disorder and not sensitive enough in Ondine's curse. According to this theory, spontaneous (i.e., unexpected)

352Essential Psychopharmacology

panic attacks are thought to be mediated by this mechanism whereas chronic anxiety or fear is not.

Neuroanatomic findings. Positron emission tomography (PET) scans of patients experiencing a panic attack suggest abnormalities of neuronal activity projections to the hippocampus, possibly causing asymmetry of metabolic activity. Animal studies suggest that the locus coeruleus appears central to modulation of vigilance, attention, and anxiety or fear. Thus, hypersensitivity of the limbic system has been considered a possible etiology or mechanism mediating panic disorder. Few human studies have been conducted, but lactate-sensitive patients with panic disorder have been found to have abnormal hemispheric asymmetry of parahippocampal blood flow on PET scans. Also, patients with temporal lobe epileptic foci frequently experience panic-like symptoms; however, only an extremely small minority of panic disorder patients have been found to have abnormal electroencephalograms. Nevertheless, the ictal seizure-like analogy may be useful, for panic may be tantamount to seizure-like neuronal activation in parts of the brain that mediate emotions, whereas true epilepsy may involve locations in the brain mediating movement and consciousness rather than emotions of anxiety and panic (see Figs. 4—19 and 4—20).

Since there are both noradrenergic projections to the hippocampus from the locus coeruleus and serotonergic projections to the hippocampus from the raphe, it is possible that dysregulation of these projections may account for neurophysiological

abnormalities hypothesized to occur in panic attacks. Changing the outputs of these monoamine neurotransmitter systems to the hippocampus may also explain the ther apeutic actions of various antidepressants that reduce panic attacks (see Figs. 5-26 and 5-54).

v

Treatments

Figure 9 — 5 shows the variety of options for treating panic disorders.

Serotonin selective reuptake inhibitors. Many medications originally developed or used in treatment of depression have been found to be effective in treating panic disorder, especially the SSRIs. The documentation of efficacy for panic disorder and of the safety of these agents has now made them first-line treatments for this condition. Since many patients have coexisting depression and panic disorder, SSRIs can treat both conditions in the same patient at the same time. Each of the five SSRIs (fluox- etine, paroxetine, sertraline, fluvoxamine, and citalopram) has advantages and disadvantages for individual patients with panic disorder. However, all SSRIs have been shown to be about equally effective in large-scale studies and to take on average 3 to 8 weeks before benefit may be noticed (about the same time as it takes antidepressants to work). Patients with panic disorder tend to be more sensitive to SSRIs (and indeed to all antidepressants) than are depressed patients, since they can easily develop jitteriness or even short-term worsening of their panic when treatment is initiated. Thus, panic patients usually start at a lower dose than depressed patients. Doses must generally be increased to the same or greater levels as antidepressants over time and as tolerated (see Table 9—9). The five SSRIs are all discussed in detail in Chapter 6.

FIGURE 9-5. Shown here are the variety of therapeutic options for treating panic disorder.

Table 9-9. SSRI profile for panic/social phobia and PTSD

Usual starting dose is lower than the starting dose for depression due to activating symptoms

Panic and other target symptoms may therefore get worse before they get better Maintenance doses will be higher than starting doses, and may need to be higher than

usual antidepressant doses, particularly for paroxetine. Onset of action is usually 2 to 8 weeks. Usual response is more than 50% reduction of symptoms, especially in combination with

other treatments such as benzodiazepines, trazodone, or cognitive behavioral psychotherapy.

Newer antidepressants. Although the SSRIs are the only antidepressants formally approved for the treatment of panic disorder, recent evidence suggests that several other antidepressants are promising treatments for panic disorder as well. These include nefazodone, venlafaxine XR, mirtazapine, and reboxetine. Bupropion, however, does not seem to have apparent antipanic actions. Since the documentation of efficacy of these newer antidepressants in panic disorder is still emerging, they tend to be used as second-line therapy after SSRIs fail to improve panic or in patients who cannot tolerate them.

Tricyclic antidepressants. Imipramine and clomipramine have been the most extensively studied of the tricyclic antidepressants and both have demonstrated efficacy in treating panic disorder. Other tricyclic antidepressants that have shown some evidence of efficacy include desipramine, doxepin, amitriptyline, and nortriptyline.

354 Essential Psychopharmacology

The tricyclics have few or no overall advantages compared with SSRIs, although occasionally a patient will respond to a tricyclic and not to an SSRI. The tricyclics have disadvantages that make them secondor third-line treatments for panic disorder, including anticholinergic side effects, orthostatic hypotension, and weight gain (due to actions at receptors discussed in Chapter 6).

Monoamine Oxidase (MAO) Inhibitors. The classical irreversible MAO inhibitors are effective in treating panic disorder, with anecdotal observations suggesting that they may be even more effective than imipramine. Clinical experience with reversible inhibitors of MAO A (RIMAs) (see Chapter 6) is also favorable for the treatment of panic disorder. However, the RIMAs may be somewhat less effective than the irreversible MAO inhibitors, but this is not well established. The disadvantages of the MAO inhibitors make them secondor third-line treatments for panic disorder; these include orthostatic hypotension, weight gain, sexual dysfunction, and dietary restrictions (low tyramine diet), with the potential for a tyramine-induced hypertensive crisis. The RIMAs appear safer, with lessened potential for side effects, as discussed in Chapter 6, but also possibly with less efficacy.

Benzodiazepines. Benzodiazepines have become adjunctive treatment to antidepressants (particularly SSRIs), especially for long-term treatment when dependence on benzodiazepines can become problematic. The primary advantage to using benzodiazepines is rapid relief from anxiety and panic attacks. As already mentioned, antide-pressants have a delayed therapeutic onset. The disadvantages of benzodiazepines include sedation, cognitive clouding, interaction with alcohol, physiological dependence, and the potential for a withdrawal syndrome. Misinformation and stigma about the benzodiazepines can prevent patients from accepting appropriate treatment with these agents and can prevent clinicians from prescribing them.

High-potency benzodiazepines (alprazolam, clonazepam) generally are more effective in panic disorder than low-potency benzodiazepines (diazepam, lorazepam, etc.). Although less research has been done on the low-potency benzodiazepines, it is generally accepted that they frequently result in sedation prior to adequately relieving panic attacks. The reader is referred to the discussion of benzodiazepines in Chapter 8 for a detailed overview of mechanism of action. A critique of the issues of benzodiazepine dependence and appropriate use is given in Chapter 13.

Currently, many physicians adopt a "benzodiazepine-sparing strategy" by using benzodiazepines when necessary but conservatively. That is, benzodiazepines can often be helpful when treatment is initiated or when a rapid-onset therapeutic effect is desired. They can also help improve the short-term tolerability of SSRIs by blocking the jitteriness and exacerbation of panic sometimes observed when initiating treatment with an SSRI or other antidepressant. Benzodiazepines can also be useful to "top up" the patient's treatment on an as-needed basis for sudden and unexpected decompensation or short-term psychosocial stressors. Finally, if a patient is not fully responsive to an antidepressant or combinations of antidepressants, longterm treatment with concomitant benzodiazepines and antidepressants may become necessary to effect full or adequate control of symptoms. Sometimes, once symptoms are suppressed for several months to a year, the benzodiazepine can be slowly discontinued and the patient maintained long-term on the antidepressant alone. The consequences of inadequate treatment of panic disorder can be very severe loss of social and oc-

cupational functioning, as well as suicide, and must be weighed as the risk/benefit ratio for benzodiazepine treatment is calculated for each patient individually.

Alprazolam has been researched more extensively than any other benzodiazepine in panic disorder, and is very effective. Because of its short duration of action, it generally must be administered in three to five daily doses. Clonazepam, which has a longer duration of action than alprazolam, has also been investigated in panic disorder. It can generally be administered twice a day. Clonazepam is reported to have less abuse potential than alprazolam and to be easier to taper during discontinuation owing to its longer half-life.

Cognitive and behavioral psychotherapies. Cognitive and behavioral psychotherapies are commonly combined in the treatment of panic disorder with or without agoraphobia. Cognitive therapy focuses on identifying the cognitive distortions and modifying them, whereas behavioral therapy specifically attempts to modify a patient's responses, often through exposure to situations or physiologic stimuli that are associated with panic attacks. Behavioral therapy appears to be most effective in treating the phobic avoidance aspect of panic disorder and agoraphobia and does not appear as effective in treating the panic attacks. These treatments have had as high a rate of effectiveness as have the antipanic drugs. Furthermore, for those who are able to complete an adequate period of behavioral treatment, their improvements are perhaps more likely to be sustained after discontinuing treatment than are druginduced improvements after discontinuation of antipanic drugs.

-----

Combination therapies. The term combination therapy can refer either to combinations of two drugs or to combinations of antipanic drugs with cognitive-behavioral psychotherapy (Fig. 9—6). Combining two drugs for the treatment of panic disorder remains an underdeveloped approach, since few studies have been made comparing single-mode and combination therapy. However, as in the treatment of depression (discussed extensively in Chapter 7), common clinical practice for treating many panic disorder patients is indeed the artful choosing of combinations of available treatments. Tailoring a treatment program to the individual patient is becoming the state of the art, although such combinations are generally inadequately investigated in controlled clinical trials. Figure 9 — 6 summarizes various options for combination treatments of panic disorder.

DRUG COMBINATIONS Probably the most common combination treatment is concomitant use of an SSRI and a benzodiazepine, especially on initiation of treatment (Fig. 9 — 6). The benzodiazepines (especially alprazolam and clonazepam) not only appear to act synergistically to increase the onset of therapeutic action and perhaps even boost the efficacy of SSRIs, but they also appear to block the anxiogenic actions of the SSRIs and lead to better tolerability as well as the ability to attain therapeutic dosing levels for the SSRIs. Sometimes sedative-hypnotics such as zale-plon or zolpidem are required in addition to an SSRI, especially on initiation of SSRI treatment.

Some of the same augmentation strategies discussed in detail in Chapter 7 for the treatment of depression, mentioned above for the treatment of OCD, can also be applied to the treatment of panic disorder. Thus, adding the 5HT2A antagonist trazodone to an SSRI can boost the actions of an SSRI, as possibly also could the

FIGURE 9—6. Various treatments can be given in combination for panic disorder (i.e., panic combos). The basis of all many combination treatments is a serotonin selective reuptake inhibitor (SSRI). Other antidepressants such as venlafaxine, nefazodone, mirtazapine, tricyclic antidepressants, and monoamine oxidase inhibitors can all have antipanic actions, although they are second-line treatments, as are the benzodiazepines. On the other hand, benzodiazepines are often added to SSRIs, particularly at the initiation of an SSRI and intermittently when there is breakthrough panic. Cognitive and behavioral psychotherapies can also be added to any of these drug treatments.

combination of mirtazapine with an SSRI (heroic combo in Fig. 9—6). Other medication combinations include some of the newer antidepressants whose efficacy in panic is being documented now (including venlafaxine, nefazodone, and mirtazapine) with a benzodiazepine (Fig. 9 — 6). Even tricyclic antidepressants and MAO inhibitors have a role in treating panic disorder, especially when other antidepressants or combination fail and possibly in combination with a benzodiazepine (Fig. 9 — 6).

COGNITIVE-BEHAVIORAL PSYCHOTHERAPY COMBINATIONS WITH ANTIPANIC

DRUGS Virtually any antipanic agent can be combined with cognitive-behavioral therapy in well selected patients. Many clinicians consider some patients to be so anxious or depressed or disabled initially that they are unable to participate in or receive much benefit from psychotherapy, so these patients are sometimes excluded from psychotherapy until their symptoms improve somewhat on medication. Other therapists may believe that benzodiazepines interfere significantly in cognitivebehavioral therapy, since a certain amount of anxiety must be present for behavioral therapy to be effective. Until conclusive data are reported, there is no contraindication for using combination therapy, and there may be additional benefit. Nevertheless, the combination of drugs and behavioral therapy must be individualized for the case at hand.

Relapse after medication discontinuation. Relapse rates after discontinuation of antidepressants in the treatment of major depressive disorder have been much more thoroughly studied than have relapse rates of panic disorder in patients discontinued from antipanic agents. Although panic disorder can frequently be in remission within 6 months of beginning treatment, on the basis of existing studies, the relapse rate is apparently very high once treatment is stopped, even for patients who have had complete resolution of symptoms. When a patient has been asymptomatic on medication for 6 to 12 months, it may be reasonable to have a trial off medication. If medication is discontinued, this should be done slowly, and the benzodiazepines in particular should be tapered over a period of at least 2 months and possibly as long as 6 months. More commonly now, panic disorder is considered a chronic illness, which requires rnaintenance therapy. Investigations are underway to provide much clearer guidelines for chronic therapy in panic disorder, but they tend to mirror the guidelines developed for the long-term maintenance treatment of depression, discussed in Chapter 5.

New prospects

NOVEL ANTIDEPRESSANTS Given the importance of SSRIs in the treatment of panic disorder, other, newer antidepressants are developing an efficacy portfolio for panic disorder (and other anxiety disorders) as well. Thus, venlafaxine XR, nefazodone, and mirtazapine hold promise for the treatment of panic disorder. One early study also suggests that the new antidepressant reboxetine may be effective in panic disorder.

NOVEL SEROTONERGIC AGENTS The same agents in testing as antidepressants and discussed in the section "Other antidepressants in clinical trials," in Chapter 7, may also be promising antipanic agents. Such compounds tend to be tested first as

358 Essential Psychopharmacology

antidepressants and then for anxiety disorders such as panic disorder. This includes agents that are 5HT1A antagonists, 5HT1D antagonists, neurokinin antagonists, and other neuropeptide antagonists.

PARTIAL AGONISTS AT BENZODIAZEPINE RECEPTORS AS discussed for general

anxiolytic agents in Chapter 8, the partial benzodiazepine agonists could be a theoretical advance over the marketed benzodiazepines. Partial agonists should have the same efficacy as full agonists but less potential for sedation, dependence, and withdrawal effects.

NONBENZODIAZEPINE LIGANDS AT BENZODIAZEPINE SITES This is a variation on the theme of partial benzodiazepine agonists, as these agents act at the same or similar site as benzodiazepines but are not structurally related to them. Thus, the pharmacology of nonbenzodiazepines is that of a partial agonist, but their chemistry is different from that of a benzodiazepine. This is similar to the approach that novel sedative-hypnotics such as zaleplon and zolpidem have taken, and perhaps a less sedating nonbenzodiazepine partial agonist could hold promise for the treatment of panic disorder.

REVERSIBLE INHIBITORS OF MONOAMINE OXIDASE A Clinical experience with

RIMAs in those countries where these agents are approved for marketing or testing suggests potential utility as antipanic agents. Further research is required to determine the relative advantages and relative efficacy of these compounds as compared with available antipanic agents.

Phobic Disorders: Specific Phobias, Social Phobia, and Agoraphobia

Clinical Description of Phobias and Phobic Disorders

Phobia is fear, and there are several disorders that are classified as phobias. Here we will briefly discuss agoraphobia, specific phobias, and social phobia, also known as social anxiety disorder.

Agoraphobia literally translated means "fear of the marketplace," or essentially fear of going out from one's home. However, the diagnosis of agoraphobia more precisely refers to anxiety about being in all the different situations from which escape might be difficult or in which help may not be available in the event of having a panic attack. This anxiety leads to avoidance of such situations (called phobic avoidance), often to the extent that the patient becomes housebound. Agoraphobia is usually seen in conjunction with panic disorder, but it can be a separate disorder when it is diagnosed as "agoraphobia without history of panic disorder." About one-third of panic disorder patients also have agoraphobia. Patients who have panic disorder accompanied by agoraphobia appear to have a more severe and complicated course than patients, with panic disorder alone.

Specific phobias used to be called "simple phobias." They are excessive and unreasonable fears of specific objects or situations, such as flying in an airplane, heights, animals, seeing an injection, or seeing blood. In specific phobias, exposure to the feared situation or object causes an immediate anxiety response or even a full-blown