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Table 9—4. OCD spectrum disorders

Gambling

Paraphilia

Body dysmorphic disorder

Trichotillomania

Hypochondriasis

Somatization disorder

Tourette syndrome

Autism

Asperger's disorder

Kleptomania

Impulse control disorders

Obsessive compulsive personality disorder

Bulimia

Anorexia nervosa

(5HT). The serotonin hypothesis of OCD, which states that OCD is linked to 5HT dysfunction, stems largely from pharmacological treatment studies.

It has been known since the mid-1980s that clomipramine, a potent but nonselective serotonin reuptake inhibitor, is effective in reducing OCD symptoms. Since then, numerous studies have confirmed the superiority of clomipramine over placebo in OCD patients, whereas other antidepressant medications with less potent inhibitory effects on serotonin reuptake (e.g., nortripytline, desipramine) seem to be ineffective in OCD. Demonstration of the anti-OCD actions of all five SSRIs, namely, fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram, also supports the hypothesis that the antiobsessional effects of these various pharmacologic agents is due to their potent serotonergic reuptake blocking activity.

The hypothesis that SSRIs work in OCD by a serotonergic mechanism is also supported by studies showing a strong positive correlation between improvement in obsessive-compulsive symptoms during clomipramine treatment and drug-induced decreases in cerebrospinal fluid (CSF) levels of the serotonin metabolite 5- hydroxyindoleacetic acid (5-HIAA) and platelet serotonin concentrations. Thus, peripheral markers of 5HT function link the symptomatic improvement in OCD symptoms produced by SSRIs to changes in 5HT function. However, these markers do not consistently highlight a 5HT abnormality in untreated patients with OCD.

Dopamine and obsessive-compulsive disorder. Up to 40% of OCD patients do not respond to SSRIs. Thus, at least some OCD patients fail to demonstrate convincing dysregulation in serotonin function. Therefore, other neurotransmitters may be involved in the pathophysiology of OCD in some patients.

Several lines of evidence show that dopamine (DA) is implicated in the mediation of some obsessive-compulsive behavior. Animal studies demonstrate that high doses of various dopaminergic agents, such as amphetamine, bromocriptine, apomorphine, and L-DOPA, induce stereotyped movements in animals, which resemble compulsive behaviors in OCD patients. Increased dopaminergic neurotransmission may be responsible for this. Human studies consistently report that abuse of stimulants such

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as amphetamine can cause seemingly purposeless, complex, repetitive behaviors, which resemble behaviors occurring in OCD. Cocaine can also worsen compulsive symptoms in patients with chronic motor tic disorders such as Tourette syndrome.

The strongest support for a role of DA in mediating OCD symptoms comes from the relationship between OCD symptoms and several neurological disorders associated with dysfunction of DA in the basal ganglia (Von Economo encephalitis, Tourette syndrome, and Sydenham chorea). There is even recent evidence that autoimmune-mediated damage to the basal ganglia in some vulnerable children may be linked to the development of OCD. The most intriguing relationship between DA in the basal ganglia and OCD may be the link between the Tourette syndrome and obsessive-compulsive symptoms. Tourette syndrome is a chronic neuropsychiatric disorder characterized by multiple motor and vocal tics. Between 45% and 90% of Tourette patients also have obsessions and compulsions. If OCD symptoms were considered alone, a high percentage of Tourette patients would meet diagnostic criteria for OCD. Family genetic studies show that Tourette syndrome and OCD are linked, leading to proposals that a common genetic factor may manifest itself as tics in some individuals and as obsessions and compulsions in others. Put differently, perhaps tics are the behavioral manifestations of a genetically based basal ganglia dysfunction, with Tourette syndrome being manifested as "tics of the body" and OCD as "tics of the mind."

Also supportive of DA involvement in the pathophysiology of OCD are observations that adjunctive therapy with the older conventional antipsychoticsneuroleptics (which block DA receptors) added to ongoing SSRI treatment reduces the severity of OCD symptoms in OCD patients resistant to SSRI treatment alone, especially in those with concomitant Tourette syndrome.

Serotonin-dopamine hypothesis. On the basis of the studies of both 5HT and DA in OCD, it seems possible that at least in some forms of OCD (e.g., OCD with a history of Tourette syndrome), both 5HT and DA transmitter systems may be involved in the pathophysiology of symptoms. It is not clear whether the primary abnormality is in 5HT function, DA function, or serotonin-dopaminergic balance. This hypothesis is supported by many preclinical data, which suggest that important anatomic and functional interactions exist between serotonergic and dopaminergic neurons. This will be discussed in detail in Chapter 11 in the sections on antipsychotic drugs that work simultaneously on DA and 5HT receptors.

Thus, it may be that decreases in 5HT tonic inhibitory influences on DA neurons could lead to increased dopaminergic function due to the functional connections between DA and 5HT neurons in the basal ganglia. Thus, OCD patients with a history of Tourette syndrome may represent a subtype of the disorder in which two neurotransmitters and the balance between them are involved in the pathophysiology of their symptoms.

Consistent with the role of both serotonin and dopamine in OCD, some OCD patients benefit from treatment with the new serotonin-dopamine antagonists (also known as atypical antipsychotics), especially when there is inadequate response to an SSRI. On the other hand, other patients have no therapeutic response to these new agents, and the condition of still others is even worsened by these drugs. The atypical antipsychotics and serotonin dopamine antagonism are discussed in Chapter 11.

FIGURE 9—1. Shown here are the variety of therapeutic options for treating obsessive-compulsive disorder

(OCD).

In summary, the hypothesis that an abnormality in neurotransmitter functioning might underlie OCD has generated numerous studies of 5HT and DA neuronal systems. To date, no compelling or consistent neurotransmitter dysfunction has been described that can adequately explain the neurobiological basis for OCD. However, it seems clear that changes in 5HT neuronal systems are caused by the known therapeutic agents for OCD, which suggests an important role for 5HT in mediating treatment responses in OCD.

Neuroanatomy. Abnormalities on positron emission tomography (PET) scans of neuronal activity of cortical projections to the basal ganglia have been confirmed by a number of investigators in OCD patients. Specifically, projections from the orbitofrontal —medial prefrontal cortex may be implicated in OCD. Such PETdemonstrated abnormalities in cortical projections to the basal ganglia may even be linked to the severity of symptoms in OCD patients, since they diminish as OCD patients improve, whether that improvement occurs after drug treatment or after behavioral therapy (see Fig. 5 — 53).

Drug Treatments

A summary of OCD treatments is shown in Figure 9—1, and combination therapies are depicted graphically in Figure 9—2.

Serotonin reuptake inhibitors. Clomipramine is a tricyclic antidepressant first recognized more than 30 years ago as an effective treatment for depression. It has only been recognized widely and on a worldwide basis for the treatment of OCD since the

mid-1980s. Originally, the efficacy of clomipramine in OCD was debated because depression is frequently present in OCD patients, leading some researchers to propose that clomipramine was only effective in treating concomitant depressive symptoms and not the obsessions and compulsions in these patients. Others suggested that clomipramine was only effective in treating core OCD symptoms if symptoms of depression were also present. However, it is now clearly recognized that clomipramine has unique anti-OCD effects independent of its antidepressant effects in OCD patients.

Since clomipramine is a potent inhibitor of serotonin reuptake, it is hypothesized that the anti-OCD effects of clomipramine are linked to its serotonin reuptake blocking properties. This is strongly supported by the findings that all five of the SSRIs are also effective in treating OCD. Although clomipramine is also metabolized to a norepinephrine reuptake blocker (i.e., desmethylclomipramine), there does not appear to be a robust role for norepinephrine reuptake blockade in the mechanism of action of clomipramine, since more selective noradrenergic reuptake inhibitors such as desipramine and nortriptyline appear to have little or no anti-OCD actions. Recent findings even suggest that it may be necessary to have serotonin reuptake blockade to treat comorbid depression in OCD. In patients with both OCD and depression, an SSRI was found to improve both, but the norepinephrine reuptake inhibitor desipramine not only failed to improve OCD as expected, but also was less effective that the SSRI in treating the concomitant depression. This suggests that although depression in general may involve serotonin, norepinephrine, or both, the depression that coexists with OCD may be particularly serotonergic.

Although similarities exist between the treatment of OCD with SSRIs and the treatment of depression with SSRIs, there are also some important differences. In general, doses of SSRIs for treating OCD are greater than doses for treating depression. Also, the onset of therapeutic effects may be even more delayed in OCD (6 to 12 weeks or longer) than in depression (4 to 8 weeks) following SSRI administration (Table 9-5).

There are also differences in treatment responses between OCD and depression following SSRI treatment. Whereas many patients with depression recover completely after SSRI treatment, the average response of an OCD patient is about a 35% reduction in symptoms after 12 weeks of treatment (Table 9 — 5). Relapse rates appear to be higher and to occur sooner after drug discontinuation in OCD than in depression.

One other important difference in the mechanism of SSRIs in OCD versus depression is that the therapeutic response in OCD may be less dependent on the immediate availability of 5HT than is the therapeutic response in depression. Thus, when tryptophan is depleted from depressed patients and 5HT synthesis is suddenly diminished, patients who have responded to SSRIs transiently deteriorate until 5HT

FIGURE 9—2. Various treatments can be given in combination for obsessive-compulsive disorder (OCD) (i.e., OCD combos). The basis of all combination treatments is a serotonin selective reuptake inhibitor (SSRI) or clomipramine. Added to this basis may be a serotonin 1A partial agonist, a serotonin 2A antagonist, lithium, a benzodiazepine or a sedative-hypnotic, a conventional antipsychotic or an atypical antipsychotic, or behavioral psychotherapy.

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Table 9—5. Profile of serotonin selective reuptake inhibitors (SSRIs) in obsessive-compulsive disorder (OCD)

The starting dose for OCD is the same as the starting dose for depression

The maintenance dose for OCD may be higher than the maintenance dose for depression because therapeutic effects are not as robust for SSRIs in OCD. Usual clinical response

is less robust in OCD than in depression, usually with less than

50% reduction of symptoms, although this can range from complete reduction to no reduction for individual patients. The onset of response is slower in OCD than in

depression, about 12 to 26 weeks being

required to determine whether a response will be seen. Target symptoms do not worsen before they improve once treatment with an SSRI is

initiated. Some patients respond much better to one SSRI than to another.

synthesis is restored. By contrast, when tryptophan is depleted from OCD patients who have responded to SSRI treatment, their OCD symptoms are not worsened. This may suggest that SSRIs work via a different mechanism in OCD than they do in depression. They certainly appear to be working on serotonin in different pathways in OCD (Fig. 5 — 53) than they do in depression (Fig. 5 — 52).

In summary, SSRIs undoubtedly improve symptoms in OCD, just as they improve symptoms in depression. However, as compared to the use of SSRIs in depression, OCD responses to SSRIs specifically require 5HT and not norepinephrine reuptake inhibition, the OCD responses are generally slower, less robust, more likely to relapse after SSRI discontinuation, and not as immediately dependent on synaptic 5HT availability.

Adjunctive treatments. Although SSRIs are the foundation of treatment for OCD, many patients are refractory to SSRI treatment, or their responses are incomplete and unsatisfactory. This has led to a variety of strategies to augment SSRIs to attain a more satisfactory therapeutic response (Fig. 9—2). Augmentation strategies include those that are directed at serotonergic functioning, those that are pharmacological but directed at other neurotransmitter systems, and those that are nonpharmacological.

SEROTONERGIC AUGMENTATION STRATEGIES Since SSRIs do not work well for

all OCD patients and do not work at all as monotherapies for some OCD patients, psychopharmacologists have attempted to boost the effectiveness of SSRIs with various agents capable of augmenting serotonergic action. These have been previously discussed in the treatment of depression in Chapter 7, and several are outlined in Figures 7 — 31 to 7 — 33 and in Figure 7 — 37. Such serotonin 1A, serotonin 2A, and lithium augmentation strategies can also be effective in OCD (see Fig. 9 — 2).

NEUROTRANSMITTER COMBINATION STRATEGIES Rather than boosting the SSRI

with a pharmacologic intervention aimed at helping the SSRI at the serotonergic neuron, it is also possible that adding another neurotransmitter mechanism to the SSRI's action at the serotonin neuron would boost the SSRI's action indirectly. At

least two such strategies have proved useful in some OCD patients whose response to SSRIs is unsatisfactory.

For example, one possibility for boosting the SSRI is to add a benzodiazepine, especially clonazepam (Fig. 9 — 2). The SSRI boosting effect of clonazepam may be mediated partially by allowing a high dose of SSRI to be tolerated, partially by reducing nonspecific anxiety symptoms associated with OCD, and partially by a direct serotonin-enhancing action of clonazepam itself. Other benzodiazepines can be added for treatment of concomitant generalized anxiety. Sedative-hypnotic nonbenzodiazepines such as zaleplon or zolpidem or sedative-hypnotic benzodiazepines may also have to be added for short-term reduction of associated insomnia, particularly when initiating treatment with an SSRI (Fig. 9 — 2).

As discussed earlier, the addition of a conventional antipsychotic that blocks DA receptors can be useful in some patients with OCD, particularly those with concomitant Tourette syndrome. Other OCD patients, including those who have associated schizophreniform symptoms or whose obsessions border on delusions without any insight, may also respond to the boosting effect of a conventional antipsychotic agent (Fig. 9—2). As also mentioned above, augmenting the treatment of some patients with an atypical antipsychotic may be helpful, but this can be tricky, because other patients may be made worse (Fig. 9 — 2).

BEHAVIORAL THERAPY The most common concomitant therapy to use with SSRIs is behavioral psychotherapy (Fig. 9 — 2). Used by itself in selected cases, behavioral therapy can be as effective as SSRIs, and its therapeutic effects may last longer after discontinuance of treatment than the therapeutic effects of SSRIs after they are stopped. Little is known from formal studies combining SSRIs with behavioral therapy, but it is well known from anecdotal clinical experience that this combination can be much more powerful than SSRIs or behavioral therapy alone. Although behavioral therapy may have enduring effects that carry over after the sessions are finished, SSRIs apparently have to be given indefinitely in OCD.

PSYCHOSURGERY For extremely severe cases refractory to all these treatments alone and in combination, there is the possibility to gain some relief from a neurosurgical procedure cutting the neuronal loop connecting the cortex with the basal ganglia. Few centers have any experience with this procedure in OCD, and longterm outcomes are as yet unknown. However, early results in some patients with very severe, very refractory OCD cases are encouraging, but this is not an option for most patients with refractory OCD.

New prospects. Given that there are at least five serotonin reuptake blockers available to treat OCD, and that each is roughly comparable the other in efficacy, it does not seem likely that much more therapeutic ground will be gained merely by developing yet another SSRI for OCD. On the other hand, it is not clear what pharmacological mechanism to target other than serotonin reuptake blockade in order to devise an effective anti-OCD therapy.

It is theoretically possible that novel agents combining the actions of single agents might be more powerful than a drug that is merely an SSRI. However, this is purely hypothetical at the moment because the mechanisms of action of the combinations described above are not proved. It is also possible that certain novel, agents acting

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Table 9—6. Symptoms of a panic attack

Palpitations, pounding heart, or accelerated heart rate Sweating

Trembling or shaking »

Sensations of shortness of breath or smothering Feeling of choking

Chest pain or discomfort Nausea or abdominal distress

Feeling dizzy, unsteady, lightheaded, or faint

Derealization (feelings of unreality) or depersonalization (being detached from oneself) Fear of losing control or going crazy

Fear of dying Paresthesias

Chills or hot flushes

uniquely on serotonin and other neurotransmitter systems and being tested as antidepressants or antipsychotics will also prove to be anti-OCD agents, such as substance P and neurokinin antagonists. If the past is any indication of the future, new treatments of OCD may arise from agents being tested for depression.

Panic Attacks and Panic Disorder

Clinical Description

A panic attack is a discrete episode of unexpected terror accompanied by a variety of physical symptoms. Associated symptoms include fear and anxiety, as well as catastrophic thinking with a sense of impending doom or the belief that loss of control, death, or insanity is imminent. Physical symptoms can be neurologic, gastrointestinal, cardiac, or pulmonary and therefore may mimic many different types of medical illnesses. Panic attacks have therefore sometimes been called the "great medical imposters." Behaviors associated with panic attacks typically include an attempt to flee the situation and eventually to avoid anxiety-producing situations or any situation that has previously been associated with a panic attack.

A panic attack usually lasts from 5 to 30 minutes, with the symptoms peaking at about 10 minutes, but attacks have been reported to last for hours. A person must have at least 4 of the 1.3 symptoms listed in Table 9 — 6 for an episode to be classified as a panic attack. Panic attacks may occur during sleep, in which case they are known as nocturnal panic attacks. These attacks may wake the person from sleep but are otherwise similar in symptoms to daytime panic attacks. A majority of patients with panic disorder will experience nocturnal panic, but only a few patients describe having the majority of their panic attacks at night.

It is common to confuse panic attacks with panic disorder. Many psychiatric disorders can have panic attacks associated with them (Table 9—7). However, to qualify for the diagnosis of panic disorder itself, patients must have some panic attacks that are entirely unexpected (Table 9 — 7). Panic attacks can also be reproducibly triggered by certain specific situations for various individuals, and therefore can be

+ to + + + , present; —, not usually present; +/-, frequently present but not needed for diagnosis.

expected (Table 9—7). Situations that frequently act as triggers for panic attacks include driving or riding in a vehicle, especially in heavy rain or over bridges, shopping in crowded stores, and waiting in lines. The perception of lack of control or feeling "trapped" is a common theme in situational triggers.

As already emphasized, not all who have panic attacks have panic disorder (Table 9-7), and the distinguishing factor is the type of panic attacks. Patients with social phobia, posttraumatic stress disorder, or specified phobias will frequently experience panic attacks that are expected, since they are in response to specific situations or stimuli. However, such patients do not experience unexpected panic attacks. Unexpected panic attacks are thus uniquely characteristic of panic disorder. The DSM-IV diagnostic criteria for panic disorder are given in Table 9—8. Panic disorder can occur with or without a type of phobic avoidance behavior called agoraphobia. The diagnostic criteria for agoraphobia are also listed in Table 9 — 8, and the clinical characteristics of agoraphobia are discussed below in the section on phobic disorders.

Panic disorder, therefore, is the presence of recurrent unexpected panic attacks followed by at least a 1-month period of persistent anxiety or concern about recurrent attacks or consequences of attacks, or by significant behavioral changes related to the attacks. The presence of persistent anxiety or behavioral changes is important, because approximately 10% of the normal population report having had panic attacks at some time in their lives; however, since they do not develop persistent anxiety and do not modify their behavior, they do not develop panic disorder.

Panic disorder affects up to 2% of the population, but less than one-third receive treatment. Panic disorder typically begins in late adolescence or early adulthood but can present in childhood. Onset is rare after age 45. Panic disorder is more prevalent in women, who have perhaps twice the rate in men. Genetic studies demonstrate a 15 to 20% rate of panic disorder in relatives of patients with panic disorder, including a 40% concordance rate for panic disorder in monozygotic twins.

Although not generally recognized by medical or mental health practitioners, panic disorder patients have a suicide rate comparable with that of patients with major depression; 20 to 40% of panic disorder patients report having made suicide attempts, and about half admit to having had suicidal ideation. This high rate of suicide attempts does not appear to be caused by the presence of depression in panic disorder patients.

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Table 9 — 8. DSM-IV diagnostic criteria for panic disorder

1.Recurrent unexpected panic attacks

2.At least one of the attacks has been followed by one month or more of the following:

a.Persistent concern about having additional attacks

b.Worry about the implications of the attack or its consequences (losing control, having a heart attack, "going crazy")

c.A significant change in behavior related to the attacks

3.May or may not meet the diagnostic criteria for agoraphobia. The diagnostic criteria for concomitant agoraphobia include:

a.Anxiety about being in places or situations from which escape is difficult or in which help may not be available in the event of an unexpected or situationally predisposed panic attack or panic-like symptoms. Agoraphobic fears typically involve characteristic clusters of situations, which include being outside the home alone, standing in a line or being in a crowd, being on a bridge, and traveling in a bus, train, or automobile.

b.The situations are avoided, are endured with marked distress or with anxiety about having a panic attack or panic-like symptoms, or require the presence of a companion.

c.The anxiety or phobic avoidance is not better accounted for by another mental disorder, such as social phobia (e.g., avoidance limited to social situations because of fear of embarrassment), specific phobia (e.g., avoidance limited to a single situation such as elevators), obsessive-compulsive disorder (e.g., avoidance of dirt on someone for fear of contamination), posttraumatic stress disorder (e.g., avoidance of stimuli associated with a severe stressor), or separation anxiety disorder (e.g., avoidance of leaving home or relatives).

4.The panic attacks are not due to the direct physiological effects of a substance or a general medical condition.

5.The panic attacks are not better accounted for by another mental disorder such as those listed above under diagnostic criteria for concomitant agoraphobia.

Panic disorder patients report a subjective feeling of poor physical and emotional health, impaired social and marital functioning, and increased financial dependency. Because of this disorder, 70% of patients lose or quit their jobs, with an average length of work disability of more than 2½ years, and 50% are unable to drive more than 3 miles from their home. Panic disorder patients also have the highest use of emergency rooms of any psychiatric population.

Biological Basis of Panic Disorder

Neurotransmitter dysregulation

NOREPINEPHRINE One theory about the biological basis of panic disorder is that there is an initial excess of norepinephrine (Fig. 9—3). This theory is supported by evidence that panic disorder patients are hypersensitive to alpha-2 antagonists and hyposensitive to alpha-2 agonists. Thus, yohimbine, an alpha-2 antagonist, acts as a promoter of norepinephrine release by "cutting the brake cable" of the presyn-aptic norepinephrine autoreceptor, as shown earlier in Figure 7—6. The consequence