SSRIs generalized anxiety

With regard to generalized anxiety disorder, it has been postulated that an overactivity of the stimulatory 5-HT pathways occurs. Drugs such as buspirone and ipsapirone are effective in such conditions because they stimulate the inhibitory S-HT a autoreceptors on the raphe nuclei and thereby reduce serotonergic function. It is noteworthy that the SSRIs often worsen anxiety initially because they temporarily enhance serotonergic function. Adaptive changes in the pre- and postsynaptic 5-HT receptors then occur leading to a reduction in the anxiety state. 

In recent years many of these primary care cases that would formerly have been seen as anxiety disorders have been portrayed as anxious-depressives and have led to treatment with antidepressants, in particular the more recent serotonin reuptake inhibitors. As part of this rebranding a variety of states such as panic disorder, post-traumatic stress disorder, social phobia and generalized anxiety disorder have appeared, along with more traditional disorders such as obsessive compulsive disorder (OCD). Many of these diagnoses are likely to lead to prescriptions of an SSRI although the evidence for benefit from SSRIs is poor except for OCD. 

Antidepressant drugs, such as the tricyclic antidepressants and the selective serotonin reuptake inhibitors (SSRIs), are very important for the treatment of psychotic depression (see Chapter 34). They have been shown to be effective when used in the treatment of several anxiety disorders, including general anxiety, obsessive-compulsive disorder, and several phobias, including agoraphobia. Because the SSRIs are less toxic than the tricyclic antidepressants, their use in the treatment of anxiety is safer and less likely to produce serious side effects. 

The selective serotonin reuptake inhibitors (SSRI) have been used in adults for a wide variety of disorders, including major depression, social anxiety (social phobia), generalized anxiety disorder (GAD), eating disorders, premenstrual dysphoric disorder (PMDD), post-traumatic stress disorder (PTSD), panic, obsessive-compulsive disorder (OCD), trichotillomania, and migraine headaches. Some of the specific SSRI agents have an approved indication in adults for some of these disorders, as reviewed later in this chapter. The SSRIs have also been tried in children and in adults for symptomatic treatment of pain syndromes, aggressive or irritable ( short fuse ) behavior, and for self-injurious and repetitive behaviors. This chapter will review general aspects of the SSRIs and discuss their approved indications in children and adolescents. 

FDA, Food and Drug Administration GAD, general anxiety disorder OCD, obsessive-compulsive disorder PMDD, Premenstrual dysphoric disorder PTSD, post-traumatic stress disorder SRI, serotonin reuptake inhibitor SSRI, selective serotonin reuptake inhibitor. 

Venlafaxine is approved by the U.S. Food and Drug Administration for the treatment of both major depression and generalized anxiety disorder. Preliminary data suggest that it might also have a role in the treatment of chronic pain conditions and perhaps other disorders against which SSRIs are effective. Serotonin reuptake inhibition is prominent at lower doses of venlafaxine at higher doses, inhibition of norepinephrine reuptake becomes more significant. 

Generalized anxiety disorder Buspirone, benzodiazepines, venlafaxine, SSRIs... 

Disadvantages of the benzodiazepines include the risk of dependence, depression of central nervous system functions, and amnestic effects. In addition, the benzodiazepines exert additive central nervous system depression when administered with other drugs, including ethanol. The patient should be warned of this possibility to avoid impairment of performance of any task requiring mental alertness and motor coordination. In the treatment of generalized anxiety disorders and certain phobias, newer antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are now considered by many authorities to be drugs of first choice (see Chapter 30). 

Clinical experience suggests that nefazodone may also be useful in panic disorder, posttraumatic stress disorder, and generalized anxiety disorder, but without the 5HT2A-activating side effects associated with the SSRIs. 

FIGURE 8-9. By the 1990s the serotonin selective reuptake inhibitors (SSRIs) replaced classical anxiolytics as first-line treatments for anxiety disorder subtypes and for mixtures of anxiety and depression but not for generalized anxiety disorder. 

SSRIs show efficacy in social phobia, and combined serotonin and norepinephrine uptake inhibitors are effective in generalized anxiety disorder. 

Antidepressant drugs of various classes (tricyclics, monoamine oxidase inhibitors, SSRIs) have broad efficacy in generalized anxiety and in panic disorder, for which they are the treatments of choice (6,7). While not likely to cause benzodiazepine-like dependence or abuse, they do have a significant therapeutic latency, and the older drugs are very toxic in overdose. 

Clinicians will readily recognize in Table 3.7 the experiences reported by many of their patients when receiving treatment for depression or other related psychiatric disorders. By looking at the Function affected column, it is possible to understand why some medications (say, SSRIs) are effective in variable degrees in several conditions associated with serotonin dysfunction (depression, OCD, social anxiety disorder, posttraumatic stress disorder, generalized anxiety disorder, panic disorder, and bulimia nervosa). 

PMDD is not the only mental disorder that can be treated with SSRIs. There are many kinds of syndromes that SSRIs have been approved to treat. These syndromes include eating disorders, obsessive-compulsive disorder, post-traumatic stress disorder, panic disorder, and generalized anxiety disorder. Although each SSRI would probably be just as effective in treating these syndromes, the companies that own them have done extensive research to find a niche for their drug. Thus some SSRIs, such as Paxil (paroxetine), are approved for social phobia simply because the company that owns them has done the clinical studies proving it is effective and therefore should be licensed for it. Indeed, there seems to be no end to syndrome niche markets in which SSRIs can be effective. There are now efforts to market some SSRIs as treatments... 

However, it must be noted that most of Effexor s reported side effects are much less severe than those associated with SSRIs. Indeed, Effexor s popularity has increased following FDA approval of the drug as a treatment for such syndromes as social anxiety disorder (SAD) and generalized anxiety disorder (GAD). Social anxiety disorder is not simply shyness, but a paralyzing inability to interact with people, such as casual acquaintances or even friends. Generalized anxiety disorder is the clinical term for a personality marked by a chronic state of worry. People afflicted with GAD often feel so overwhelmed with real or imagined problems that they have trou-... 

Antidepressants tend to provide a more sustained and continuous improvement of the symptoms of attention-deficit/hyperactivity disorder than do the stimulants and do not induce tics or other abnormal movements sometimes associated with stimulants. Indeed, desipramine and nortriptyhne may effectively treat tic disorders, either in association with the use of stimulants or in patients with both attention deficit disorder and Tourette s syndrome. Antidepressants also are leading choices in the treatment of severe anxiety disorders, including panic disorder with agoraphobia, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder, as weU as for the common comorbidity of anxiety in depressive illness. Antidepressants, especially SSRIs, also are employed in the management of posttraumatic stress disorder, which is marked by anxiety, startle, painful recollection of the traumatic events, and disturbed sleep. Initially, anxious patients often tolerate nonsedating antidepressants poorly (Table 17-1), requiring slowly increased doses. Their beneficial actions typically are delayed for several weeks in anxiety disorders, just as they are in major depression. 

SSRIs are the drugs of choice for PD. All SSRIs have demonstrated effectiveness in controlled trials, with 60% to 80% of patients achieving a panic-free state.28,48,49 With similar efficacy reported and no trials comparing SSRIs with other SSRIs, selection generally is based on pharmacokinetics, drug interactions, side effects, and cost differences (see Chap. 35 for more discussion). The most common side effects of SSRIs include headaches, irritability, nausea and other gastrointestinal complaints, insomnia, sexual dysfunction, increased anxiety, drowsiness, and tremor.49 SSRIs should not be discontinued abruptly to avoid a withdrawal syndrome characterized by dysphoric mood, irritability, and agitation. 

Early controlled studies demonstrated the effectiveness of irreversible MAOIs, particularly phenelzine and tranylcypromine, for generalized social anxiety disorder. Prior to the advent of the SSRIs, MAOis were considered the gold standard treatment for social anxiety disorder. The best studied of the MAOis, phenelzine, has proved snperior to both beta blockers and the benzodiazepine alprazolam in treating generalized social anxiety disorder. 

Generalized Sociai Anxiety Disorder, Treatment Resistance. A significant minority of patients will not experience a satisfactory treatment response to antidepressant therapy, even after a trial of adequate duration at full strength doses. For those with comorbid depression who are experiencing no benefit from SSRI treatment for either the anxiety or depression, then switching treatment is advisable. The options include switching to another SSRI, a SNRI (venlafaxine or perhaps dulox-etine), or, when other alternatives fail, phenelzine. 

Serotonin-Boosting Antidepressants. The SSRIs have also been studied in the treatment of generalized social anxiety disorder, and paroxetine, sertraline, and venlafaxine are effective. Preliminary data suggests that the serotonin-boosting atypical antidepressants (mirtazapine and nefazodone) may also be helpful. Like the MAOIs, they appear to be effective at doses comparable to those used to treat depression. They may help avoidant patients to gradually increase their social interaction and become more assertive. 

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