Serotonin generalized anxiety

The full complement of anxiety syndromes including panic, generalized anxiety, obsessive-compulsiveness, and post-traumatic stress disorder can arise in the after-math of TBI. In fact, anxiety may be the most common neuropsychiatric complication of TBI. Anxiety appears to be most likely to arise when the injury occurs to the right side of the brain. The treatment alternatives for post-TBl anxiety parallel those used when treating anxiety disorders and include serotonin-boosting antidepressants, buspirone (Buspar), and the benzodiazepines (see Table 12.1). 

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. 

Buspirone has been shown to be very effective in treating generalized anxiety disorder (GAD). It is especially useful when combined with a benzodiazepine, probably because using these two drugs together causes the activation of two neurotransmitter systems (GABA and serotonin). 

Generalized anxiety disorder is still considered the gold standard indication for benzodiazepines (P. J. Perry et al. 1990]. However, buspirone, a serotonin-la partial agonist, has been demonstrated as effective in this disorder... 

The anxiolytic activity of several compounds in some, but not all, animal models of anxiety in fact suggests that different receptor subtypes may modulate different types of anxiety as discussed below. It would not be surprising if the specific serotonin links to disorders of anxiety also differ among the various disorders of anxiety such as generalized anxiety versus obsessive-compulsive disorder versus panic disorder versus social phobia versus mixed anxiety depression. Such studies are in progress, and much further research is necessary to clarify the potential links between subtypes of anxiety and subtypes of serotonin receptors. 

Of interest was the continued improvement in the subjects symptoms during the extension phase of this study. Symptoms of general anxiety, social anxiety, and social avoidance demonstrated continued clinical improvement during this phase of treatment. This evidence suggests that patients treated with the serotonin reuptake inhibitors may require treatment of 12 weeks or longer to receive an adequate clinical trial of these agents. 

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. 

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). 

In addition to its efficacy as a first-line antidepressant, mirtazapine may have enhanced efficacy due to its dual mechanism of action (Fig. 7—3), especially in combination with other antidepressants that block serotonin and/or norepinephrine reuptake. This will be discussed below in the section on antidepressant combinations. Mirtazapine may also have utility in panic disorder, generalized anxiety disorder, and other anxiety disorders, but has not been intensively studied for these indications. 

The serotonin 1A partial agonist buspirone, whose primary use is in generalized anxiety disorder, is also used as a popular augmenting agent for treatment-resistant depression, particularly in North America (serotonin 1A combo in Fig. 7—30). Its potential mechanism of action as an antidepressant augmenting agent is shown in Figures 7—31 to 7—33. 

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. 

A 27-year-old married woman developed symptoms of generalized anxiety disorder and was given buspirone 30 mg/day (32). During treatment she felt depressed and decided to take St John s wort. Two months later she started to have nervousness, aggressiveness, hyperactivity, insomnia, blurred vision, and very short periods of confusion and disorientation. The symptoms were consistent with serotonin syndrome. St John s wort was withdrawn and her symptoms resolved after 1 week. 

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). 

The mood and anxiety disorders in their various permutations constitute a major source of personal suffering and impaired ability to engage in productive Avork and interpersonal relationships. Between 5 and 9% of women and between 2 and 3% of men meet the diagnostic criteria for major depression at any time 10-25% of all women suffer major depression sometime in their lives, while 5-10% of men will develop major depressive disorder (American Psychiatric Association, 1994). The anxiety disorders obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), panic disorder, and generalized anxiety disorder (GAD) show lifetime prevalence rates of approximately 2.5%, 7%, 2.5%, and 5% respectively. Between 3 and 13% of individuals in community samples are regarded to meet the diagnostic criteria for social phobia. Mood and anxiety disorders are common comorbidities (American Psychiatric Association, 1994) and the most common antidepressant medications including the serotonin reuptake inhibitors, the mixed serotonin-catecholamine reuptake inhibitors, the tricyclic antidepressants, and the monoamine oxidase inhibitors, are all effective treatments for anxiety and panic attacks. 

Escitalopram is a selective serotonin reuptake inhibitor that inhibits the CNS neuronal nptake of serotonin, potentiating serotonergic activity. It is indicated in the major depressive disorders and generalized anxiety. 

Paroxetine is a selective serotonin reuptake inhibitor that blocks reuptake of serotonin, enhancing serotonergic function. It is used to treat panic disorder or social anxiety disorder (except Pexeva), as defined in the DSM-IV major depressive disorder, as defined in DSM-111 (immediate release) orDSM-lV (controlled release). Immediate release only for obsessive-compulsive disorder (OCD) generalized anxiety disorder (GAD) (except Pexeva) posttraumatic stress disorder (PTSD), as defined in the DSM-IV (except Pexeva). 

Venlafaxine is a serotonin and norepinephrine reuptake inhibitor that potentiates norepinephrine, serotonin, and dopamine neurotransmitter activity in the CNS by inhibiting their neuronal reuptake. Effexor, Effexor XR are used in treatment of major depressive disorder. Effexor XR is used in treatment of generalized anxiety disorder and treatment of social anxiety disorder. 

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