Anxiety and serotonin

Kahn RS, van Praag HM, Wetzler S, et al Serotonin and anxiety revisited. Biol Psychiatry 23 189-208, 1988... 

SSRIs are theorized to reduce the frequency of hot flashes by increasing serotonin in the central nervous system and by decreasing LH. Of the SSRIs, citalopram, paroxetine, and sertraline all have been studied and have demonstrated a reduction in hot flashes while treating other symptomatic complaints such as depression and anxiety.33 Venlafaxine, which blocks the reuptake of serotonin and norepinephrine, has demonstrated a reduction in hot flashes primarily in the oncology population.34 Overall, these antidepressant medications offer a reasonable option for women who are unwilling or cannot take hormonal therapies, particularly those who suffer from depression or anxiety. These agents should be prescribed at the lowest effective dose to treat symptoms and may be titrated based on individual response. 

Substance P, an undecapeptide, is abundant both in the periphery and in the central nervous system. It is usually co-localized with one of the classical neurotransmitters, most commonly serotonin. Substance P is thought to have a role in the regulation of pain, asthma, psoriasis, inflammatory bowel disease and, in the CNS, emesis, migraine, schizophrenia, depression and anxiety. The substance-P-preferring receptor neurokinin-1 has been focused on most intensively in drug development, and existing... 

The selectivity of the SSRIs does not mean that they are totally without side effects. First, serotonin-secreting nerve cells are distributed throughout the brain and control a wide array of nervous system activities. As a result, increasing serotonin not only relieves depression, it can also produce many side effects such as abdominal discomfort, sexual dysfunction, and anxiety. Second, the selectivity of the SSRIs is not absolute but relative. Although the main action of the SSRIs is the same, they do have differences. For patients, this means that the drug interactions and side effects of the SSRIs vary somewhat. It also means that a patient who does not respond to one SSRI may respond to another. 

Venlafaxine (Effexor, Effexor XR). Venlafaxine works by blocking the reuptake of both serotonin and norepinephrine. Because of this dual action, some believe that venlafaxine may be more effective than the SSRIs when treating severe depression. Its side effects and toxicity are similar to the SSRIs with abdominal discomfort, sexual dysfunction, and anxiety being commonly reported. At higher doses, it may mildly elevate blood pressure therefore, blood pressure should be checked periodically. When stopping venlafaxine, serotonin discontinuation symptoms may be especially problematic. Therefore, gradually tapering of the dose every 2-4 weeks is recommended. 

Monoamine Oxidase Inhibitors (MAOIs). As mentioned earlier, the MAOIs are excellent treatments for both depression and anxiety. They act by increasing neurotransmission of three neurotransmitter systems serotonin, norepinephrine. 

The closest things to true antiserotonin medications used by psychiatrists are those used to treat serotonin-induced side effects. In particular, cyproheptadine has an overall serotonin-blocking effect. With repeated use, this medication can theoretically cause depression and anxiety, and there are case reports of recurrence of depressive symptoms following frequent administration of cyproheptadine. 

Venlafaxine is a serotonin and noradrenaline re-uptake inhibitor indicated in depression and may be used in generalised anxiety disorder. Venlafaxine can cause diarrhoea and headache as side-effects. It does not cause blurred vision. 

Lorazepam is a short-acting benzodiazepine indicated for use in relieving anxiety and insomnia. Lorazepam may also be administered perioperatively to alleviate pain and in status epilepticus. Imipramine is a tricyclic antidepressant, paroxetine is a selective serotonin re-uptake inhibitor, venlafaxine is a serotonin and adrenaline re-uptake inhibitor and moclobemide is a reversible monoamine oxidase inhibitor. Imipramine, paroxetine, venlafaxine and moclobemide are all classified as antidepressants. 

Sertraline is a recent antidepressant that is called a selective serotonin reuptake inhibitor (SSRI). It is chemically unrelated to the older tricyclic antidepressants (see Section 5.3). It works by preventing the movement of the neurohormone serotonin into nerve endings. It can help to improve mood and mental alertness, increase physical activity, and improve sleep patterns. It is prescribed for obsessive-compulsive disorder and obesity. It may offer some advantage over fluoxetine by exhibiting little central nervous system (CNS) action. It has less sedation and anxiety and is shorter acting. 

Golani I, Kafkafi N, Drai D (1999) Phenotyping stereotypic behavior collective variables, range of variation and predictability. Appl Anim Behav Sci 65 191-220 Graeff FG (2002) On serotonin and experimental anxiety. Psychopharmacology (Berl) 163 467-476... 

Ohara K, Suzuki Y, Ochiai M, Tsukamoto T, Tani K (1999) A variable-number-tandem-repeat of the serotonin transporter gene and anxiety disorders. Prog Neuropsychopharmacol... 

Studies in which the availability of serotonin is manipulated in combination with a laboratory panic challenge has considerably increased insight into the relationship between serotonin and panic disorder. Tryptophan depletion caused an increased panic response to a 5% or 35% CO2 challenge in panic disorder patients (Miller et al. 2000 Schruers et al. 2000). Conversely, panic anxiety and symptoms, as well as the number of panic attacks following 35% CO2 inhalation, were significantly reduced by pretreatment with the serotonin precursor L-hydroxytryptophan, suggesting that under certain circumstances serotonin may act to inhibit panic (Schruers et al. 2002). 

Lesch KP, Wiesmann M, Hoh A (1992) 5-HTlA receptor-effector system responsivity in panic disorder. Psychopharmacology (Berl) 106 111-117 Levin AP, Doran AR, Liebowitz MR, Fyer AJ, Klein DF, Paul SM (1987) Pituitary adrenocortical unresponsiveness in lactate-induced panic. Psychiatry Res 21 23-32 Lines C, Challenor J, Traub M (1995) Cholecystokinin and anxiety in normal volunteers—an investigation of the anxiogenic properties of pentagastrin and reversal by the cholecystokinin receptor subtype-b-antagonist L-365,260. Br J Clin Pharmacol 39 235-242 Low K, Crestani F, Keist R, Benke D, Brunig I (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290 131-134 Lucki I (1996) Serotonin receptor specificity in anxiety disorders. J Clin Psychiatry 57(Suppl 6) 5-10... 

The biology of the monoamines is described in detail elsewhere. In simple terms, they facilitate transmission in neural pathways that originate in nuclei of the brainstem and have descending projections to the autonomic nervous system and widespread ascending projections to sites in the limbic system and cortex. These pathways modulate many aspects of behavioural function as well as anxiety responses. Of the three monoamines, the role of serotonin in anxiety is best understood, but the picture is complex as increased serotonergic activity may be anxiogenic or anxiolytic depending on the site of action (Bell and Nutt 1998). 

---