Depression and cognitive impairment

In humans, the involvement of cytokines in the regulation of the behavioural symptoms of sickness behaviour has been studied by application of the bacterial endotoxin LPS to human volunteers (Reichenberg et al., 2001). LPS, a potent activator of proin-flammatory cytokines, was found to induce mild fever, anorexia, anxiety, depressed mood, and cognitive impairment. The levels of anxiety, depression and cognitive impairment v ere found to be related to the levels of circulating cytokines (Reichenberg et al., 2001 Reichenberg et al., 2002). 

Phenobarbitone may be as effective as phenytoin and carbamazepine in partial and generalised tonic-clonic seizures but its other central effects such as sedation, depression, listlessness and cognitive impairment mar its usefulness. 

The most commonly used therapies for anxiety and depression are selective serotonin reuptake inhibitors (SSRIs) and the more recently developed serotonin noradrenaline reuptake inhibitors (SNRIs). SSRIs, which constitute 60% of the worldwide antidepressant and antianxiety market, are frequently associated with sexual dysfunction, appetite disturbances and sleep disorders. Because SSRIs and SNRIs increase 5-HT levels in the brain, they can indirectly stimulate all 14 serotonergic receptor subtypes [2,3], some of which are believed to lead to adverse side effects associated with these drugs. Common drugs for short-term relief of GAD are benzodiazepines. These sedating agents are controlled substances with addictive properties and can be lethal when used in combination with alcohol. The use of benzodiazepines is associated with addiction, dependency and cognitive impairment. 

Major depression is one of the most common mental disorders. It has a lifetime prevalence of 17% in the general population, and a current prevalence of 4.9%, constituting a significant public health problem (Blazer et al. 1994). It is characterized by intense sadness and cognitive impairments most notable in concentration, worry, pessimism, and lowered self-esteem (American Psychiatric Association 1994). Interpersonal relationships may suffer and social withdrawal occurs. Physio-... 

Sedation, ataxia, and cognitive impairment occur more frequently with high BZD dosages. Other adverse effects reported when BZDs were used to treat schizophrenia include behavioral disinhibition, exacerbation of psychosis, and increase in anxiety and depression ( 163, 188, 189,190, 191,192, 193,194 and 195, 351). Concomitant use of a BZD and the atypical antipsychotic clozapine may increase the risk of sedation, dizziness and collapse with loss of consciousness ( 196). Respiratory compromise has also been reported with this combination (395, 396). 

Bipolar affective (manic-depressive) disorder occurs in 1-3% of the adult population. It may begin in childhood, but most cases are first diagnosed in the third and fourth decades of life. The key symptoms of bipolar disorder in the manic phase are excitement, hyperactivity, impulsivity, disinhibition, aggression, diminished need for sleep, psychotic symptoms in some (but not all) patients, and cognitive impairment. Depression in bipolar patients is phenomenologically similar to that of major depression, with the key features being depressed mood, diurnal variation, sleep disturbance, anxiety, and sometimes, psychotic symptoms. Mixed manic and depressive symptoms are also seen. Patients with bipolar disorder are at high risk for suicide. 

Putten, rediscovered drug-induced dysphoria, which was noted to be associated with neurological effects, especially akathisia2 (Van Putten 1974, 1975). This was later labelled as akinetic depression (Van Putten May 1978). In the 1990s the term neuroleptic-induced deficit syndrome was coined to describe affective and cognitive impairment (Lader 1994) and drug-induced dysphoria was revisited (Hollister 1992 King, Burke, Lucas 1995). 

Antidepressants do not appear to elevate mood in healthy volunteers (see Chapter 10), but neither, as we have seen, is there good evidence that they do so in depressed patients. Although reports of effects of SSRIs suggest that effects on sleep may sometimes differ between patients and volunteers (Mayers Baldwin 2005), in general side effects of antidepressants in patient trials are consistent with those found in healthy volunteers. For example, tricyclics show sedation and cognitive impairment (Deptula Pomara 1990 Herrmann McDonald 1978), while SSRIs show gastrointestinal upset and drowsiness in both patients and volunteers (Dumont et al. 2005). 

The portrayal of drugs for manic depression as specific treatments is misleading. It obscures the real questions about the pros and cons of treatment, the process of weighing up a lifetime of emotional blunting and cognitive impairment with a possible small reduction in the risk of recurrence. By clouding these questions it may act as a hindrance to people s own efforts to exert some mastery over this frightening condition. 

The example of amisulpride (launched by Sanofi-Synthelabo in 1986) also supports the primary importance of dopamine D2 (as well as D3) but not 5-HT2A receptors in atypical antipsychotic action. This benzamide derivative displays high affinity only to D2 and D3 receptors (with some selectivity toward D3) [42], and in low doses (i.e., 50-100 mg day-1) it acts preferentially on negative [43] symptoms and at higher doses (400-800 mg day-1) on depressive symptoms [44] and cognitive impairment [45]. 

A systematic review of observational studies of post-stroke depression produced an estimated overall prevalence of 33% among all stroke survivors (Hackett et al. 2005). Predictors of depression include severity of stroke and cognitive impairment (Hackett and Andersen 2005). It has been postulated that left-sided brain lesions are more likely to cause depression, but this remains unproven (Bhogal et al. 2004). Mood disorder may impede rehabilitation and contribute to disability and handicap but usually improves with time. Treatment includes support and counseling and antidepressants. 

Both vitamin B12 and folate deficiencies are associated with psychiatric illness. Folate deficiency is most commonly associated with depression, whereas cognitive impairment and dementia are seen in about 25% of patients with either deficiency (Bottiglieri, 1996 Green and Miller, 1999). Herbert (1962) noted insomnia, forgetfulness, and irritability during the development of self-imposed folate deficiency which responded well to the administration of the vitamin. 

Centrally acting H3 antagonists are under study by several drug companies. Agents are sought for a variety of disorders. These include treatment of depression, mild cognitive impairment, Alzheimer s disease, schizophrenia, narcolepsy, obesity, and attention-deficient hyperactivity disorder. Two examples are JNJ 5207852 (63), a compound that increases... 

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