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Neurochemical Disorders Affective Disorders


Neurochemical Disorders I: Affective Disorders
‘Affect’ refers to mood and affective disorders comprise of both a pathological lowering (depression) and elevation (mania) of mood. Bipolar affective disorder (manic-depression) refers to an oscillation between depression and mania. These conditions are not simply characterized by mood changes, however, and depression may comprise a number of characteristic features.

Both depression and mania may be accompanied by features of psychosis (delusions and hallucinations; see Chapter 58). The nature of the psychosis tends to be mood-congruent: in depression, the patient may believe that he or she is guilty of something or hear voices that are critical and unpleasant. Mania may be accompanied by grandiose delusions.

Neurochemical basis of depression

Depression
Aetiology
This is a common and mania disorder with a lifetime prevalence that has been estimated to be as high as 15%, with women affected more than men (approximately 2:1). It can occur in response to adverse circumstances (reactive depression), as well as for no apparent circumstantial reason (endogenous depression), although often the distinction between these two different types of depression is not that clear-cut. In both cases the depression probably arises through a combination of genetic and environmental factors.
·     Genetic: while a number of genes have been implicated in affective disorders, specific genes for depression have not been identified, so it is thought to have a polygenic component – which is maybe more significant in patients with bipolar disorders.
·       Environmental and psychological factors are also extremely important. Background personality factors have been implicated as have social stressors, which have been hypothesized to produce depression by inducing in individuals a sense that they have no personal control over events in their lives (akin to learned helpless- ness in rats). This basic psychological model has been extended and superseded by the view that ‘depressive cognitions’ are fundamental to depression. That is, because an individual holds specific beliefs and attributional styles, he or she may be more vulnerable to the development of a depressive illness. This view is central to the emerging use of cognitive therapies in depression.

Neurochemical basis of depression
The monoamine theory of depression suggests that the illness is caused by reduced monoamine transmission. It derives from the observation that the tricyclic antidepressants – remarkably effective in the treatment of the illness – upregulate monaminergic transmission. However, the direct evidence for monoamine disturbance in depression is scant and inconsistent.
The serotonin hypothesis suggests that depression is linked to reduced serotoninergic function and gains support from the antidepressant efficacy of the newer generation of treatments: the selective serotonin reuptake inhibitors (SSRIs). Furthermore, temporary depletion of tryptophan (a precursor of serotonin) levels causes a transient but profound resurgence of depressive symptoms in people who have been successfully treated with SSRIs and in people with a depressive illness in remission.

Cognition in depression
Depression is associated with impairments or changes in performance on a number of tests of cognitive function. Memory deficits are prominent and occur across memory domains (working memory and episodic memory; see Chapter 46) and across modalities (verbal and visuospatial). Psychomotor retardation is also common with depressed people showing an apparent lack of motivation (see Chapter 47) and marked slowing of speech and motor functions, the latter manifest in generally slowed reaction times. Sustained attention may be poor, as may planning and problem- solving. Interestingly, some of the changes in memory and attention are characterized by an interaction with the emotional nature of test material. For example, patients may preferentially remember or attend to stimuli that have negative connotations. They may also be more likely to perceive neutral stimuli as being emotionally negative.

Treatment
A number of different therapies are employed for the treatment of depression, including psychotherapy and electroconvulsive therapy (ECT); however, the most commonly used approach is with antidepressant drugs. Most of the drugs used in the treatment of depression inhibit the reuptake of noradrenaline (norepinephrine) and/or serotonin (5-hydroxytryptamine [5-HT]). Less commonly used drugs are monoamine oxidase inhibitors (MAOIs). Because both uptake inhibitors and MAOIs increase the amount of noradrenaline and/or 5-HT in the synaptic cleft and so enhance the action of these transmitters, it has been argued that depression resulted from an ‘underactivity’ of these monoaminergic systems (see above). In mania and bipolar affective disorders lithium has a mood-stabilizing action. Lithium salts have a low therapeutic: toxic ratio and adverse effects are common. Carbamazepine valproate and lamotrigine also have mood-stabilizing actions and can be used in cases of non-response or intolerance to lithium. The mechanisms involved in the mood-stabilizing effects of these drugs are unknown.
Amine uptake inhibitors
Tricyclic antidepressants (e.g. imipramine, amitriptyline) have proven antidepressant actions but no one drug has greater efficacy. The choice of drug is determined by the most acceptable or desired side effects. For example, some have sedative actions (e.g. amitriptyline, dosulepin) and are more useful for agitated and anxious patients (see Chapter 59). Withdrawn and apathetic patients may benefit from less sedative drugs (e.g. imipramine, lofepramine). In addition to blocking amine uptake, the tricyclics block muscarinic receptors, α-adrenoreceptors and H1 histamine receptors. These actions frequently cause dry mouth, blurred vision, constipation, urinary retention, tachycardia and postural hypotension. In overdosage, the anticholinergic activity and a quinidine-like action may cause cardiac arrhythmias and sudden death (cardiotoxicity).
Some newer drugs (serotonin-noradrenaline reuptake inhibitors), e.g. venlafaxine, inhibit the reuptake of serotonin and noradrenaline but lack the antimuscarinic and sedative effects of the tricyclics.
Drugs that selectively inhibit serotonin re-uptake (SSRIs) (e.g. fluoxetine) are less sedative, do not have the troublesome autonomic side effects of the tricyclics and are safer in overdoses. However, they have their own spectrum of adverse effects, the most common being nausea, vomiting, diarrhoea and constipation. They may also cause sexual dysfunction.

Monoamine oxidase inhibitors
The older MAOIs (e.g. phenelzine) are irreversible non-selective inhibitors of monoamine oxidase. Their efficacy is similar to that of the tricyclics. They are rarely used now because of their adverse effects (postural hypotension, dizziness, anticholinergic effects and liver damage). Also there may be potentially serious interactions with sympathomimetic amines (e.g. ephedrine), often present in cough mixtures and decongestive medicines, or food containing tyramine (e.g. game, cheese). Tyramine is normally metabolized by MAO in the liver. If the enzyme is inhibited, the tyramine enters the circulation and displaces noradrenaline from sympathetic nerve terminals. This may cause severe hypertension and even stroke.
Moclobemide is a newer drug that selectively inhibits MAOA and lacks most of the unwanted effects of non-selective MAOIs.

Atypical antidepressants
These drugs have little, if any, effect on serotonin or noradrenaline reuptake and do not inhibit MAO. Mirtazapine and trazodone are sedative antidepressants but have few autonomic effects. Because they are less cardiotoxic than the tricyclics, they are less dangerous in overdosage.