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.
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 This basic psychological model has been extended and superseded by the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.
