Psychiatric illness has always existed. In early times and in certain cultures people with psychiatric illness were often incorporated into society or tolerated and supported, eg village idiot, some shamans etc. Today it is still clear that higher levels of social support produce better outcomes in this group.

With the development of larger cities and the industrial revolution such support was not so available. Institutions were created to lock many patients away. A wide range of treatments were tried. Much of the early pharmacotherapy was directed towards sedation and chemically restraining patients.

In the early 20th century some antihistamines were used for sedation. They had anticholinergic side effects, which were recognised to be atropine-like. These compounds were amenable to chemical manipulation.

These drugs were modified and, in the 1950s, the prototypical phenothiazine, chlorpromazine was developed. It was noted not only to sedate patients but also to reduce psychotic symptoms. In addition to its sedative effects, it had anticholinergic effects, peripheral vasodilation and some patients developed Parkinsonian features. As it obviously had a large number of actions, its trade name was Largactil (Large Action). It was later found to have effects on even more receptors. The observation of Parkinsonian features (largely not seen in the antihistamine ancestor drugs) led to the dopamine theory of schizophrenia.

The chemists returned to the lab and more modifications occurred. Imipramine [the first tricyclic antidepressant (TCA)] was developed and noted to have efficacy in treating depression. It also had many of the same side effects of the phenothiazines it was developed from and, in addition, it had more marked effects on the ECG. This drug was found to inhibit synaptic catecholamine reuptake. This finding supported the catecholamine theory of depression. Other drugs were found to have effects on catecholamines, isoniazid was also known to improve depression in patients suffering from TB, it was found to be a monoamine oxidase inhibitor. Subsequent development of the tricyclics led to clomipramine a tricyclic, which seemed to have efficacy where others in the class had failed. This was shown to relate to blocking of serotonin uptake.

For all of these older chemically related agents, toxicity can look quite similar as dose escalates although some receptors have more predominant effects at lower doses eg cardiotoxicity or proconvulsant effects.

By and in large, up until the late 60s much of the understanding of the neurochemical basis for psychiatric disorders had been discovered ‘accidentally’ by the use of some pharmacologically ‘dirty’ compounds i.e. the compounds affected a wide range of receptors. Thereafter more effort was placed on creating drugs that specifically targeted certain receptors in an effort to increase efficacy and reduce side effects. This has led to the new antidepressants and atypical antipsychotics. Many of these drugs were specifically developed to reduce the likelihood of pharmacokinetic drug interactions by targeting specific P450 isoenzymes (this is sometimes used in their marketing literature) or targeting specific receptors. The new antidepressants appear to be a more specific and elegant group of drugs than many of the new antipsychotics, which still remain a bit ‘dirty’ although cleaner than their grandparents.

As a generalisation, all of these drugs have high lipid solubility, high volumes of distribution and are hepatically metabolised by P450 enzymes.

Figure. A Generic View of the Synapse (from Wikipedia)

Neurotransmitters are released from vesicles into the synapse; they can then bind postsynaptically to have an effect. There is often a presynaptic receptor, which can detect excess neurotransmitter and reduce the production/release of vesicles. Neurotransmitter can be broken down in the synapse or taken up by the presynaptic terminal Drugs can mimic the neurotransmitter; increase its release; block reuptake or breakdown; or block the postsynaptic receptor.

We should now look at the clinical toxicity of the major psychiatric medications. Read the references and go through the Problems for Discussion.

These drugs are relatively benign when taken in overdose although some patients may develop serotonin toxicity which is generally not life threatening. The major issue relates to co-ingestion of other agents that affect synaptic serotonin concentration generally through a synergistic mechanism (eg MAO inhibitor which inhibit breakdown of serotonin). Some other agents such as venlafaxine are serotonin reuptake inhibitors (SSRIs) and in addition block catecholamine (norepinephrine) reuptake (SNRI). Monamine oxidase inhibitors increase synaptic amines by inhibiting their breakdown. See: WikiTox: SSRI monograph and Serotonin syndrome, WikiTox: Venlafaxine monograph, and WikiTox: Monoamine oxidase monograph.

Tricyclic Antidepressants and Monoamine Oxidase Inhibitors but with a better side effect and safety profile. As these drugs are relatively new it is not yet clear that these goals have been achieved.

Venlafaxine and nefazodone are serotonin noradrenergic reuptake inhibitors (SNaRIs), mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) and Reboxetine is a noradrenaline reuptake inhibitor (NaRI).

At low doses, where serotonin reuptake inhibition predominates venlafaxine is very similar in action to the SRIs; at higher doses, noradrenaline reuptake inhibition also occurs.

Nefazodone inhibits the 5-HT2 receptor and this is thought to increase the binding of serotonin to the 5-HT1A receptor. Additionally, nefazodone causes weak inhibition of noradrenaline and serotonin reuptake.

Mirtazapine inhibits α2-adreoreceptors, 5-HT2 and 5-HT3 receptors. This results in increased noradrenaline and serotonin release; the later having its main affect on 5-HT1A-mediated neurotransmission.

Most neuroleptics remain pharmacologically dirty drugs with a wide range of effects on multiple receptors. The newer atypical neuroleptics have tended to focus on more selective blockade of dopamine receptor subtypes without necessarily improving the side effect profile caused by the actions on other receptors.

NMS discussion: One important complication of neuroleptic toxicity that is not clearly dose related is neuroleptic malignant syndrome. This syndrome is described in the accompanying reading. It is important to understand as it can be in the differential for a number of toxic syndromes caused by other psychotropic drugs. See: WikiTox: Neuroleptics.

The classic hypnosedative poisoning was barbiturates, which, in addition to sedation, caused marked respiratory depression and hypotension. Replacement with benzodiazepines led to a reduction in mortality. Both drug classes act by enhancing the inhibitory neurotransmitter gamma amino benzoic acid (GABA).

Tolerance to the effects of these drugs occurs, leading individuals to require higher doses to attain the same effect. Cross-tolerance between drug classes also occurs.
An understanding of the relationship of glutamate and GABA is important in toxicology when considering the aetiology and treatment of seizures. See: WikiTox: Miscellaneous Anxiolytics and Sedative Hypnotics and WikiTox: Benzodiazepines.

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2. Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. Q J Med 2003;96:369-374.(fulltext)
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