22.11 — Drugs That Act on the Brain

The brain runs on chemistry, and every drug in this chapter changes that chemistry somewhere.

What makes this category different from the rest of pharmacology is that the target organ is the one experiencing the effect. A statin lowers cholesterol whether or not you notice. A drug that changes mood, alertness or perception is changing the instrument you would use to judge it.

Which is why the practical rules here — how long to wait, how to stop, what to expect in the first fortnight — matter more than in any other chapter.

Antidepressants

SSRIs

Sertraline, escitalopram, citalopram, fluoxetine, paroxetine.

They block the transporter that pulls serotonin back into the neuron after release, so serotonin stays in the synapse longer (Chapter 11.2).

And the timing tells you that is not the whole story. Serotonin levels change within hours; the benefit takes weeks. The current view is that the useful change is downstream — in receptor adaptation and in neuroplasticity (Chapter 20.7).

What to expect, in order:

Week 1 to 2: nausea, headache, jitteriness, disturbed sleep. Usually settling.

Week 2 to 4: sleep and appetite often improve before mood does.

Week 4 to 6: mood improvement, continuing to build to 8 weeks.

Stopping at two weeks because it has not worked is the commonest way treatment fails.

Side effects worth naming:

Sexual dysfunction — reduced desire, delayed orgasm, erectile difficulty. Affects a substantial minority, and is consistently under-discussed, which leads to silent discontinuation. Dose reduction, switching to bupropion or mirtazapine, or adding a drug are all options.

Low sodium, particularly in older people — presenting as confusion, unsteadiness or falls.

Increased bleeding risk, because platelets use serotonin. Relevant when combined with NSAIDs or anticoagulants.

And the early-weeks warning: increased agitation and, rarely, increased suicidal thinking, particularly under 25. Which is why early review is standard.

Citalopram and escitalopram prolong the QT interval, so there are dose limits, particularly in older people.

Fluoxetine has a very long half-life, which makes it the easiest to stop and the slowest to clear before starting something else.

Paroxetine has the worst discontinuation symptoms and is the most anticholinergic of the group.

Other classes

SNRIs — venlafaxine, duloxetine. Blocking serotonin and noradrenaline reuptake. Useful where pain coexists. Venlafaxine raises blood pressure at higher doses and has severe discontinuation symptoms.

Mirtazapine — increases noradrenaline and serotonin release by a different route.

Sedating and appetite-stimulating, and more so at lower doses, which is counter-intuitive: at low doses the antihistamine effect dominates; at higher doses the noradrenergic effect offsets it. Useful when insomnia and weight loss are part of the picture.

Bupropion — noradrenaline and dopamine. Fewer sexual side effects, and also used for smoking cessation. Lowers the seizure threshold, so avoided in epilepsy and eating disorders.

Tricyclics — amitriptyline, nortriptyline, imipramine.

Effective, and with many extra receptor effects — anticholinergic, antihistamine, alpha-blocking (Chapter 22.1). Dangerous in overdose because of cardiac effects, which is the main reason they are no longer first line.

At low doses they are used for nerve pain and migraine prevention, well below antidepressant doses (Chapter 22.5).

MAO inhibitors — effective, and requiring avoidance of tyramine-rich foods (aged cheese, cured meats, fermented products) because the enzyme that breaks tyramine down is blocked, and the result is a hypertensive crisis. Rarely used now, and still valuable in specific cases.

Stopping antidepressants

And this deserves its own space, because it was understated for years and people were told symptoms meant relapse.

Discontinuation symptoms: dizziness, electric-shock sensations sometimes described as brain zaps, nausea, irritability, vivid dreams, flu-like feelings, and anxiety.

They usually begin within days of stopping or reducing, and for most people resolve within weeks. For a minority they are prolonged and severe.

The distinction from relapse: discontinuation symptoms start quickly, include physical sensations that were not part of the original depression, and improve within hours of taking a dose. Relapse builds over weeks and looks like the original illness.

How to stop: taper slowly, more slowly at the lower doses than at the higher ones, because the receptor occupancy curve is steepest at the bottom. Hyperbolic tapering — proportionally smaller reductions as the dose falls — is now the recommended approach, and liquid formulations make the small steps possible.

Continue for 6 to 12 months after recovery before considering stopping, and longer after repeated episodes.

Antipsychotics

All block dopamine D2 receptors to some degree (Chapter 20.9).

First generation — haloperidol, chlorpromazine, flupentixol. More movement side effects.

Second generation — risperidone, olanzapine, quetiapine, aripiprazole, lurasidone. More metabolic side effects.

Clozapine — the most effective, requiring blood monitoring for agranulocytosis.

The side effects, grouped by mechanism, which makes them predictable:

Blocking dopamine in movement pathways — parkinsonism, akathisia (a distressing inner restlessness that is frequently mistaken for worsening agitation and treated with more drug), acute dystonia, and tardive dyskinesia.

Blocking dopamine in the pituitary pathway — raised prolactin, causing breast enlargement, milk production, sexual dysfunction and menstrual disturbance.

Blocking histamine — sedation and weight gain.

Blocking muscarinic receptors — dry mouth, constipation, blurred vision.

Blocking alpha-adrenergic receptors — dizziness on standing.

Metabolic effects — weight gain, diabetes, raised lipids. Worst with olanzapine and clozapine. These matter enormously, because they are the main driver of reduced life expectancy in serious mental illness (Chapter 20.9), which makes physical health monitoring part of the treatment.

Neuroleptic malignant syndrome — fever, severe rigidity, confusion, autonomic instability. Rare and life-threatening.

And a specific caution repeated from earlier chapters: antipsychotics in dementia increase mortality, and people with dementia with Lewy bodies have severe sensitivity to them (Chapter 20.4).

Mood stabilisers

Lithium (Chapter 20.9) — the most effective, the only one with clear evidence for reducing suicide, and requiring blood level, kidney and thyroid monitoring.

Toxicity: coarse tremor, vomiting, diarrhoea, unsteadiness, confusion, seizures. Raised by dehydration, NSAIDs, ACE inhibitors and some diuretics. Vomiting and diarrhoea in someone on lithium is a reason to check the level.

Valproate — effective and highly teratogenic, restricted in women of childbearing potential.

Lamotrigine — better for the depressive pole, titrated very slowly because of severe rash risk.

Carbamazepine — a strong enzyme inducer, so it interacts widely.

Sedatives and sleeping tablets

Benzodiazepines — diazepam, lorazepam, temazepam, clonazepam.

They enhance GABA, the brain's main inhibitory signal (Chapter 11.2), by increasing the frequency with which the chloride channel opens when GABA binds.

Which is why they are anxiolytic, sedative, muscle-relaxing and anticonvulsant all at once — the same mechanism doing all four.

Tolerance within weeks. Dependence follows. Withdrawal can include seizures and is potentially dangerous.

And the specific harm in anxiety treatment: taking one during exposure prevents the learning that would otherwise resolve the fear (Chapter 20.8).

In older people they increase falls, fractures and confusion measurably.

Short-term use in a crisis, or for a specific indication such as status epilepticus or alcohol withdrawal, is entirely appropriate. Months of daily use for anxiety or insomnia is not, and is very common.

Stopping requires a slow taper over months, frequently after converting to diazepam because its long half-life smooths the reduction.

Z-drugs — zopiclone, zolpidem. Acting at the same receptor complex, with a similar dependence profile despite being marketed as different. Zopiclone leaves a persistent metallic taste, which is its most recognisable feature.

Melatonin — a body clock signal rather than a sedative. Timing matters more than dose (Chapter 20.11).

Promethazine and other sedating antihistamines — tolerance within days, and significant anticholinergic burden.

And CBT for insomnia outperforms all of them in the long term (Chapter 20.11), which is the point worth repeating whenever a sleeping tablet is being considered.

Stimulants and ADHD medication

Methylphenidate and amfetamine derivatives — increasing dopamine and noradrenaline in the prefrontal cortex.

And the apparent paradox that stimulants calm hyperactivity dissolves once you know the mechanism: they improve the function of the brain regions responsible for inhibition and attention (Chapter 11.5), which are underactive rather than overactive.

Effective, with among the largest effect sizes in psychiatry.

Side effects: reduced appetite, poor sleep, headache, raised heart rate and blood pressure, and a small effect on growth in children, which is monitored.

Atomoxetine and guanfacine — non-stimulant alternatives, slower to work, without the same misuse potential.

And treating ADHD properly is associated with reduced rates of accidents, substance misuse and criminal justice involvement, which is a strong argument against the view that it is over-treated.

Anti-epileptics

Covered in Chapter 20.2, and worth restating for two facts that belong in a pharmacology chapter.

Most work by stabilising sodium channels or enhancing GABA.

And several are strong enzyme inducers — carbamazepine, phenytoin, phenobarbital — which reduces the effectiveness of hormonal contraception and of many other drugs (Chapter 22.2).

Drugs for dementia

Cholinesterase inhibitors — donepezil, rivastigmine, galantamine. Increasing acetylcholine. Side effects follow: nausea, diarrhoea, vivid dreams, and a slow heart rate, which occasionally causes falls.

Memantine — an NMDA receptor blocker for moderate to severe disease.

And the anti-amyloid antibodies, assessed honestly in Chapter 20.4.

The rules that apply across the whole chapter

Give it time. Most of these drugs take weeks. Judging in days produces a cycle of switching that never lands anywhere.

Start low, go slow, particularly in older people.

Never stop abruptly. Antidepressants, benzodiazepines, antiepileptics and antipsychotics all need tapering, for different reasons.

Alcohol interacts with essentially all of them.

Report early effects rather than stopping silently — the first fortnight is when most treatment is abandoned, and it is the fortnight when the side effects are worst and the benefit has not arrived.

And these drugs work best alongside the non-drug treatment rather than instead of it. The therapy, the exercise, the sleep and the social contact are not the soft alternative; in several conditions they have comparable evidence and lower relapse rates.

What the next page fixes

Chapter 22.12 covers steroids and anti-inflammatories — the most powerful drugs in general medicine, and the ones whose rules are least well known by the people taking them.