How do different psychotropic medications, including antidepressants (e.g. selective serotonin reuptake inhibitors (SSRIs) like fluoxetine (Prozac)), mood stabilizers (e.g. lithium), antipsychotics (e.g. olanzapine (Zyprexa)), and anxiolytics (e.g. benzodiazepines), work and affect the brain?

Mechanisms of Action of Psychotropic Medications

Antidepressants

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs like fluoxetine (Prozac) work by blocking serotonin transporters in the synaptic cleft, preventing reuptake of serotonin and increasing its availability in the brain, particularly affecting the prefrontal cortex, hippocampus, and amygdala 1.

• SSRIs bind to serotonin transporters and block reuptake of serotonin, leading to increased serotonergic neurotransmission throughout the brain 2.
• The primary therapeutic effects occur in brain regions regulating mood, anxiety, and emotional processing, including the prefrontal cortex and limbic system 1.
• SSRIs have minimal direct effects on norepinephrine or dopamine systems, though indirect modulation may occur through serotonergic pathways 2.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

SNRIs boost both serotonin and norepinephrine throughout the brain by combining robust serotonin transporter inhibition with various degrees of norepinephrine transporter inhibition 2.

• These medications work in the prefrontal cortex, hippocampus, and other brain regions by blocking both serotonin and norepinephrine reuptake pumps 2.
• The dual mechanism provides broader neurotransmitter coverage compared to SSRIs alone 2.

Tricyclic Antidepressants (TCAs)

TCAs increase norepinephrine and sometimes serotonin by blocking the reuptake pumps for norepinephrine or both norepinephrine and serotonin in the synaptic cleft 2.

• TCAs work primarily in the prefrontal cortex and other brain regions involved in mood regulation 2.
• These medications have broader receptor effects than SSRIs, including effects on histamine and acetylcholine receptors, which contribute to their side effect profile 2.
• TCAs can prolong the QT interval and delay AV-node conduction, affecting cardiac tissue 2.

Mood Stabilizers

Lithium

Lithium modulates multiple neurotransmitter systems and cellular signaling pathways throughout the brain, with effects on serotonin enhancement, neuroprotection, and regulation of intracellular signaling cascades 3.

• Lithium works in the prefrontal cortex, hippocampus, and other brain regions by enhancing central serotonin function 3.
• The medication affects the pain modulatory system in the brain and spinal cord when used for chronic pain management 2.
• Lithium modulates physiological stress reactions and may reduce aggressive behaviors through effects on multiple brain systems 3.

Valproate (Valproic Acid)

Valproate enhances GABAergic neurotransmission and modulates voltage-gated sodium channels throughout the brain, affecting neuronal excitability in the prefrontal cortex, limbic system, and other mood-regulating regions 3.

• Valproate works by increasing GABA availability and reducing neuronal hyperexcitability in brain regions controlling mood and behavior 3.
• The medication affects the pain modulatory system in the brain and spinal cord when used for chronic pain 2.

Lamotrigine

Lamotrigine stabilizes neuronal membranes by blocking voltage-sensitive sodium channels, reducing excessive glutamate release in the prefrontal cortex and limbic structures 3.

• This medication is particularly effective for preventing depressive episodes in bipolar disorder through its effects on glutamatergic neurotransmission 3.
• Lamotrigine works primarily in brain regions involved in mood regulation and emotional processing 3.

Antipsychotics

Typical Antipsychotics (e.g., Haloperidol)

Typical antipsychotics work primarily by blocking dopamine D2 receptors in the striatum, mesolimbic pathway, and mesocortical pathway, with haloperidol being more effective in stimulating dopamine release in the striatum than in the prefrontal cortex 4.

• These medications reduce psychotic symptoms by blocking dopamine receptors in the mesolimbic pathway (the "reward pathway") 4.
• Typical antipsychotics have strong effects on the striatum, which explains their high risk of extrapyramidal side effects 4.
• They have minimal effects on serotonin systems compared to atypical antipsychotics 4.

Atypical Antipsychotics (e.g., Olanzapine, Risperidone, Quetiapine)

Atypical antipsychotics work through synergistic blockade of both serotonin 5-HT2 receptors and dopamine D2 receptors, with preferential effects in the prefrontal cortex over the striatum, and clozapine being much more effective in the medial prefrontal cortex than in the striatum 4.

• The combination of 5-HT2 and D2 receptor blockade produces a synergistic increase in extracellular dopamine in the medial prefrontal cortex 4.
• Atypical antipsychotics increase both dopamine and noradrenaline release in the prefrontal cortex through 5-HT2 receptor inhibition 4.
• The increase in extracellular noradrenaline in the medial prefrontal cortex is explained by inhibition of 5-HT2 receptors, not dopamine D2 receptors 4.
• These medications work in the mesolimbic pathway (reducing positive symptoms), mesocortical pathway (improving negative symptoms and cognition), and have varying effects on the striatum depending on the specific agent 4.
• Olanzapine, risperidone, and ziprasidone show similar efficacy in both the prefrontal cortex and striatum, while clozapine shows preferential effects in the prefrontal cortex 4.

Mechanism Differences Between Typical and Atypical Antipsychotics

The key distinction is that typical antipsychotics increase dopamine release primarily in the striatum, while atypical antipsychotics (especially clozapine) are more effective in the medial prefrontal cortex due to their combined 5-HT2 and D2 receptor antagonism 4.

• Benzamide antipsychotics (sulpiride, raclopride) increase dopamine release in the striatum but do not affect dopamine or noradrenaline release in the medial prefrontal cortex unless dopamine/noradrenaline reuptake inhibitors are present 4.
• When 5-HT2 receptor agonists are co-administered with antipsychotics, they block the increase in both dopamine and noradrenaline in the medial prefrontal cortex 4.

Anxiolytics

Benzodiazepines

Benzodiazepines enhance the effect of GABA (gamma-aminobutyric acid) at GABA-A receptors throughout the brain, increasing inhibitory neurotransmission in the amygdala, hippocampus, and cortex 2.

• These medications bind to GABA receptors and increase chloride channel opening, leading to neuronal hyperpolarization and reduced anxiety 2.
• Benzodiazepines work rapidly in brain regions controlling anxiety, fear responses, and arousal 2.
• In vitro studies have shown both inhibition and activation of potassium currents during exposure to benzodiazepines, though no changes in QT duration occur in clinical use 2.

Buspirone

Buspirone works as a partial agonist at serotonin 5-HT1A receptors in the prefrontal cortex and limbic system, modulating serotonergic neurotransmission without affecting GABA systems 3.

• This medication takes 2-4 weeks to become effective, unlike benzodiazepines which work immediately 3.
• Buspirone works in brain regions regulating anxiety and mood through serotonergic mechanisms 3.

Neuromodulation for Chronic Pain

Psychotropic medications used for chronic pain modulate neurochemistry both peripherally and centrally, with their presumed mechanism of action in the modulation of the pain modulatory system in the brain and spinal cord 2.

• Low-dose tricyclic antidepressants, serotonin noradrenergic reuptake inhibitors, and mirtazapine work on descending pain pathways in the brain and spinal cord 2.
• These medications are not primarily targeting mood symptoms when used for pain, but rather modulating pain perception through effects on serotonergic and noradrenergic systems 2.
• Higher doses of SSRIs or bupropion are only indicated when significant psychiatric comorbidity exists 2.

Important Clinical Considerations

Drug Interactions and Receptor Effects

Psychotropic medications can have direct effects on microglia (immunological/inflammatory cells in the brain), and various antipsychotics, antidepressants, and antiepileptics modulate microglial activity, which may contribute to their therapeutic effects 5.

• The relationship between microglia, neurotransmitters, and psychiatric disorders represents an emerging area of understanding for psychotropic drug mechanisms 5.
• Modulating microglia may be a key target in the treatment of various psychiatric disorders 5.

Combination Therapy Mechanisms

When combining medications from different classes, the mechanisms are additive or synergistic—for example, combining a mood stabilizer with an antipsychotic provides both GABAergic/sodium channel modulation and dopamine/serotonin receptor blockade 2.

• Evidence supporting medication combinations based on matching medication mechanism of action with hypothesized CNS abnormalities is rudimentary at best 2.
• Basing treatment decisions on theories about CNS functioning or clinical correlates of hypothesized neurotransmitter abnormalities may put patients at risk for unnecessary medication combinations 2.

Common Pitfalls

Avoid assuming that covering multiple neurotransmitter systems with multiple medications is always beneficial—this approach lacks strong evidence and may expose patients to unnecessary polypharmacy 2.

• The risk of using psychotropic medications in combination with other CNS active drugs has not been systematically evaluated in many cases 6, 7.
• Drug interactions can occur through pharmacodynamic effects (combined receptor actions) or pharmacokinetic effects (altered metabolism through cytochrome P450 enzymes) 6, 7, 1.
• SSRIs can inhibit metabolism of other drugs through CYP2D6 and other enzyme systems, potentially increasing levels of co-administered medications 6, 7, 1.