Take-home points

This case emphasizes the need for full therapeutic trials of antidepressant treatments, augmentations, combinations

This case emphasizes the need to continually evaluate if medications are effective and warranted, and that streamlining of medications is sometimes prudent

This case emphasizes utilizing each medication, in combination, to complement the next with regard to maximizing the monoamine systems, in that there was very little overlap of pharmacodynamic mechanisms among the combined agents utilized to treat the depression

• – For example, when the TCA was started, the SNRI was removed

• – Alternatively, when the stimulant was added, the NDRI was removed

• – The rational polypharmacy goal here is to avoid combining identical, redundant antidepressant pharmacodynamic mechanisms of action

This case emphasizes that use of rating scales can detect underlying comorbidities and better pinpoint response versus remission

• – In this case, stimulants were used and escalated as successive ratings showed a clear dose–response curve for this patient

Finally, manipulating monoamine neural circuits may provide for depression relief, but at the same time cause serious side effects. The clinician must think carefully about the additive or synergistic effects of adding agents together with regard to both efficacy and tolerability

Performance in practice: confessions of a psychopharmacologist

What could have been done better here?

• – Was the patient on too many medications?

• – Should the patient have been directed more toward MAOI monotherapy, or use of ECT, or psychotherapy?

Does it make sense to antagonize D2 receptors with an atypical antipsychotic while agonizing them with a stimulant?

Possible action items for improvement in practice

• – Make sure that augmentation with atypical antipsychotics is not the only option offered, or the only option offered early, as these drugs can be expensive and can have notable and sometimes permanent side effects

• – Be aware of the pharmacodynamic mechanisms of action of all agents utilized with regard to combining them for efficacy, but also be aware of potential toxicity and side effects

Tips and pearls

Atypical antipsychotics have a solid evidence base in the treatment of MDD

They may also carry distinct risk of metabolic disorder and movement disorder, which should clearly be incorporated into the informed consent process and also should be considered while prescribing in a rational polypharmacy approach

Other approaches for TRD have much less definitive evidence to support their use but may actually have fewer risks

Two-minute tutorial (four-minute foray…if you combine two tutorials)

Part 1: Combining stimulants and atypical antipsychotics in TRD

This type of combination is often used in children and adolescents who suffer from attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and intellectual disability or autism spectrum disorder (ASD)

The stimulants are felt to promote DA activity in the cortex and throughout the brain. This promotes better attention, concentration, vigilance, and motivation

Stimulants often do not treat the affective lability and dyscontrol in these disorders and atypical antipsychotics are often added to help these residual symptom clusters

Some atypical antipsychotics actually facilitate DA and NE release in the dorsolateral prefrontal cortex (DLPFC) to help cognitive and executive function symptoms

Atypical antipsychotics that antagonize 5-HT2C receptors in the brainstem theoretically allow for a reduction in GABA interneuron tone there, secondarily allowing the locus coeruleus (LC) and the ventral tegmental area (VTA) to promote greater NE and DA projection activity into the cortex

Combining atypical antipsychotics and stimulants therefore may have a mechanistic rationale in that this combination may better maximize DA activity through multiple mechanisms

A similar approach may be used in TRD where vegetative, amotivated, and executively dysfunctioned patients may benefit from stimulants, atypical antipsychotics, or both

Unfortunately, there are negatives to this combination

The atypical antipsychotics have a risk for TD and this patient did appear to have a withdrawal dyskinesia when her atypical antipsychotic was stopped

The stimulants may cause motor tics and dyskinesias due to dopaminergic toxicity instead of D2 receptor blockade. Tics are more often noted in children and adolescents who are treated with stimulants for ADHD and are reversible, whereas TD may not be

Theoretically, this patient’s aripiprazole (Abilify) had the ability to promote DA activity through its novel partial agonist activities at the D3 receptor. This could increase tonic DA tone in the frontal cortex, which is believed to be beneficial in treating certain depression symptoms. This drug also blocks DA activity at the D2 receptor in the basal ganglia, which may lead to EPS/TD symptoms

The mixed amphetamine salts (Adderall-XR) product has the ability to block the DA reuptake pump, reverse this pump, and reverse the vesicular monoamine transporter activity, providing a robust, high level of DA availability and neurotransmission

In this case, this patient’s basal ganglia had one drug blocking DA transmission, while the other was promoting it, setting up a conflict where movement disorder could occur. Depending upon which drug was more effective at manipulating the neurocircuit, too little DA could cause TD or too much could cause a toxicity based dyskinesia

In removing the patient’s aripiprazole (Abilify) initially, the patient was left with elevated hyperdopaminergic tone likely providing DA excess and resultant dyskinesia. This scenario is not unlike a Parkinson’s disease patient developing dyskinesia if taking too much levodopa (Sinemet)

The clinician tried to re-establish DA transmission balance by restarting aripiprazole (Abilify) at a low dose while slowly tapering the mixed amphetamine salt (Adderall-XR)

This minimized the movement disorder when the atypical antipsychotic was removed and only a small dose of stimulant remained

Upon total stimulant removal, all movement disorder symptoms resolved, suggesting that the patient’s jaw movements, tics or dyskinesias were likely caused by the stimulant use, especially in the face of D2 receptor blockade from the atypical antipsychotic

Part 2: Monitoring for TD