How to Personalize the Treatment of Depression

The Clinaptica™ Depression Consultant app for iPad breaks new ground in matching antidepressants to patients, but how? 

Richard J. Metzner, M.D.

Clinical Professor

Semel Institute for Neuroscience and Human Behavior at UCLA


The answer is in the strategy of using the strengths of different antidepressant classes against the two main kinds of emotional problems seen in depression:

1) elevated negative emotions, e.g., anxiety, anger, and irritability

2) reduced positive emotions, e.g., lack of pleasure, reduced energy, and loss of motivation.

In the Targeted Treatment Depression Inventory (TTDI)®, precursor to Clinaptica™, the scales measuring these two dysfunctions were called “demodulation” and “deactivation.” Clinaptica™ calls the restorative functions of antidepressants in these two categories “calming” and “activation.” For depressed patients, “calming” is the answer to the profound internal unrest that can be present day and night, while “activation” is the antidote to the energy erosion that can disable so completely.  In mild to moderate depressions one or the other of these dyfunctions may predominate, but in severe cases, both are pervasive. In bipolar disorder, manic mood swings can deplete energy so dramatically that during depressive cycles, negative affect may be diminished along with positive affect. In mania, the opposite is true and both positive and negative affect are typically exaggerated.

Symptoms of increased negative affect are best addressed by serotonergic antidepressants, i.e., SSRIs such as citalopram (Celexa). The activation associated with some non-SSRI antidepressants can worsen these symptoms. SSRIs have received FDA approval for treating many disorders associated with increased CNS reactivity, such as anxiety disorders, panic disorders, post-traumatic stress disorders, obsessive-compulsive disorders, and premenstrual dysphoric disorders. In many of these conditions, the reactivity is not simply about exaggerated responses to external stressors, but also to one’s own thoughts, emotions and other internal sensations, fueling, for example, self-loathing, affective lability and hypochondria.

Symptoms of decreased positive affect are best addressed by NDRIs (norepinephrine dopamine reuptake inhibitors) such as bupropion (Wellbutrin, Aplenzin, Budeprion). Here the use of SSRIs can be counterproductive because of side effects like fatigue and emotional blunting. Decreased motor activity is often seen in depression, but even when patients can go through the physical motions of daily life, reductions in mental activity can be present and are manifested in low motivation, lack of initiative and poor concentration. NDRIs can be very effective in combating these symptoms.

When both decreased positive affect and increased negative affect are present, dual-mechanism regimens such as the SNRIs (serotonin norepinephrine reuptake inhibitors), e.g., venlafaxine (Effexor), can provide the necessary combined effects. So can medications like the tricyclics, e.g. amitriptyline (Elavil) and the MAOIs (monoamine oxidase inhibitors), e.g. tranylcypromine (Parnate), although the higher side-effect burdens and lethality on overdose of these older medications limit their use in practice. Combining two different classes of newer antidepressants such as the SSRIs and the NDRIs can actually be safer and permit more accurate titration of effects.

As for the symptoms everyone thinks of in connection with the depression - sadness, hopelessness and despair - these usually benefit from improvements in either negative or positive affect. The problem is that addressing only one of the two creates an incomplete solution, and that is exactly what non-personalized antidepressant treatments produce.  "Then why not use broad-spectrum treatments like SNRI's for everybody?" one might ask. In real estate, they say " location, location, location." When it comes to the "real estate" of the brain, stimulating receptors unnecessarily typically means "side-effects, side-effects, side-effects." Whether we are talking about sedation, sexual dysfunction, G-I symptoms or any other undesirable outcome, the result can be further distress and understandable non-adherence by the patient. Personalizing antidepressant treatment is, not the least, an effort to avoid such outcomes.

Antidepressants should be used cautiously, if at all, in bipolar disorder and only in conjunction with mood stabilizers like valproic acid (Depakote). Atypical neuroleptics like quetiapine (Seroquel) can also be very beneficial and have their place as well in the treatment of unipolar depressions predominantly characterized by elevated negative affect.

Personalizing the treatment of depression also applies to important non-pharmacologic interventions like psychotherapy, physical exercise, nutrition, etc. The important point is that the patient's needs and capabilities must be considered carefully before recommending any theraputic methods. For example, it doesn't help when those with severely deactivated depressions are given cognitive-behavioral or physical task assignments they can't complete or those with high levels of emotional reactivity are provoked into "losing it" during individual, conjoint or group psychotherapy. These methods will be more successful and patients will be spared unnecessary failure experiences if they are applied when patients can best handle them.

We have observed the benefits of personalizing the treatment of depression close at hand for the past twenty years, and have seen our clinical experience replicated in health care settings across the US. Our system has been available online to any professionals who wanted to use it since 2005. Hundreds have accessed it and thousands of patients have been treated with its guidance.

We remain an independent voice in the depression treatment world. We have received no research grants from pharmaceutical companies, private investors or government agencies. We are dedicated to improving the treatment of depression and hope that our new tool will make a positive difference in the lives of as many depressed people as possible.



This detailed results screen illustrates how Clinaptica™ derives specific recommendations about antidepressants from scales measuring the need for calming (M) and activation (A). The Depression score (D) is the sum of the two.

Copyright 2012, Scaled Psychiatric Systems, Inc. All rights reserved.